Open access peer-reviewed chapter

Pathogenesis of Insulin Resistance

Written By

Gaffar S. Zaman

Submitted: 05 November 2019 Reviewed: 18 May 2020 Published: 17 June 2020

DOI: 10.5772/intechopen.92864

From the Edited Volume

Cellular Metabolism and Related Disorders

Edited by Jesmine Khan and Po-Shiuan Hsieh

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Abstract

Insulin resistance is interpreted as being a normal or raised insulin level giving rise to a biological reaction which is attenuated in effect; classically this cites to the weakened sensitivity to the disposal of insulin arbitrate glucose. Compensatory hyperinsulinemia eventuates when the secretion of the β cells of pancreas gets elevated to sustain the level of blood glucose in normal levels. The term insulin resistance syndrome is used to refer to a group of abnormalities and interconnected physical consequences that eventuate in long-standing insulin-resistant persons. Under standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases. There are a number of risk factors for insulin resistance. Four major metabolic abnormalities characterize type 2 diabetes mellitus (T2DM): impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction. The evolution (and subsequent progression) of type 2 diabetes mellitus is delineated by a gradual deterioration of glucose tolerance over several years. Glucose tolerance testing, hyperinsulinemic euglycemic clamp, modified insulin suppression test, homeostatic model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI) method for insulin assessment are some of the methods by which insulin resistance can be measured. Moreover, longer-term effective researches as well are essential to preferably ascertain the significance of the glycemic index in the blood glucose regulation and to prevent the complications of diabetes, particularly in relations to insulin resistance risk factors. The possible role of insulin resistance in the glycemic index in depleting oxidative stress postprandially and related pro-inflammatory situations also merits further appraisal.

Keywords

  • insulin resistance
  • compensatory hyperinsulinemia
  • type 2 diabetes mellitus
  • obesity

1. Introduction

One of the most renowned hormones of our body is insulin which enables glucose to go inside the cells which additionally decreases blood glucose. The hormone insulin is secreted by the pancreas in response to glucose entering the bloodstream after a meal. Insulin resistance (IR) is contemplated as a pathological situation in which our body cells decline to react normally to insulin hormone [1]. To avert hyperglycemia and apparent damage to our body organs in the future [2], insulin production by the body starts when glucose enters into the bloodstream, predominantly from the dietary carbohydrate digestion and absorption. Under standard situations of insulin reactivity, the response of insulin triggers the intake of glucose into the body cells, for utilization as energy, and impedes the utilization of fat for energy, as a result of which, the concentration of glucose circulating in the blood decreases, which results in glucose remaining within the normal range in case of consumption of a substantial amount of carbohydrates. Carbohydrates contains sugars, i.e., from only one glucose containing monosaccharides, such as fructose and glucose; two glucose containing disaccharides, like cane sugar; and many glucose containing polysaccharides (e.g., starches) and glycoprotein, glycolipids, etc. Fructose, ultimately metabolized into triglycerides inside the liver, stimulates the production of insulin and is seen to have a more impressive sequel than other carbohydrates. A customarily increased intake of carbohydrates, and specifically fructose, imparts to insulin resistance and has been connected to gain of weight and obesity [3, 4, 5]. If surplus blood glucose is not adequately transported into the cells even in the insulin’s presence, the augmented level of blood glucose can elicit in the classic hyperglycemic triad of polydipsia (increased thirst), polyphagia (increased appetite), and polyuria (increased urination). Circumventing carbohydrates, a zero-carbohydrate diet or conditions of fasting can counteract insulin resistance [6, 7]. The first narration of insulin resistance is found historically in the 1960s, soon after the invention of radioimmunoassays helped in making serum insulin quantification possible and subsequently revealed that people having late-onset diabetes mellitus had high levels of insulin [8, 9]. Drs. Yalow and Berson [8, 9] defined insulin resistance as “a state in which a greater than normal amount of insulin is required to elicit a quantitatively normal response.” The next milestone discovery in this context was the detection and ascertaining of the insulin receptor and also the discovery that insulin resistance led to hyperinsulinemia and the fact that this was interconnected very much with atypical/unconventional binding of insulin hormone with its receptor in various rodent models [10, 11]. The succeeding milestone discovery in the history of insulin resistance came with the pioneering recognition of the receptor for insulin and the observation that high insulin in blood, secondary to the insulin resistance, was interconnected with atypical binding of insulin hormone to its receptor [10, 11]. It was not before the year 1976 when the evidence came that defects in receptor for insulin could be interlinked with resistance to the insulin hormone in humans, provided genetic translational verification for the significance of insulin resistance [10]. Researchers like Kahn et al. [10] delineated two syndromes that were distinguished by virilization, acanthosis nigricans, hirsutism, anovulation, acne, and flawed binding of insulin on the insulin receptor of lymphocytes circulating in the blood. This initial syndrome was designated as type A insulin resistance when it took place without the existence of anti-insulin antibodies and the corresponding accountability of the insulin receptor was the main factor, and in contrast it was designated as the type B when it occurred with the clinical characteristics of various autoimmune ailments and it always occurred when neutralizing anti-insulin antibodies were present [10]. After this specification of type A and type B syndrome, all rare and extreme levels of insulin resistance like acanthosis nigricans syndrome, hyperandrogenism, the Rabson-Mendenhall syndrome, lipodystrophy, and leprechaunism were discovered [12, 13]. To defend the idea by Himsworth that some cases of diabetes were not secondary to absolute insulin deficiency, it was imperative to prove the truth that insulin circulating in the blood was present in the insensitive form in those patients as classified by Himsworth. This was put to rest with the publication by Yalow and Berson in 1960 of an immunoassay research of endogenous blood insulin in humans. During this novel innovative work, Berson and Yalow delineated an excellent immunological technique for measuring the amount of insulin that integrated the degree of specificity with sensitivity required to take the measurement of even the smallest concentrations of insulin contained in the body circulation. Utilizing this novel technique to categorize immunoreactive insulin amounts present in plasma in normal people to those particular patients having maturity-onset type diabetes, it was conceived that the amounts of insulin were on the average elevated in the patients with diabetes. Putting stress on the rationale of these particular outcomes, both of them summarized that the tissues of a person with maturity-onset diabetes do not have a good response to the level of insulin; on the contrary, the tissues of a nondiabetic person respond very well to his level of insulin. In the words or terminology of Himsworth, patients with this character in diabetes can be considered as “insulin insensitive.” In spite of the fact these results of the novel publication by Yalow and Berson were afterwards authenticated by various research groups, it became evident that the interconnection between insulin concentrations and plasma glucose in patients having type 2 diabetes was not such a simple one. To be precise, in a person with comparatively slight increments of fasting plasma glucose concentration, the responses of plasma insulin to oral glucose were equivalent or prominently higher than the normal but with elevated proportions of glucose intolerance and with the appearance of noteworthy hyperglycemia during fasting [14, 15, 16, 17]. It was obligatory to evolve an exploratory perspective that would