Demographics, loneliness scores, frequency of physical activity, and bio- markers values of the sample.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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He obtained his Master in 1995 and his Doctorate in 1997 both from UNIFESP. He is a specialist in laparoscopy (Cleveland Clinic Foundation, 2000) and has a PhD in reproductive medicine (2008). Due to the relevance of his research he obtained the title of Associate Professor of the Department of Obstetrics of UNIFESP (2006). He has experience in the field of Medicine, with emphasis in Gynecology and Obstetrics, acting mainly in the following subjects: ectopic pregnancy, methotrexate, ultrasonography, beta-hCG, polymorphisms, serological markers and multiple pregnancy. He has published a predictive score for medical treatment in ectopic pregnancy and reference charts for twins. He has published 68 articles in international and national journals, is a reviewer in several national and international journals, and a speaker at a number of national and international congresses. He wrote the book 'Ectopic Pregnancy' (2010), was an editor of the books 'Multiple Pregnancy - New Challenges' (2019) and 'Non-Tubal Ectopic Pregnancy' (2020), as well as an author of numerous chapters in national and international books. He has been nominated several times as an honored Professor by his students at the Medical School of Federal University of São Paulo (UNIFESP).",institutionString:"Federal University of Sao Paulo",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Federal University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1067",title:"Maternal-Fetal Medicine",slug:"maternal-fetal-medicine"}],chapters:[{id:"62717",title:"Historical Studies of Hellin’s Law",slug:"historical-studies-of-hellin-s-law",totalDownloads:992,totalCrossrefCites:0,authors:[{id:"249480",title:"Prof.",name:"Johan",surname:"Fellman",slug:"johan-fellman",fullName:"Johan Fellman"}]},{id:"62902",title:"Twinning as an Evolved Age-Dependent Physiological Mechanism: Evidence from Large Brazilian 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Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, which is defined as a chronic metabolic disorder characterized by hyperglycemia. In this disease, the body is able to produce insulin; however, its secretion is irregular and/or the body\'s cells fail to use and respond appropriately to this hormone (insulin resistance), leading to an accumulation of blood glucose [1, 2].
Although the reasons for the development of T2DM are still unknown, it is a multifactorial disease that involves a genetic predisposition as well as other factors, including a poor diet, sedentary lifestyle, age (45 or older), previous gestational diabetes, and overweight or obese physical conditions, which represent the most common risk factors for the development of insulin resistance [3, 4].
Epidemiologically, the number of individuals with T2DM (representing 85-95% of all cases of diabetes mellitus) in recent decades has increased rapidly worldwide. This disease usually affects adults, especially males, but an increase in the number of cases in children and adolescents has also been observed [5, 6]
The high incidence of T2DM is associated with economic development, aging populations, increasing urbanization, dietary changes, reduced physical activity and changes in lifestyle and other cultural patterns. It is estimated that more than 382 million people suffer from this disease worldwide (8.3% prevalence). In 2013, 5.1 million deaths were reportedly caused by diabetes. If these trends continue, it is estimated that by the year 2035, approximately 592 million people (1 in 10 adults) will be carriers of the disease [7-9].
Therefore, the increasing number of new cases of diabetes per year combined with high prevalence and mortality rates impose high costs socially and economically to the populations of all countries. In 2013, approximately 548 billion dollars were spent worldwide on diabetic patients. Thus, understanding this disease and all the variables involved, including prevention, diagnosis and treatment must be a priority [8].
The diagnosis of T2DM is based on summarized plasma glucose quantification criteria (either fasting or after a glucose tolerance test). Furthermore, the assessment of the amount of glycated hemoglobin (HbA1c) is included as a diagnostic option for diabetes. However, many individuals with T2DM are asymptomatic in the early stages of this disorder and only discover the disease after the onset of more severe symptoms and other complications. The first symptoms of T2DM may include polyuria, polydipsia, constant hunger, appearance of wounds with delayed healing, visual changes and frequent infections [10, 11].
When undiagnosed or poorly controlled, this disease is a risk factor for the onset of various complications at both the microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiovascular disease) level. Diabetes is one of the major factors that leads to blindness, kidney failure, lower limb amputation and development of cardiovascular disease, the latter being the primary cause of death worldwide [3, 11].
Therefore, simple lifestyle changes, including increased physical activity, diet modification and weight loss are recommended for the management of pre-diabetes and early diabetes. These changes have been shown to be effective in preventing or delaying the progression of T2DM or damage to target organs [4, 12].
The treatment of diabetes mainly targets glycemic control, thus aiming to relieve symptoms, improve the quality of life of patients, prevent further complications and reduce mortality. However, the use of other therapeutic treatments is needed as a strategy for reducing multifactorial risks [3, 13].
The basic strategies for the treatment and control of diabetes mostly consist of a specific balanced diet, physical activity and proper use of medications (oral and/or insulin agents). Patient education coupled with self-care and support from family and physicians are essential procedures for the prevention of acute complications and reduction of long-term complications. Additionally, frequent tests (including blood pressure measurement and lipid profile), foot care (avoiding the appearance of lesions), stress control and reduction in the consumption of alcoholic beverages and tobacco are important actions related to disease control [1, 14, 15].
Compared with type 1 diabetes mellitus patients, the majority of type 2 patients typically do not require daily insulin doses. The disease can be treated with oral medications and changes in lifestyle until resistance becomes difficult to control, after which an insulin regimen is usually required [8].
Thus, drug treatment of T2DM is based on the knowledge of patient characteristics together with the severity of the hyperglycemia and availability of therapeutic options. Many oral drugs are used to control diabetes, such as metformin (biguanide), sulfonylureas and thiazolidinediones, which have been used for decades with satisfactory results. These antidiabetic drugs compose the most studied cast of oral pharmacologicals worldwide and play an important role in glycemic control; in addition, they are often recommended as the first option for the treatment of the disease by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) [10, 15, 16]. Technological advances and new avenues of drug research have enabled the development of new drug therapies for the treatment of T2DM, and approximately 180 new drugs are currently under study [17, 18].
Typically, various drug classes can be used to control type 2 diabetes, including human insulin analogs, drugs that reduce insulin resistance (biguanides and thiazolidinediones or glitazones), secretagogues and their analogues (sulfonylureas, meglitinides, inhibitors of dipeptidyl peptidase IV (DPP-4) or agonists and analogues of glucagon-like peptide-1 (GLP-1)), and drugs that reduce the rate of carbohydrate degradation (alpha-glucosidase inhibitors). Dapagliflozin is one of the newer medications for glycemic control and was recently approved by the FDA (January 2014). Its mechanism of action inhibits the sodium-glucose cotransporter 2 (SGLT2), a protein responsible for glucose reabsorption in the kidney, which leads to the elimination of excess glucose in the urine [17, 18].
Multiple therapies, or a combination of oral hypoglycemic drugs and/or other drugs, are also an option for the control of diabetes mellitus [11, 19]. However, the therapeutic use of drugs is limited by factors such as their efficacy, adverse events, costs, side-effects, dose management problems, inflexible dosages, weight gain, etc.; therefore, such effects should be critically evaluated for each patient [19].
For example, weight loss is a priority in obese diabetics. If glycemic control is not achieved after 4-6 weeks of treatment with drugs that increase sensitivity to insulin action (such as biguanides and thiazolidinediones) medications may be given to control obesity, which include drugs that affect the appetite and induce satiety, such as orlistat. If necessary, drugs may also be used that retard the degradation of sugars in the diet (such as acarbose or miglitol) or drugs such as sulfonylureas or meglitinides that increase insulin secretion in the pancreas [20-23].
In terms of therapeutic classes, the action of biguanides, whose main representative is metformin, is related to decreased peripheral insulin sensitivity, reduced hepatic glucose output, and modified lipid metabolism. All of these effects contribute to the control of T2DM. The advantages of these drugs include the absence of hypoglycemia and its anorectic effect, which also aids in patient weight loss. The adverse effects of this class are few but include diarrhea, nausea, metallic taste and intestinal colic, which gradually decreases with continued use [16, 19, 23].
The class of sulfonylureas that act by directly stimulating insulin secretion (secretagogues) includes chlorpropamide, glibenclamide, gliclazide and glimepiride. These drugs have several adverse effects, including nausea and vomiting (gastrointestinal), hypoglycemia (glucose), leukopenia, agranulocytosis, thrombocytopenia and hemolytic anemia (hematological) and weight gain. Accordingly, the use of newer insulin secretagogues (glinides class, including mitiglinide, repaglinide and nateglinide) is suggested as an alternative for patients treated with sulfonylureas who have irregular meal times or late postprandial hypoglycemia. Because of their rapid absorption, the action of these drugs is initiated 30 minutes after administration [16, 22].
The thiazolidinedione drugs (pioglitazone and rosiglitazone) are oral hypoglycemic agents capable of increasing the sensitivity of liver, muscle and fat cells to insulin, which results in reduced peripheral resistance. This class is contraindicated in patients with hepatic dysfunction and heart conditions and adverse effects include upper respiratory tract infections, headaches, weight gain, anemia and edema [12, 16, 23].
With respect to alpha-glucosidase, competitive inhibitors such as acarbose, miglitol and voglibose act as antagonists of amylase and sucrose, thereby decreasing the intestinal absorption of glucose. These drugs are contraindicated in pregnant or lactating patients and in diabetic patients with renal or hepatic dysfunction [6, 18].
Another recent class of oral hypoglycemic drug is the DPP-4 inhibitors (sitagliptin, vildagliptin and saxagliptin), which act by increasing the levels of hormones that help to control glucose concentrations. These drugs have few adverse events, and incidences of hypoglycemia and weight gain are low [16, 23].
In addition to these oral medications, subcutaneous administration of exenatide (GLP-1 agonist) can stimulate insulin secretion (secretagogue). In addition to facilitating glycemic control, this medicine also helps in patient weight loss. Possible adverse events include nausea, vomiting and diarrhea [16, 23, 24]
For injectable drugs, the application of human insulin analogs (lispro, aspart and glargine) for the treatment of T2DM may be indicated for patients who no longer respond to diet combined with exercise and oral hypoglycemic agents or in more severe hyperglycemia cases. In addition to the different types of administration (including the innovation of inhalable insulin), this hormone may be used in combination with oral hypoglycemics [12, 25].
In short, with the emergence of new treatments for diabetes, various individualized treatment options are possible that consider ease of access, cost, mode of administration and patient characteristics.
Thus, the aim of this chapter is to evaluate the available treatments for T2DM as well as their mechanisms of action and adverse effects and describe the new drugs and therapeutic trends that are available. Such diabetes treatment updates for healthcare professionals and caregivers is essential for proper disease management and health promotion.
Metformin and phenformin are oral antidiabetic drugs of the biguanide class. Metformin is the drug of choice for the treatment of adults with type 2 diabetes because of its lower frequency of side effects. This drug is currently used by nearly one-third of the diabetic patients in Italy and is the most prescribed in the U.S. (> 40 million prescriptions in 2008). Phenformin is no longer marketed in many countries, although it is still available in Italy [26-28].
Both metformin and phenformin increase weight loss in obese non-diabetic patients without substantially reducing blood glucose levels. This weight loss is attributed to the drugs’ anorectic effect and a slight reduction in the gastrointestinal absorption of carbohydrates [29]. Phenformin was withdrawn from clinical practice in the 1970s because of a greater tendency to develop severe and fatal adverse events, such as lactic acidosis.
Metformin is sold in 500 and 850 mg tablets, and the maximum dosage is 2.5 g/day, although there are reports in the literature of dosages up to 3 g, which are always administered after meals to minimize gastrointestinal side effects [30]. It has been reported that this drug increases the number and improves the affinity of insulin receptors both in adipocytes and muscle. In muscle, glucose uptake increases from 15 to 40% and gluconeogenesis is stimulated. In adipocytes, metformin inhibits lipolysis and the availability of free fatty acids (FFA). Furthermore, metformin improves insulin action in the liver by reducing hepatic glucose production from 10 to 30%, and at the cellular level, it increases the tyrosine kinase activity of the insulin receptor in the muscles, which stimulates GLUT4 translocation and the activity of glycogen synthetase [31].
The use of metformin also improves the lipid profile by decreasing triglyceride levels by 20-25%, LDL-cholesterol by up to 10% and plasminogen activation inhibitor (PAI-1) by 20-30% and increasing HDL-cholesterol by 17%. Insulin secretion to stimuli may remain unchanged or decrease, and its anorectic effect helps in weight loss. In addition to being associated with weight reduction, its effectiveness in glycemic control is similar to that of sulfonylurea [32]. Another advantage is the absence of hypoglycemia because insulin secretion is not stimulated [33].
The isolated use of metformin in type 2 diabetes lowers blood glucose levels by approximately 25%, or 60 to 70 mg/dl, and glycosylated hemoglobin by 1.5 to 2% [31]. Intensive glucose control using metformin significantly decreases the risk of cardiovascular disease and diabetes mellitus-related mortality and is associated with less weight gain and a lack of treatment-induced hypoglycemia associated with insulin or sulfonylureas [34].
Metformin is absorbed in the intestine, excreted by the kidneys and minimally metabolized by the liver. Metformin has a low affinity for mitochondrial membranes and does not interfere with oxidative phosphorylation, and it is indicated as a monotherapy in obese or even glucose intolerant diabetics. Approximately 5 to 10% of patients each year fail to have an appropriate response to this drug. In these cases, metformin can be used in combination with sulfonylurea, acarbose, thiazolidinediones, repaglinide and/or insulin to achieve satisfactory control [35-40].
The most common side effects of metformin are diarrhea (15%), metallic taste and nausea, which often decrease with continued use of the medication. The occurrence of lactic acidosis is rare (0.03 to 0.4/1000/year) and occurs most often in people who have a contraindication to metformin, such as chronic liver disease (elevated transaminases 2-3 times the normal values) and heart, respiratory, or renal conditions (clearance < 70 ml/min or serum creatinine ≥ 1.5 mg/dL). The use of metformin is not advisable in people over 80, pregnant women, infants or alcoholics. In patients with proteinuria who are subjected to radiological examination containing iodine, it is prudent to provide adequate hydration and discontinue the medication a few days prior to such examinations [33]. This drug shows a synergistic effect with cimetidine and may decrease the absorption of vitamin B12 [30].
The thiazolidinediones (TZDs) are popularly known as glitazones, and representatives include the drug troglitazone (withdrawn from the market because of liver toxicity), rosiglitazone and pioglitazone (second generation TZDs).
TZDs are widely used in the treatment of type 2 diabetes and increase and sensitize insulin action in the liver, muscles and adipocytes, thereby decreasing peripheral resistance. They activate intracellular nuclear receptors (PPAR-gamma-peroxisome proliferator-activated receptor) that regulate the expression of genes encoding glucose and lipid metabolism and are responsible for glucose uptake mediated by insulin in the peripheral tissues and differentiation of preadipocytes into adipocytes. Additionally, these drugs inhibit peripheral lipolysis in adipocytes and assist in reducing the levels of free fatty acids and visceral adipose tissue, resulting in improved glycemic and metabolic parameters. These drugs show good results in terms of long-term glycemic control compared with other consecrated therapeutic options, such as sulfonylureas and metformin [41-43].
TZDs decrease glucose levels by approximately 20% but do not increase insulin secretion. They inhibit the oxidation of long-chain fatty acids in the liver, decreasing gluconeogenesis and the availability of free fatty acids. Although these drugs reduce triglycerides by 15 to 20% and increase HDL-cholesterol by 5 to 10%, the total cholesterol and LDL-cholesterol levels may not change or may increase from 10 to 15% [33]. When compared to metformin, troglitazone has a greater potentiating effect of peripheral insulin action and little effect on the reduction of hepatic glucose production. The association of thiazolidinedione with metformin is interesting because it produces additive effects [39].
TZDs also increase the expression of glucose transporters (GLUT4) and lipoprotein lipase and reduce the expression of leptin and tumor necrosis factor (TNF-alpha). These results make it one of the most widely prescribed classes for the treatment of T2DM [33, 44].
Side effects occur in less than 5% of patients, and they consist of upper respiratory tract infections, headaches, elevated transaminase levels, edema, weight gain and anemia. Hypoglycemia can occur when its use is concomitant with secretagogues or insulin. The drugs are contraindicated for use in children and pregnant women and in individuals with liver disease and elevated transaminase levels (2-3 times the reference values) [33].
In mice subjected to arterial injury, troglitazone inhibited the growth of vascular smooth muscle cells and intimal hyperplasia, suggesting that TZDs decrease the progression of atherosclerosis. Diabetic patients treated with troglitazone show decreases in platelet adhesion, activation of plasminogen activator inhibitor (PAI-1) and blood pressure levels. These multiple effects strengthen its indication for the treatment of the metabolic syndrome. However, caution is advised with troglitazone treatment because of possible liver complications, including fatal cases. In addition, caution is required when troglitazone is used with cardiac patients because of the possibility of edema [33, 45, 46].
Pioglitazone may be used as a monotherapy or in combination with metformin (increasing the anti-hyperglycemic effect), sulfonylurea, meglitinide, or even insulin, especially in diabetic patients with metabolic syndrome. The dose varies from 15 to 45 mg, which can be administered once a day. Pioglitazone displays a similar mechanism of action and side effects as rosiglitazone and less liver toxicity than troglitazone. However, it can interact with other drugs that are metabolized by P45 enzymes and alter their serum levels. An example is a decrease of approximately 30% of the contraceptive effect of ethinyl estradiol and norethindrone. Therefore, the contraceptive dose should be increased in diabetic women who do not wish to become pregnant. Its pharmacokinetics are not altered by mild to moderate renal impairment, so dose modification is required [47].
Rosiglitazone is more powerful and has less liver toxicity than troglitazone. Additionally, it does not induce metabolism by cytochrome P450 (CYP) 3A4; thus, there is no interaction with oral contraceptives such as digoxin, ranitidine, nifedipine, etc. The rosiglitazone dose varies from 4 to 8 mg, which can be administered once a day. Similar to pioglitazone, rosiglitazone’s pharmacokinetics are not altered by mild to moderate renal impairment, so dose modification is required [48].
Recently published safety data have raised concerns related to a possible association between the chronic use of rosiglitazone and increased risk of cardiovascular events, which is consistent with the use of TZDs in clinical practice. In addition, recently published studies have indicated that there is a loss of bone mass and increased possibility of fracture in patients using these medications [42, 44, 49].
Insulin secretagogue agents act by stimulating endogenous insulin secretion via pancreatic β cells, and they include classes of sulfonylureas and meglitinides used in the treatment of T2DM. Meglitinide analogues consist of a relatively new class of oral hypoglycemic, and their clinical use in adult patients with T2DM was approved in 2000. These drugs were developed to promote the rapid increase in insulin secretion from β cells and therefore affect postprandial glucose levels. The mechanism of action of meglitinides is quite similar to that of sulfonylureas; however, meglitinide analogues have the advantage of a reduced risk of hypoglycemia because of their shorter half-life. Meglitinides are secretagogues of short-acting insulin, and they act primarily on postprandial hyperglycemia. Because of their characteristics, the meglitinides are preferable to insulin secretagogues such as sulfonylureas, especially in elderly patients [50-53]. Representatives of the meglitinide class include repaglinide, nateglinide and mitiglinide derived from benzoic acid and the amino acid D-phenylalanine, whose action is initiated approximately 30 minutes after administration because of rapid absorption. The advantages of these drugs are that they have no interactions with other drugs and are not contraindicated in pregnancy, during lactation or in the presence of other pathologies [52, 54].
Repaglinide was the first meglitinide analogue approved for use in adults with T2DM; it is the S(+) enantiomer of 2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid and has a molecular weight of 452.6 Da [50]. Repaglinide stimulates insulin release in a rapid action style, thereby promoting a decrease in blood glucose levels. Because of the rapid action, repaglinide is one of the most commonly used antidiabetic drugs in patients who have high postprandial glycemia [55-57].
The mechanism of action by which the meglitinide analogue stimulates insulin secretion comes from blocking the ATP-dependent potassium channels (KATP) of pancreatic β-cells, which results in membrane depolarization and calcium influx through voltage-dependent calcium channels. This mechanism culminates in an increased influx of calcium into the β cells, which stimulates exocytosis of insulin-containing granules [50, 58].
With regard to pharmacokinetics, repaglinide, whose absorption is independent of concurrent food intake, is rapidly absorbed following oral administration with 63% bioavailability. The maximum concentration is reached approximately 45 minutes after administration (Tmax ~ 45 min), and the half-life of plasma elimination is relatively short (approximately 1 hour); therefore, the drug is eliminated from the body within 6 hours. The drug is metabolized in the liver via cytochrome P450 (CYP3A4), with approximately 90% of the metabolites excreted in the bile and only 8% secreted in the urine. Altogether, 2% of the drug is eliminated in an unchanged form, and because the metabolites are not biologically active, there is no effect on the blood glucose. There is a rapid elimination of repaglinide through the biliary tract and no apparent accumulation in the plasma after multiple doses [50, 59-61].
Hepatic metabolism via cytochrome P450 means that concentrations of repaglinide may be increased by concomitant use of substances that inhibit the CYP3A4 enzyme, such as certain antibiotics and steroids; however, the concomitant intake of CYP3A4-inducing agents, such as barbiturates and carbamazepine, can lead to an increased metabolism of the meglitinide analogue, thus reducing its concentrations [50, 59-61].
Another insulin secretagogue agent that also belongs to the class of meglitinides corresponds to nateglinide. Similar to repaglinide, nateglinide ((N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine A-4166) phenylalanine derivative) acts through the inhibition of KATP and causes the depolarization of the plasma membrane of β cells. This culminates in the influx of calcium ions into the cell and subsequent secretion of insulin [50, 62].
Despite the similar mechanism of action of these two meglitinide analogues, in vitro studies have demonstrated that nateglinide inhibits KATP channels faster and with a shorter duration of action than repaglinide. In addition, the half-life of repaglinide at the receptor of action is approximately 3 minutes, whereas the half-life of nateglinide is 2 seconds. Therefore, the time required for nateglinide to dissociate from the receptor is 90 times faster than that of repaglinide, so nateglinide has a very fast and ephemeral effect on insulin release. In vitro experiments have demonstrated that the action of nateglinide is enhanced in the presence of glucose compared to that glyburide and repaglinide, so that the response of the KATP channel with nateglinide is significantly less in periods of euglycemia than in periods of hyperglycemia. Thus, the minimum total insulin exposure generated by this meglitinide analogue protects the body against hypoglycemic attacks and allows the patient greater flexibility in relation to the intervals between meals. Pharmacodynamic studies have demonstrated that when nateglinide is administered before meals in type 2 diabetic patients, a secretion of early stage insulin occurs that causes a significant dose-dependent reduction in postprandial hyperglycemia [50, 59, 63].
Regarding its pharmacokinetic properties, nateglinide is absorbed rapidly, with peak plasma concentrations reached within 1 hour. This drug is rapidly eliminated from the plasma, with a half-life of 1.8 hour. Because of the short half-life, nateglinide is not accumulated at any administration dose. The drug is metabolized mainly via the cytochrome P450 (CYP2C9 and CYP3A4) and is eliminated via the kidneys, with 10% eliminated unchanged in the urine and 20% eliminated unchanged in the bile [50, 59, 64].
Both repaglinide and nateglinide may be used as a monotherapy or in combination with other agents, such as metformin and glitazones. The meglitinides have similar abilities in reducing fasting blood glucose, postprandial levels of plasma glucose and early insulin secretion, and they improve the insulin sensitivity and function of pancreatic β cells. However, repaglinide was more effective in reducing the glycosylated hemoglobin HbA1c and is also preferred to nateglinide in patients with chronic renal disease because nateglinide has active metabolites that are eliminated by the kidneys [52, 63].
Mitiglinide ((-)-2(S)-benzyl-4-(cis-perhydroisoindol-2-yl) butyric acid) is the third meglitinide analogue and corresponds to a benzylsuccinic acid derivative. It presents a similar mechanism of action to the other two meglitinide analogs, and its selective action on KATP channels of pancreatic β cells promotes insulin secretion with few adverse effects on the cardiovascular system [58, 59, 65]. Similar to nateglinide, mitiglinide is often used in early stage diabetes mellitus because it induces a rapid and short duration of postprandial insulin secretion, mimicking the normal insulin secretion and glucose metabolism of healthy individuals and thereby promoting a reduced risk of hypoglycemia [66, 67]. A randomized clinical trial demonstrated a similar efficacy between mitiglinide and nateglinide when used as a monotherapy in patients treated with diet and exercise in the three months leading up to trial [68].
Mitiglinide is rapidly absorbed and eliminated by the body [66] and metabolized in the kidneys and liver and generates metabolites with little of the secretory activity of insulin. The half-life of mitiglinide is 1.48 h [54], and it has been shown to prevent increases in oxidative stress and inflammation markers after meals in patients with diabetes mellitus because of the suppression of postprandial hyperglycemia promoted by this drug [69]. Because of its characteristics, mitiglinide is currently considered an ideal drug for the treatment of T2DM and is widely used in clinical practice [54].
The competitive inhibitors of alpha-glucosidase, such as acarbose, miglitol and voglibose, are administered orally and inhibit alpha-glucosidase, which is an enzyme that converts polysaccharides (e.g., amylase, maltase and sucrase) into monosaccharides, thus acting as an antagonist enzyme. Therefore, such inhibitors decrease the intestinal absorption of glucose, particularly postprandial absorption that modulates insulin secretion [70]. The slower rise in postprandial blood glucose concentrations is potentially beneficial in both type 1 and type 2 diabetes. In older patients with type 2 diabetes, acarbose may also increase insulin sensitivity [71]. These inhibitor lower the incidence of cardiovascular events, and they have no systemic absorption [72].
In addition, alpha-glucosidase is inhibited competitively, and its availability for oligosaccharides derived from the diet is reduced. Thus, there is a reduced formation of monosaccharides and less insulin is required for metabolism, which leads to a reduction of glucose (because it is not absorbed) as well as postprandial insulin-induced increases [73]. These effects reflect a significant decrease in glycated hemoglobin, which was observed in a meta-analysis of 41 trials of alpha-glucosidase inhibitor therapy (primarily acarbose trials) in which beneficial effects were observed (compared with placebo) on HbA1c (-0.77 percentage points), fasting, and postload glucose and postload insulin levels. These benefits are more evident in highly hyperglycemic patients. Hyperglycemia in patients with mild or moderate glycemic control is less common than in those using other oral antidiabetic agents. In such cases, competitive inhibitors of alpha-glucosidase can be used in combination with insulin or any other oral hypoglycemic agents [74-76].
The most frequent side effects of alpha-glucosidase inhibitors are observed at the intestinal level and include flatulence, diarrhea, abdominal pain and elevated transaminases [35, 77-79]
The occurrence of hypoglycemia and an increase in body weight are rare because the agent does not stimulate insulin release or hypersecretion. These effects are only observed when miglitol is combined with other therapies, and its use is contraindicated in cases of inflammatory bowel disease, pregnancy, lactation, and hepatic or renal impairment. In one prospective study of 893 patients treated with acarbose, only 16 to 20% were still taking the drug after one year, and half of the patients had stopped the drug during year two because of the side effects [80].
Recently, a mixed-treatment comparison (MTC) meta-analysis showed that there was no significant increase in hypoglycemia risk or body weight with alpha-glucosidase inhibitors [81].
Acarbose has a microbial origin and is structurally similar to natural oligosaccharides, with an affinity 104-105 times higher than drugs of the same class of alpha-glucosidases. With regard to its pharmacokinetic aspects, acarbose is poorly absorbed in the intestine (less than 2%). The products produced by bacterial enzymes cleave acarbose, yielding intermediate 4-methyl pyrogallol, which is conjugated and excreted as sulfates or glucuronidate [75].
Several trials have demonstrated the efficacy of acarbose in patients with type 2 diabetes [35, 82-85]. In one trial, 96 patients who were inadequately controlled by diet alone were randomly assigned to receive either glyburide or acarbose, and their HbA1c values and fasting blood glucose concentrations fell by a similar amount; the postprandial blood glucose concentrations, however, remained high in the glyburide group but fell in the acarbose group [83]. A second trial evaluated 354 patients treated with diet alone or diet plus a sulfonylurea, metformin or insulin. Compared with the placebo, the addition of acarbose in each of these groups reduced the mean postprandial blood glucose concentration and lowered the HbA1c values [35]. In general, acarbose has resulted in a greater improvement of HbA1c values than in fasting blood glucose concentrations, which is consistent with its predominant effect on postprandial hyperglycemia [85].
In a randomized, double-blind, placebo-controlled trial [82], satisfactory control of fasting and postprandial glucose occurred with acarbose in T2DM. In a multicenter, randomized, double-blind, placebo-controlled clinical trial [83] conducted for patients with T2DM who were subjected to a specific diet and use of insulin, the patients showed decreased levels of blood glucose and glycated hemoglobin as well as a reduced daily requirement for insulin.
In a systematic review of the literature, it was concluded that acarbose inhibits postprandial hyperglycemia by lowering insulin levels after a glucose overload. However, it presents no advantages with respect to corporal weight or lipid metabolism, and there are no statistically significant effects on mortality, morbidity and quality of life in patients with T2DM. Compared with the placebo, acarbose reduces HbA1c, fasting plasma glucose and postprandial glucose. Compared with sulfonylureas, it reduces glycemic control and has major adverse effects, particularly gastrointestinal effects [76]. Thus, treatment with acarbose might have a favorable effect on endothelial function in type 2 diabetes patients with ischemic heart disease [86-90]
Voglibose also has a microbial origin, and only 3-5% of the drug is absorbed at the intestinal level. It is a potent inhibitor of alpha-glucosidase, but it is weaker than acarbose in the inhibition of sucrase and has little effect on pancreatic alpha-amylase [75]. Furthermore, voglibose decreases the level of postprandial glucose with very low risk of hypoglycemia, but it is associated with frequent gastrointestinal side effects [91].
Miglitol has a synthetic origin and unique pharmacokinetic properties. It is absorbed rapidly through a transport mechanism in the jejunum that is close to the mechanism of glucose, and it is quantitatively excreted unchanged by the kidneys. Miglitol differs from acarbose because it does not inhibit alpha-amylase but rather inhibits intestinal isomaltase [75].
Based on studies in which miglitol was given alone or in combination with insulin or a sulfonylurea, the efficacy was similar to that of a placebo [92-95]. Miglitol is also effective when combined with metformin [96]. Thus, miglitol can be expected to suppress postprandial glucose more strongly than acarbose [97], so it should reduce the incidence of cardiovascular events [98].
Another class of drugs used in the treatment of T2DM are the sulfonylureas chlorpropamide, acetohexamide, tolazamide and tolbutamide (first generation), glibenclamide, glipizide, gliclazide (second generation) and glimepiride (third generation). This class has long been established in the treatment of diabetes, and it was the first oral glucose-lowering medication to be introduced into clinical practice in the 1950s and has since been recognized as a first-line therapy as either a monotherapy or in combination [85, 99]. In the United Kingdom, sulfonylureas have been the second-line choice after metformin [100]. Furthermore, sulfonylureas are the drug of choice for type 2 diabetics who do not benefit exclusively from diet and exercise [101, 102].
Sulfonylureas usually lower blood glucose concentrations by approximately 20% and HbA1c by 1 to 2% [103, 104]. Recently, a systematic review of double-blind randomized control trials found that sulfonylurea monotherapy reduced HbA1c by an average of 1.5% (16 mmol/mol) compared with that of placebo groups [99, 105]. These drugs are most effective in patients whose weight is normal or slightly increased. In contrast, insulin should be used in patients (regardless of age) who are underweight, losing weight, or ketotic despite adequate caloric intake. Some of these latter patients may actually have type 1 diabetes, which can be confirmed by the presence of islet cell antibodies [106, 107].
Sulfonylureas act as insulin secretagogues and exert their main action on islet β cells, stimulating insulin secretion and thereby reducing the plasma glucose concentration. The mechanism of action involves binding of the drug to the subunit SUR1 of the ATP-sensitive potassium channels in the plasma membranes of β cells; these channels are then closed, which leads to a change in the membrane voltage, calcium influx and exocytosis of insulin granules [108-111]. The ATP-sensitive potassium channels are also present in other tissues but often contain different types of SUR subunits (e.g., SUR1 in β cells, SUR2A in heart cells, SUR2B in smooth muscle cells). The sensitivity of these different types of channels to sulfonylureas is variable [110].
The net effect of sulfonylureas is an increased responsiveness of β cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released at all blood glucose concentrations. Thus, sulfonylureas are useful only in patients with some β cell function. Sulfonylureas may also have extrapancreatic effects, which includes an increased tissue sensitivity to insulin; however, the clinical importance of these effects is minimal [101, 103].
The basal secretion and insulin secretory response to various stimuli are intensified in the early days of treatment with sulfonylureas. With long-term treatment, circulating insulin levels decline to levels that occurred before treatment; however, despite this reduction, the decreased plasma glucose levels are maintained. The mechanism for this response is still unknown but may be associated with reduced plasma glucose, which allows the circulating insulin to have more pronounced effects on their target tissues, as well as the impairment of insulin secretion by chronic hyperglycemia.
Sulfonylureas are well absorbed after oral administration by the gastrointestinal tract. However, the presence of food and hyperglycemia may reduce their absorption. The peak plasma concentrations occur within 2-4 hours, and the duration of the effect varies. All of these drugs bind tightly to plasma albumin and are involved in interactions with other drugs (e.g., salicylates and sulfonamides) such that there is competition for binding sites. All sulfonylureas are metabolized by the liver, and their active metabolites are mostly excreted in the urine; thus, their action is increased in elderly patients or those with renal or hepatic disease.
The choice of sulfonylurea is primarily dependent upon cost and availability because their efficacy is similar. However, because of the relatively high incidence of hypoglycemia in patients taking glyburide or chlorpropamide, shorter acting drugs should be used, especially in elderly patients [112]. In a patient who is not a candidate for metformin or cannot tolerate metformin as initial monotherapy, a shorter-duration sulfonylurea such as glipizide is suggested.
The first-generation sulfonylureas vary considerably in their half-lives and the extent of their metabolism. The acetohexamide half-life is short, but the drug is reduced to an active compound whose half-life is similar to that of tolazamide and tolbutamide (4 to 7 hours). If required, these drugs can be divided into daily doses. Chlorpropamide has a long half-life (24 to 48 hours) [113]
The action of chlorpropamide, acetohexamide, tolazamide and tolbutamide is long lasting, and there is substantial excretion in the urine. Therefore, these drugs can cause severe hypoglycemia in elderly patients who have experienced a progressive decline in glomerular filtration. These drugs cause flushing after alcohol consumption and exert similar effects to that of the diuretic hormone on the distal nephron, producing hyponatremia and water intoxication [113].
The second-generation sulfonylureas (glibenclamide, glipizide and gliclazide) are more potent, but their hypoglycemic effects are not much improved, and they fail to control blood glucose, which is commonly observed with tolbutamide. All of these drugs contain the sulfonylurea molecule, but different substitutions result in differences in pharmacokinetics and duration of action. Glibenclamide should be avoided in the elderly and patients with mild renal impairment because of the risk of hypoglycemia because several of its metabolites are excreted in the urine and are moderately active [113].
The sulfonylureas cross the placenta and stimulate insulin release by fetal β cells, causing severe hypoglycemia at birth. Consequently, their use is contraindicated during pregnancy, and gestational diabetes is treated by diets supplemented with insulin when required [113].
In general, sulfonylureas are well tolerated. The observed side effects are hematological, including hypoglycemia, leukopenia, agranulocytosis, thrombocytopenia, and hemolytic anemia, gastrointestinal, including nausea, vomiting, and cholestatic jaundice (rare), and allergic reactions. Sulfonylureas may also cause weight gain, and their binding to plasma proteins can be potentiated by other drugs used concomitantly, which may cause hypoglycemia. This condition is the most problematic adverse event and may be prolonged, which can have severe consequences in elderly patients, patients treated with multiple drugs and those with impaired renal function. Moreover, sulfonylureas stimulate appetite and can occasionally cause allergic rashes and bone marrow injury [113].
Sulfonylureas have structural characteristics that allow them to be given in much lower doses than the first-generation sulfonylureas. Nevertheless, the different sulfonylureas are equally effective in lowering blood glucose concentrations. There are, however, differences in absorption, metabolism and effective dose [114], which is partly caused by the formation of active metabolites [115]. These drugs also cause greater suppression of overnight hepatic glucose output, thereby lowering fasting blood glucose concentrations. These benefits may be counterbalanced by an increased risk of hypoglycemia [112].
The US Food and Drug Administration (FDA) approved glimepiride in 1995 for the treatment of T2DM alone and in combination with metformin or insulin. It has prolonged action and lasts over 24 hours. Glimepiride has advantages with respect to its clinical and pharmacological profile, and it has also been shown to cause a low incidence of severe hypoglycemia compared to other representatives of its class [116, 117].
Regarding hypoglycemia, the findings observed in certain studies differ. In a systematic review and meta-analysis [118], glimepiride was found to cause increased hypoglycemia compared to other sulfonylureas and even more than other secretagogues. In other studies, the long-acting sulfonylureas, such as chlorpropamide and glibenclamide, were shown to have an increased likelihood of causing hypoglycemia [112, 119]. In a UK survey, the rate of diagnosis of hypoglycemia was higher for glibenclamide compared to other representatives of the same class [120].
With regard to weight gain, in the UK Prospective Diabetes Study [34], the mean weight change after 10 years of follow up ranged from a minimum of 1.7 kg as a result of glibenclamide use to a maximum 2.6 kg with chlorpropamide use. Glimepiride was found to be neutral with respect to body weight, whereas other authors observed weight reduction [121, 122].
Sulfonylureas have different cross reactivities with cardiovascular ATP-dependent potassium channels. The closing of these channels by ischemic preconditioning can lead to cardiovascular mortality [123].
Several compounds increase the hypoglycemic effect of sulfonylureas, and several of these interactions are potentially important from a clinical standpoint. Non-steroidal anti-inflammatory agents (including azapropazone, phenylbutazone and salicylates), coumarin, certain uricosuric agents (e.g., sulfinpyrazone), alcohol, monoamine oxidase inhibitors, certain antibacterials (including sulfonamides, chloramphenicol, and trimethoprim) and certain antifungal agents (including miconazole and possibly fluconazole) produce severe hypoglycemia when administered with sulfonylureas. The probable basis for these interactions is the competition for metabolizing enzymes, but interference in plasma protein binding or excretion may also exert some effect. The agents that reduce the action of sulfonylureas include diuretics (thiazides and loop diuretics) and corticosteroids [113].
Obesity (body mass index (BMI) above 30 kg/m2) is common in many diabetic patients, and it is important to highlight the rising prevalence of these two health conditions in the modern world [124]. Being obese or overweight produces important risk factors for type 2 diabetes and is associated with many serious health conditions, such as heart disorders and cancer, which lead to increased mortality, especially in individuals over 65. In patients previously diagnosed with type 2 diabetes, the presence of obesity can lead to a worsening of the metabolic disorders associated with diabetes, such as hyperglycemia, hypertension and hyperlipidemia [125, 126]. Thus, weight loss is required to improve glycemic control in the patient as well as to reduce the cardiovascular risk factors, which will likely reduce the risk of mortality in those individuals [127-129].
A systematic review published in 2011 [126] reported data from two clinical trials that showed a reduction of 30% to 50% in the incidence of diabetes in overweight and obese patients (with elevated plasma glucose levels) after behavioral interventions that lead to weight loss. However, the results arising from actions aimed at the prevention of obesity and changes in the obesogenic environment are often insufficient and produce insignificant weight loss that is usually regained over time. For these individuals, more invasive treatments are required to produce a sufficient weight reduction. Bariatric surgery has been a widely used intervention in obese patients because it promotes rapid and significant weight loss. However, the risks of surgery mean that this intervention is reserved for patients with morbid obesity. Thus, the FDA advises pharmacological intervention for patients with BMI ≥ 30 kg/m2 (obese) or ≥ 27 kg/m2 (overweight) when in the presence of co-morbidities related to obesity [125, 130-132].
Numerous medications have been used for weight loss in recent decades; however, the occurrence of adverse side effects has restricted their current use [125]. In the 1990s, the drugs fenfluramine and dexfenfluramine (sympathomimetic amines that promote appetite suppression) were withdrawn from the market because of the risk of heart damage. The European Medicines Agency (EMA) suggested the withdrawal of various anti-obesity drugs, such as diethylpropion (amfepramone), mazindol and phentermine (also sympathomimetic amines inhibiting appetite), in the 2000s because of the high risk of adverse events. In 2006, rimonabant (first selective blocker of endocannabinoid receptor subtype 1-CB1) became available in 56 countries; however, because of its adverse psychiatric events, this drug was never approved by the FDA and was withdrawn from the European market in 2009. Additionally, after clinical trials assessing the safety and tolerability of sibutramine (an appetite suppressant that acts as a selective inhibitor of the reuptake of norepinephrine and serotonin), the FDA considered the option to restrict access to this substance or withdraw it from the market, causing the suspension of marketing authorization in 2010 [130, 133].
From the drugs approved before 2012, several sympathomimetic amines are available. These include phentermine, diethylpropion, benzphetamine and phendimetrazine, which are approved for short-term weight management (≤ 12 weeks), and orlistat (a potent reversible inhibitor of gastric and pancreatic lipase capable of preventing the absorption of up to 30% of dietary fat), which is the only anti-obesity drug for long-term use [130, 134, 135]. In 2012, the FDA approved two new drugs for obesity control: lorcaserin (agonist of the serotonin receptor 5-HT2C) and extended release phentermine-topiramate (association between a sympathomimetic amine appetite suppressant and an anticonvulsant). The mechanism responsible for weight loss when using extended release phentermine-topiramate is believed to be the subsequent increase in activity of the neurotransmitter gamma-aminobutyric acid (GABA), although the exact association mechanism remains unclear. Both drugs were approved for long-term use [131, 136, 137].
Depression is a common side effect observed in patients with type 2 diabetes, which may be associated with a lack of glycemic control, increased risk of complications, lack of adherence to treatment and even the presence of obesity or overweightness [137, 138]. A meta-analysis in 2001 by Anderson et al. showed that the prevalence of depression was twice as high in individuals with T2DM than in those without this health condition. Thus, reducing the incidence of depression and improving the quality of life of diabetic patients, especially those who are also obese, are highly relevant clinical objectives [139-141]. The treatment of depression in diabetics is usually accomplished by the use of serotonin reuptake inhibitors, such as fluoxetine and sertraline. These drugs not only act on depression but also promote weight loss, which is highly desired in obese or overweight diabetics [68, 142].
Dapagliflozin was the first hypoglycemic agent of the new class of selective reversible inhibitors of sodium-glucose cotransporter 2 (SGLT2) approved in the US (April 2012) and demonstrates a new mechanism of action independent of insulin. This drug is recommended in adults aged 18 years or older with type 2 diabetes, both as a monotherapy and as a combination therapy with other hypoglycemic drugs, including insulin when diet and exercise does not provide adequate glycemic control [143-145].
The hypoglycemic effect occurs by reducing the reabsorption of glucose from the renal proximal tubule, which leads to increased urinary excretion of glucose with an associated loss of calories [143, 144]. On average, a daily dose of 10 mg dapagliflozin increases the amount of glucose excreted in the urine of a patient with type 2 diabetes to 50-80 g/day. This effect is observed with the first dose, and with chronic treatment, this increased excretion of glucose can be maintained for at least two years [146, 147].
In patients with type 2 diabetes, urinary loss of glucose works through a mechanism independent of insulin secretion and action [148-153] and has the potential to improve glycemic control, including control of HbA1c, fasting plasma glucose and postprandial glucose.
The selectivity of dapagliflozin for SGLT2 is 1000-3000 times greater than for SGLT1 [154].
Dapagliflozin is rapidly and extensively absorbed following oral administration. The oral bioavailability of a 10 mg dose is ≥ 75% and may be administered with or without food. It is extensively metabolized to inactive conjugates, predominantly dapagliflozin 3-
Dapagliflozin’s effectiveness is dependent on renal function and therefore should not be used by patients with moderate to severe renal impairment; dose adjustment is necessary for patients with mild renal failure or moderate hepatic impairment. Moreover, dapagliflozin should not be used in patients with severe hepatic impairment because exposure to dapagliflozin can be increased.
Interactions between dapagliflozin and other agents routinely used in the control of diabetes mellitus, including sulfonylureas, statins, warfarin and digoxin, were observed [154].
Dapagliflozin was generally well tolerated in clinical trials lasting 1 or 2 years and in studies lasting approximately 2 years [146]. Polyuria, nocturia and thirst may be experienced by some patients, and the increased excretion of glucose causes osmotic diuresis, which is similar to what is observed in patients with uncontrolled diabetes. The additional fluid loss of 300-400 ml/day is well tolerated by most patients [149, 155].
Genital infections are common in patients receiving dapagliflozin because glycosuria provides a favorable environment for the growth of microorganisms [146, 149, 155].
Dapagliflozin is recommended for patients with T2DM in the following situations [154]:
Monotherapy as an adjunct to diet and exercise when metformin is not tolerated;
Combined therapy
with metformin, diet and exercise, to improve glycemic control in patients when these measures alone do not achieve adequate glycemic control and there is little prospect of therapeutic response to metformin (e.g., high HbA1c levels);
with a sulfonylurea when sulfonylureas alone with diet and exercise do not provide adequate glycemic control; and
with insulin (alone, with metformin or a sulfonylurea or both) when existing therapy along with diet and exercise do not provide adequate glycemic control;
A number of other SGLT2 inhibitors are under investigation, including empagliflozin, canagliflozin and ipragliflozin. In addition, a non-selective SGLT inhibitor (LX4211) is under development. It is likely that these and other agents that share similar pharmacodynamic properties may become available in the coming years [146].
In 1921, insulin was introduced as a therapeutic drug, which improved the quality and life expectancy of diabetics. The first available commercial insulin preparations corrected acute diabetic decompensation but were inefficient for chronic use because their duration was too short. Thus, diabetics were required to take four to five injections daily to achieve good metabolic control. Such short-acting insulin was the only commercially available type in 1935. Prolonging the action of insulin to over 24 hours could achieve the aim of decreasing the amount of daily injections, and it was achieved by incorporating certain substances, such as oily solutions, heavy metals (zinc) and protein (protamine). In 1950, by changing the concentration of protamine and decreasing the amount of zinc, the intermediate insulin called isophane or NPH ("Neutral Protamine Hagedorn" in honor of the scientist) became available. There were still more changes in the formula that affected the time of action, and in 1954, the family of insulins slow, semi-slow, or ultra-slow containing zinc instead of protamine was produced [156, 157].
The use of insulin is essential in the treatment of type 1 diabetes mellitus. In T2DM, it is reserved for patients with severe hyperglycemia with ketonemia or ketonuria, newly diagnosed diabetics or those who do not respond to treatment with diet, exercise, oral hypoglycemic agents and the anti-hyperglycemic action of insulin sensitizers [158].
A milestone in diabetes therapy occurred with the Diabetes Control and Complication Trial (DCCT), which showed that blood glucose levels close to normal drastically reduced or even prevented the complications of diabetes when the carrier of the disease was subjected to intensive insulin treatment and follow-up with a team of diabetes educators. According to the DCCT, to achieve this control, one proposal is to replace conventional insulin treatments (one or two daily applications of insulin) with an intensive treatment of up to four applications per day [159].
Currently, attempts to achieve good metabolic control in patients with diabetes include treatment with exogenous insulin, which is an effective therapy option in cases of partial and/or total deficiency of insulin secretion by the pancreas. It is estimated that 20-25% of all patients with diabetes are treated with insulin, and 5-10% of these patients are type 1 (who need this hormone to survive) and 15% are type 2 (who show severe insulin deficiency) [157].
Commercial insulin is a protein hormone with two linked chains of amino acids that cannot be administered orally because it is degraded by digestive and intestinal enzymes. Most commercial insulin is manufactured from bovine and porcine pancreases, which are similar to the human pancreas. Bovine and human insulin differ in three amino acids, whereas porcine insulin differs in one amino acid (amino acid thirty). Chemically synthesized insulin is also produced by recombinant DNA techniques that use bacterial cells or other tissues that are free from impurities and have a minor antigenic action [160, 161].
The pharmacokinetics of insulin varies according to its type and kind, injection technique, presence of insulin antibodies, site of injection and the individual [162].
Commercial preparations of insulin are classified according to duration as either short, intermediate or long acting, and the species of origin is also a classifier, with insulin derived from human, porcine, bovine and or porcine bovine mixtures. Because of differences in the amino acid sequences, the bovine and porcine insulins have different physicochemical properties to human insulin. Human insulin has become widely available following the advent and development of recombinant DNA techniques [163]. These techniques have led to different formulations of insulin that differ according to recombinant DNA production techniques, amino acid sequences, concentrations, solubility and time of onset and duration of biological action. However, insulin produced through recombinant DNA technology are more soluble in aqueous solutions. Currently, the commercially available forms are supplied at neutral pH, resulting in improved stability, which is essential for storage over several days at room temperature [164].
The long-acting analogues such as glargine and detemir appeared on the market in 2000 and 2004, respectively [165], and they show a relatively stable profile of action over time [166]. In January 2013, the European Commission authorized the introduction of a new generation of ultra-long insulin analogues. Degludec insulin is an ultra-long acting basal insulin analogue [167].
This group of insulins includes regular, lispro, aspart and glulisine analogues.
Regular insulin is usually administered subcutaneously and often in combination with intermediate-acting or long-lasting insulin. Special buffers are used so that a pump is not required to prevent crystallization because of its slow infusion. Monomers of this insulin present as hexamers that reduce the absorption rate. Normally, regular insulin is recommended for the treatment of diabetic ketoacidosis, and it is associated with human intermediate-acting insulin or basal analogs taken before meals [168]. This insulin should be administered 30-45 minutes before meals to reduce peak postprandial glycemia, and its action lasts between 2 and 4 hours, which contributes to postprandial hyperglycemia and hypoglycemia in the period between meals because regular insulin will peak after food has been metabolized [169].
Insulin lispro is a human insulin analog developed through genetic engineering by reversing the amino acids proline and lysine at positions 28 and 29 of the β chain, which results in the insulin sequence Lys (B28) Pro (B29). This insulin in its pharmaceutical preparation with phenol and zinc form stable hexamers [168], has a reduced tendency to self-aggregate at the site of subcutaneous injection, is absorbed more rapidly than regular human insulin, and mimics the physiological profile of insulin in response to a meal. In addition, its onset of action is between 5 and 15 minutes and duration of action is 1-2 hours [170]. The use of these analogues requires an additional dose in the afternoon to compensate for the hyperglycemia that results from an afternoon snack. There is evidence that insulin lispro reduces postprandial hyperglycemic peaks and the risk of hypoglycemia compared to regular insulin, especially at night [168, 171].
In aspart insulin, one proline amino acid is replaced by aspartic acid, which is negatively charged, at position 28 of the β chain, producing electrical repulsion between the insulin molecules and reducing their self-association tendency; in vials or cartridges, it occurs as hexamers, but in subcutaneous tissue, there is rapid dissociation to dimers and monomers, which ensures its rapid absorption and onset of action between 5 and 15 minutes and duration of action of 1 to 2 hours[168].
Insulin glulisine is another ultra-rapid insulin analogue obtained by the exchange of asparagine for lysine at position 3 of the β chain and lysine for glutamic acid at position 29 of the same chain. Thus far, there have been few studies with glulisine insulin, which appears to be similar to lispro and aspart in efficacy and hypoglycemic events. Because of its faster absorption, its administration should be performed only 5-10 minutes before meals to provide greater flexibility for the patient and thereby improve their quality of life. Its shorter half-life reduces the need to eat food 2-3 hours after its administration, which is necessary with regular insulin, whose longer half-life causes postprandial hypoglycemia [172].
A recent direct and indirect meta-analysis published by Sanches et al. (2013) for glycated hemoglobin reduction outcomes compared rapid action insulin (aspart, glulisine and lispro) with human insulin (regular), and the direct meta-analysis only showed a statistically significant difference for aspart, favoring the insulin analog. However, the results of indirect meta-analyses of HbA1c reduction outcomes showed that the result of rapid-acting insulin are consistent and the difference between them is not clinically significant. The ranking suggests that the probability of selecting the short-acting insulin brings the following provision: the first choice should be regular followed by glulisine, lispro and finally aspart. No significant differences were found in the comparison of tolerability outcomes in the rapid-acting insulin (aspart and lispro) and human insulin (regular) [173].
Recent studies have attempted to alter the pharmacokinetics of fast acting insulin analogues that are associated with recombinant human hyaluronidase, and they revealed that absorption was accelerated two-fold during the first half hour of exposure, which resulted in an onset of action between 13 and 25 minutes faster and a shorter duration of effect (40 to 49 minutes). The ultra-rapid action arising from this association may be beneficial in furthering the control of postprandial blood glucose, and administering insulin lispro and hyaluronidase immediately before meals in patients with type 1 or 2 diabetes may be beneficial. Studies are being conducted for the commercial production of HUMALOG ® (Eli Lilly Nederland B.V) as part of an intensive basal-bolus insulin treatment for these patients [174].
NPH insulin was released in 1946, and it is an insulin suspension in a zinc complex and protamine phosphate buffer. Its dosage is usually once a day before breakfast or twice a day. It has an absorption peak approximately 4-6 hours after subcutaneous administration, which is followed by a steady decline in plasma insulin concentrations [175].
The major disadvantages of NPH are the wide daily variations in the timing and duration of peaks among and between individuals, which, when compared to the timing and duration of long-acting analogs, may result in non-optimal metabolic control and an increased risk for nocturnal hypoglycemia. [172].
With respect to better glycemic control and safety when comparing the use of NPH with long-term insulin analogues, a meta-analysis published in 2013 showed that in type 2 diabetic patients, glycemic control does not seem to differ among different classes, although there is evidence for a possible reduced risk of nocturnal hypoglycemia.
Other information found in the study was that only detemir (and not glargine) may be associated with less of a weight gain than is associated with NPH [176]. In an indirect meta-analysis of long-term insulin, the results of reducing HbA1c are consistent with data from direct comparison meta-analyses and allowed a ranking of probability choice of insulins to improve the reduction of HbA1c as follows: NPH, glargine and detemir [173, 177].
Glargine and detemir insulin analogs represent groups referred to as long-term or basal [168]. Detemir is produced by means of recombinant DNA technology with expression in
Glargine is synthesized from changes in the amino acid chain of human insulin through a substitution of asparagine by glycine at position A21 and the addition of two arginines at position B30. These modifications result in a unique pattern of release from the injection site, meaning that this analog precipitates in the subcutaneous tissue, allowing a gradual absorption into the bloodstream [180].
Basal insulin has been developed to promote basal levels of insulin over 24 hours and can be administered once a day or at bedtime. When comparing conventional long-acting insulin with glargine insulin, the insulin analog is observed to have a constant concentration profile without prominent peaks [181]. In addition, the onset is between 1 and 2 hours, plateau of biological action is between 4 and 6 hours and termination of effect is between 20 and 24 hours. Because of its slightly acidic pH, glargine cannot be mixed with other insulins in the same syringe; therefore, children may sometimes complain of a burning sensation at the application site [168]. The timing of administration of glargine appears to have no impact on its efficacy for glycemic control, but the administration should occur at approximately the same time each day so that its effectiveness as an insulin is maintained without peak action. If a dose is missed, 50% of the daily insulin will be missing that day [172].
In a direct meta-analysis comparing the insulin analogues (glargine and detemir) to NPH insulin in reducing glycated hemoglobin, the results were statistically significant and favored the twice-daily administration of detemir alone. The safety and tolerability results also showed minor differences between the insulin analogues and NPH insulin [173].
The insulin degludec belongs to a new class of insulin analogues and has a unique absorption mechanism that allows for an ultra-slow and stable pharmacokinetic profile. Its structure differs from human insulin at the β chain termination with removal of threonine at position B30 and a 16-carbon fatty acid attached to lysine at B29 by glutamic acid. This change allows for the formation of a deposit of soluble multi-hexamers, which accumulate in the subcutaneous tissue and have a slow release because of the dissociation of zinc ions; therefore, degludec insulin monomers are circulated in a slow and sustained fashion. In clinical trials, it was observed that the pharmacokinetic variations are four times smaller than in the other long-acting insulin analogues. Studies show that this insulin is related to a lower risk of nocturnal hypoglycemia, and because of these characteristics, administration can occur at intervals of up to 40 hours [182, 183].
New insulins, such as U300 and LY2605541 insulins, are still under investigation. Insulin glargine U300 is a new formulation containing glargine in a 300 U/mL concentration (the usual concentration is 100 U/mL). This change alters the pharmacokinetic and pharmacodynamic properties of glargine. For subcutaneous injections, a compact deposit of U300 is administered with a smaller deposit surface, and this produces a more gradual and prolonged release than conventional glargine; therefore, its pharmacokinetic profile is more regular and shows plasma concentrations even beyond 24 hours [184].
Another new insulin, LY2605541, is a long-acting insulin that is a modification of lispro insulin with a 20 kDa polyethylene glycol and half of lysine B28 through covalent urethane, which increases the hydrodynamic size of the insulin complex. This surface provides a greater delay in absorption and reduces the clearance, resulting in a prolongation of its action. This modified insulin has a low affinity for binding to the growth factor receptors linked to insulin, which reduces its mitogenic potential compared to human insulin. Its average life is 24-45 hours, and the duration of action may exceed 36 hours. Animal studies suggest selective action on hepatic metabolism [184].
The benefit of injectable insulin is often limited because of the difficulty of convincing the patient to adhere to proper treatment, which is related to the need for multiple injections to ensure adequate glycemic control [185].
To alleviate this discomfort, the first inhalable insulin (Exubera®, Pfizer/Nektar) was approved in the U.S. in January 2006. Exubera® consists of a dry powder formulation containing 1 to 3 g of human insulin administered via a single inhaler lung [186]. The technology used in this product was the development of an inhaler for polyethylene glycol in a dry powder that releases the equivalent to 3 UI and 8 UI of short-acting insulin subcutaneously [187]. Exubera® has demonstrated efficacy and a low risk of hypoglycemia; however, there was a poor acceptance by the prescriber and patient. In April 2008, clinical trials showed the first case of cancer, and there were six subsequent cases of lung cancer and a case of primary malignant lung tumor in a patient who had a history of smoking. Other important aspects are coughing, decline of lung function, and increase of anti-insulin antibodies [188]. These facts led the manufacturer to withdraw Exubera® from the market.
The insulin AERx was developed by the Aradigm Corporation and Novo Nordisk. This system generates aerosol droplets from liquid insulin, and the devices guide the user to inhale the insulin. Moreover, it offers the ability to download data on the use of insulin, such as the frequency of inhalation, which can allow for the monitoring of treatment, which is important because of the experience with Exubera® [189].
AFREZZA™ (insulin Technosphere®) overcomes some of the barriers that contributed to the withdrawal of Exubera® from the market. Studies have shown that Technosphere® is a unique formulation of ultra-rapid insulin with a relatively short duration that effectively improves glycemic control without contributing to an increase in weight gain or hypoglycemia compared to other prandial insulins. Additionally, Technosphere® insulin has shown a favorable safety and tolerability profile in clinical studies to date [190]. Technosphere® insulin (TI) combines the post-dried recombinant human insulin (Mannkind Corp.) with the MedTone® Inhaler (Pharmaceutical Discovery Corp.) [191, 192.]. Recently the FDA approved this insulin; however, a continuation of the studies is required in the post-marketing period.
Despite the variety of drugs currently available for the treatment of type 2 diabetes, there was no observed decrease in the number of patients who have inadequate glycemic control keeps the last 10 years. This occurs for a variety of reasons, such as non-adherence to treatment, inappropriate prescribing of medication, lack of efficacy of medicine, among other reasons.
The search of glycemic control in patients with T2DM is still a challenge for patients and health professionals. Importantly, the success of drug treatment also depends on the association with non-pharmacological measures such as healthy diet and exercise.
A sense of loneliness is a subjective marker for deficits in one’s social relationships conceptualized as the discrepancy between the self-perceived extent of contact and support desired and the actual level of contact and support received [1]. This disparity leads to a cascade of behavioral, neural, hormonal, cellular, and molecular changes in the short-term [2]. In the longer-term, loneliness has been shown to negatively affect health and diminish longevity, especially among older adults [3, 4].
Because of the advancement of the study of the association that exists between loneliness and health in old age, interest has been fostered in better understanding the possible biological basis of this relationship. This is especially the case in industrialized countries where population aging is dramatically increasing and, correspondingly, the costs of dealing with poor health in old age are escalating [5]. Chronic inflammation is one of the postulated bio-physiological pathways through which loneliness may exacerbate the poor health of many older adults. Findings show, for example, that inflammatory responses that lead to prolonged and systemic immune responses, such as a rise in C-reactive protein (CRP) levels, are correlated with feelings of loneliness [6], while these same inflammatory responses also predict cardiovascular diseases [7] and higher mortality [8].
Another possible explanation for the association between loneliness and health in late life is that metabolic dysregulation serves as a trajectory in which different aspects of social disconnectedness, especially loneliness, are associated with the health condition. Studies underscore that loneliness predicts metabolic dysregulation as indicated by high systolic blood pressure and age-related differences in metabolic functioning [9], on the one hand, and that metabolic processes are linked to one’s health state, on the other hand. An example of the latter case is that levels of Glycated hemoglobin (Hba1c), a glucose concentration measure, serve as criteria for diabetes diagnosis [10]. In addition, Body Mass Index (BMI), a measure to assess obesity, as well as Cystatin C, (CysC), a biomarker of kidney function, both prospectively predict cardiovascular events and all-cause mortality among older adults [11, 12]. Recently, loneliness was found to be associated with a change for the worse in several metabolic bio-markers. Specifically, lonely older adults had 39–71% higher odds of developing prospective risk levels in HbA1c, BMI, and metabolic burden [13].
The mechanism through which loneliness is related to inflammatory and metabolic markers, respectively, is yet to be elucidated. Hawkley and Cacioppo [14] outlined several potential mechanisms by which loneliness affects health including compromising health behaviors. They argued that the lonely individual perceives the social world as threatening and that this perspective weakens his or her self-regulation, thus creating patterns of health-compromising behaviors such as physical inactivity, which cause a deterioration of health [14, 15, 16]. This hypothesis was supported by Segrin & Passalacqua [17] who found that exercise mediated the association of loneliness with self-rated health. More recently another cross-sectional study carried out in Denmark found that physical inactivity mediated the relationship between loneliness and adverse health condition such as cardiovascular disease [18].
However, to the best of our knowledge, the role of physical activity as a significant agent in the prospective association between loneliness and inflammatory and metabolic biomarkers has not yet been fully tested within the same study. Studies substantiated the relationship between loneliness and engagement in physical activity, with loneliness found to be associated with transitioning from physically active status to sedentary status [19], on one hand. Studies report a positive association between physical activity and improvement in inflammatory and metabolic regulation, as manifested by a more substantial reduction in CRP levels [20] and by higher HbA1c declines [21], on the other hand.
Consequently, the aim of the current inquiry is to address the dynamics of this assumed relationship systematically. Toward this end, we examine whether physical activity mediates the postulated association between loneliness and two key biological processes among older adults, looking specifically at its effect in relation to both inflammation and metabolic deficits. The focus on older adults in the current study is warranted insofar as research has validated that older people face loneliness more frequently [22]. They are also more prone to immune and metabolic defectiveness than are younger adults [23, 24]. Moreover, social-physiological interconnections have more prominent effects on older age cohorts [9]. The spotlight on the older age strata is also crucial in that previous studies have revealed that loneliness accelerates physiological aging [16].
The data for the analysis were drawn from the Health and Retirement Study (HRS), a nationally representative, a biennial longitudinal survey sponsored by the National Institute on Aging and the Social Security Administration, and run by the Survey Research Center at the University of Michigan’s Institute for Social Research. The HRS gathers a wide range of economic, social, and health data on older adults [25]. The Institutional Review Board of the University of Michigan granted ethical approval [26]. The loneliness data and all of the social-demographic variables for the present inquiry were retrieved from Wave 7 (2006) of the HRS. Information on the frequency of physical activity was taken from Wave 8 (2008). The blood-based inflammatory and metabolic markers, which served as the outcome measures in the current analysis were collected in Wave 9 (2010) of the survey (The HRS collects bio-measures from a portion of the respondents at each Wave, on a rotation basis, and not from the entire sample [27]). The BMI scores, another metabolic outcome, were also taken from the Wave 9 data.
We limited the analytic sample to respondents aged 60 and above who had valid data regarding social-demographic background, loneliness, frequency of physical activity, and at least one inflammatory or metabolic bio-marker from Wave 9. The resultant analytic sample thus numbered some 3,735 respondents. This number varied slightly across the respective multivariate analyses, as has been similarly reported in related studies [28]. Descriptive statistics of the respondents in the current study are reported in Table 1.
Wave 7 | Wave 9 | |
---|---|---|
Women | 58.4% | |
Age, mean (SD) | 71.1 (7.2) | |
White | 84.3% | |
Married | 66.9% | |
>12 years of education | 25.7% | |
Currently working | 14.3% | |
Depressed | 10.7% | |
Loneliness, mean (SE) | 4.3 (0.03) | |
Moderate physical activity, at least once a week (wave 8) | 54.1% | |
Log-CRP, mg/dL, mean (SE) | 0.16 (0.01) | |
Hba1c, %, mean (SE) | 5.87 (0.02) | |
BMI, kg/m2, mean (SE) | 29.77 (0.11) | |
CysC, mean (SE) | 1.22 (0.01) |
Demographics, loneliness scores, frequency of physical activity, and bio- markers values of the sample.
Loneliness was evaluated by the abbreviated 3-item form of the R-UCLA Loneliness Scale, a widely used questionnaire that was developed for use in large-scale surveys and was proven to be valid and reliable [29]. Participants were asked on a 3-point scale, ranging from 1 (hardly ever) to 3 (often), how often they felt a sense of (1) being left out, (2) lack of companionship, and (3) isolation. The three items were summed to create a scale score ranging from 3 to 9, with higher scores representing a greater extent of loneliness. As can be seen in Table 1, the average loneliness score was M = 4.3, with SE = 0.03.
The bio-measures (except for BMI) were produced through the collection of Dried Blood Spot (DBS) samples, a minimally invasive and highly valid method [30]. Inflammatory processes were marked by values of CRP, subsequently log-transformed due to skewed distributions, as has been done previously [31]. Respondents with CRP levels >10 mg/L were excluded from the current CRP analyses because we were interested in low-grade inflammation, also in accordance with Yang et al. [31]. Metabolic processes were represented by levels of –Hba1c, [10] and Cystatin C (CysC, [32]), as well as by BMI (weight/height2) [33].
Respondents were asked about the frequency of moderate physical activity that they carry out in their daily life (“How often do you take part in sports or activities that are moderately energetic such as gardening, cleaning the car, walking at a moderate pace”). Vigorous physical activity (“How often do you take part in sports or activities that are vigorous, such as running or jogging, swimming, cycling, aerobics or gym workout, tennis, or digging with a spade or shove”) was also explored for sensitivity analysis. Responses for both types of activities (moderate/vigorous) ranged in the current analysis from 1 (“hardly ever or never”) to 5 (“every day”).
Variables that have been shown in other analyses to be relevant to the association that exists between social network relationships and levels of inflammatory and metabolic bio-measures among middle-aged and older adults served as covariates in the current inquiry [6, 31, 34]. Specifically, the regressions were adjusted by gender (men, women), age (60–96), ethnic affiliation (White, Black, or Hispanic), marital status (married, not married), the extent of formal education (up to and including a high-school diploma/GED, more than a high-school diploma/GED), employment status (working/not working) and depression (Yes/ No). Covariates were gathered in Wave 7, aside from depression, which was measured at Wave 8, due to low response rate on this question at Wave 7. The reference categories were men, white, not married, up to and including a high-school diploma/GED, currently not working and not depressed.
Multiple multivariate linear procedures were employed. The main effect of loneliness on the four bio-markers was analyzed separately for each of the biomarkers: log CRP, Hba1c, BMI, and CysC, after adjusting for the sundry controls (gender, age, ethnic pertaining, education, marital status, employment status, and depression status). The Ns for the respective analyses were: log-CRP (n = 3127), Hba1c (n = 3402), BMI (n = 3538), CysC (n = 3362). The STATA software program 15.0 was used in this stage of the study.
In the second phase of the analysis, physical activity was added to the regressions as a mediator. However, this potential mediation effect was explored only when the main effect of loneliness was significant in phase 1. The second phase was carried out using the PROCESS macro in the SPSS statistical program. The SPSS analytic software was preferred here because it computes the direct and indirect effects in multiple mediator models, by calculating the product of coefficients [35]. Finally, the significance of the mediation was tested by means of bootstrapping, a nonparametric technique that does not require a-priori assumptions about the data distribution [36]. This method empirically estimates the sampling distribution by repeatedly resampling the data. When the confidence interval of 95 percent, which is based upon 1000 bootstrap samples, excludes zero, the mediation effect is significant [37].
The Prediction model results showed that being lonely at Wave 7 was associated with having higher log-CRP levels (β = 0.06, p < 0.01), higher Hba1c levels (β = 0.05, p < 0.01), higher BMI scores (β = 0.06, p < 0.01) and higher CysC values (β = 0.05, p < 0.01) at Wave 9, after adjusting for gender, age, ethnic pertaining, education, marital status, employment status and depression status.
The Prediction models inFigures 1–4, depict the associations of loneliness with prospective levels of log-CRP, Hba1c, BMI, and CysC with physical activity as a potential mediator. We elaborate here on the association between loneliness with prospective levels of log-CRP (Figure 1) since all other associations present a similar pattern of results. As demonstrated in Figure 1, higher levels of loneliness were significantly associated with increased prospective values of log-CRP (path c). However, the beta coefficient for the effect of loneliness on the frequency of physical activity (path a) and the beta coefficient for the effect of frequency of physical activity on levels of log-CRP (path b), were both significant. Also, the direct effect of loneliness in the presence of the mediator (path c’) was weaker than the total effect of loneliness (path c). This highlights a feasible indirect effect of loneliness through the frequency of physical activity [38]. In other words, greater loneliness decreased the frequency of subsequent physical exercise (β = −0.14) and this reduction in physical activity elevated the prospective levels of log-CRP (β = −0.11). When the mediator was used, the direct effect between loneliness and Log-CRP levels was still significant but weaker, which suggests partial mediation.
The mediation effect of physical activity upon the association of loneliness with prospective log-CRP levels. Adjusted by all variables in the Prediction model. Based upon 1000 bootstrap samples.
The mediation effect of physical activity upon the association of loneliness with prospective Hba1c levels. Adjusted by all variables in the Prediction model. Based upon 1000 bootstrap samples.
The mediation effect of physical activity upon the association of loneliness with prospective BMI levels. Adjusted by all variables in the prediction model. Based upon 1000 bootstrap samples.
The mediation effect of physical activity upon the association of loneliness with prospective CysC levels. Adjusted by all variables in the prediction model. Based upon 1000 bootstrap samples.
To test whether the mediation effect was significant we applied a bootstrap method. As may be seen in Figure 1, the association between loneliness with prospective levels of log-CRP was partially mediated because path c’ was still significant. The confidence interval of 95 percent, which was based upon 1000 bootstrap samples, was between 0.01 and 0.02, thus indicating mediation [37]. As already mentioned, similar results emerged in all the other relevant associations that were found to be significant in the first phase (i.e, between loneliness and the prospective concentrations of metabolic biomarkers (Figures 2–4).
Dividing the (standardized) indirect effect by the (standardized) total effect [39] showed that the indirect path of physical activity accounted for 25 percent of the association of loneliness with prospective values of log-CRP, 14 percent of the association with Hba1c, 32 percent of the association with BMI, and 36 percent of the association with CysC (not shown in the Figures). Sensitivity analysis of engagement in more vigorous physical activity showed very similar results (not shown).
This study examined whether physical activity mediates the effect of loneliness on inflammatory and metabolic processes among older Americans. We found, in the first phase of the study, that loneliness was, indeed, associated with increased levels of inflammation, measured 4 years later, as reflected by heightened values of (log) CRP [6]. Similarly, loneliness was associated with subsequent low metabolic regulation, also measured 4 years later, as manifested by elevated concentrations in all three of the metabolic measures that were examined: BMI, Hba1c, and CysC. These measures encompass several different aspects of metabolic processes, such as glucose concentration, kidney function, and CVD profiling, thus emphasizing the effect of loneliness on metabolic process as a whole [10, 33].
As noted, the primary focus of the current study was to consider whether physical activity mediates the loneliness—biomarker associations that emerged in the initial phase of the analysis. The findings show that the association of loneliness with the inflammatory marker log-CRP was partially mediated by the physical activity indirect pathway, which accounted for a quarter of the total effect. In addition, all of the significant associations between loneliness and prospective metabolic bio-markers were either partially or entirely mediated by physical activity. Of particular note is that this indirect effect was not at all minor, as it accounted for a substantial portion of the associations between loneliness and prospective BMI and CysC levels, with about a third of these associations being attributed to it. To the best of our knowledge, these findings are the first to affirm the contribution (i.e., the mediation), of physical activity to the associations between loneliness and immune and metabolic processes and to provide insights concerning the mechanism by which this social—biological connection operates.
The results of this study have important implications insofar as they suggest the deleterious effects of loneliness upon inflammatory and metabolic processes in later life, which have been reported in prior studies [6, 7, 9], can be mediated by physical activity. Our analyses showed that this might indeed occur due to engagement in any level of physical activity, whether moderate or vigorous. This implies that even moderate physical activity serves as a mechanism by which loneliness affects health in old age.
One potential limitation should be taken into account when interpreting the results of our analysis. We do not control whether the loneliness scores that were taken as the baseline indicator in the current analysis (Wave 7 of the HRS) represent transient or chronic loneliness. These two types of loneliness are conceptually different. Whereas transient loneliness may motivate individuals to reconnect with other individuals, loneliness that is accrued over time increases withdrawal [15]. This is a minor shortcoming; however, insofar as most older people have stable loneliness ratings over time [40].
In conclusion, this study identifies an important psycho-physiological mechanism that may be present among older adults. It documents that physical activity mediates the effect of loneliness on inflammatory and metabolic processes in a representative national sample of older Americans. Reduced engagement in physical activities in later life explains to some degree the deleterious health effects of loneliness.
The HRS (Health and Retirement Study) is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and is conducted by the University of Michigan.
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\n\nIntechOpen will help you complete your payment safely and securely, keeping your personal, professional and financial information safe.
\n\nIn accordance with the best security practice, we do not accept card orders via email.
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\n\nIf you do not receive your order within 30 days from the date your order is shipped, please contact us to inquire about the shipping status at orders@intechopen.com.
\n\nTax: Residents of European Union countries need to add a Book Value-Added Tax Rate based on their country of residence. Institutions and companies, registered as VAT taxable entities in their own EU member state, will not pay VAT by providing IntechOpen with their VAT registration number. This is made possible by the EU reverse charge method.
\n\nCustoms: free shipping does not include any duties, taxes or clearing charges levied by the destination country. These charges are the responsibility of the customer and will vary from country to country.
\n\nP.O. Boxes cannot be used as a Ship-To Address.
\n\nIntechOpen partners do not provide shipping service from Europe to the countries listed below. Please refrain from mailing items addressed to the countries listed below, until further notice.
\n\nWhen ordering our books from the countries listed below, please provide an alternative mailing address. For any further assistance, please contact us at orders@intechopen.com.
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\n\nPOD products are non-returnable and non-refundable, except in the event of poor print quality or an error in quantity. If we delivered the item to you in error or the item is faulty, please contact us.
\n\nInspect your order carefully when it arrives. Any problems should be immediately reported to orders@intechopen.com.
\n\nPrint copies of our publications are most often purchased by universities, libraries, institutions and academia personnel, hence increasing the visibility and outreach of our authors' published work among science communities and institutions.
\n\nOur books are available at our direct Print Sales Department and through selected representatives throughout the world.
\n\nBooks International
\n\nRepresentative for: Brunei, Cambodia, Indonesia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam (ASEAN)
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\n\nRepresentative for: India, Bangladesh, Pakistan, Sri Lanka, Bhutan, Nepal, Maldives, Iran, Algeria, Bahrain, Egypt, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Malta, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunis, United Arab Emirates and Yemen
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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It has been successfully used in many fields, and in the past years it has been applied in magnetic resonance imaging (MRI) as a computer-aided diagnostic tool. Quantification of the intrinsic heterogeneity of different tissues and lesions is necessary as they are usually imperceptible to the human eye. In the present chapter, we describe texture analysis as a process consisting of six steps: MRI acquisition, region of interest (ROI) definition, ROI preprocessing, feature extraction, feature selection, and classification. There is a great variety of methods and techniques to be chosen at each step and all of them can somehow affect the outcome of the texture analysis application. 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Knobology is a terminology that describes the manipulation of ultrasound knobs and system controls in order to obtain the best image possible from diagnostic ultrasound. The inadequate use of knobology variables may impair image quality and can result in misdiagnosis. In abdominal sonography, selecting the appropriate application preset for abdominal examination is first step towards achieving an optimum image. The next step is to select an appropriate transducer frequency which must take the size of the patient into account. Transducer frequency is typically in the range of 3–5 MHz, but a lower frequency may achieve better depth penetration in larger patients. While the output power may improve image quality by increasing the intensity of transmitted sound energy, the impact is usually insignificant. The practice of using high output power should therefore be limited because of the risk of biologic effect. 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RT might inadvertently induce heart injury and result in various forms of radiation-related heart disease (RRHD). The main endpoints of RRHD include cardiac death from RT, clinical heart disease (congestive heart disease, ischemic heart disease, and myocardial infarction), and subclinical heart disease (cardiac perfusion defects). Advanced RT techniques, such as breath control, intensity-modulated RT, and image-guided RT, as well as limited target volume definition might spare or avoid cardiac doses and/or volume, which may translate into decreased incidence of RRHD. The total delivered radiation dose to cardiac implantable electronic devices was strongly recommended not to exceed 2 Gy. The treatment strategies of RRHD were based on the various recommended consensus of related heart diseases in cardiology. However, the standardized definitions of the cardiac structures, dose-volume limits during radiation planning design, the optimal dose-volume parameters, and the dose-volume effects of various cardiac substructures warrant further investigation. 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The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. 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He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. Rosales-Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"437913",title:"Dr.",name:"Guillermo",middleName:null,surname:"Urriolagoitia-Sosa",slug:"guillermo-urriolagoitia-sosa",fullName:"Guillermo Urriolagoitia-Sosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"435126",title:"Prof.",name:"Joaquim",middleName:null,surname:"José de Castro Ferreira",slug:"joaquim-jose-de-castro-ferreira",fullName:"Joaquim José de Castro Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"437899",title:"MSc.",name:"Miguel Angel",middleName:null,surname:"Ángel Castillo-Martínez",slug:"miguel-angel-angel-castillo-martinez",fullName:"Miguel Angel Ángel Castillo-Martínez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"289955",title:"Dr.",name:"Raja",middleName:null,surname:"Kishor Duggirala",slug:"raja-kishor-duggirala",fullName:"Raja Kishor Duggirala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jawaharlal Nehru Technological University, Hyderabad",country:{name:"India"}}}]}},subseries:{item:{id:"5",type:"subseries",title:"Parasitic Infectious Diseases",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. 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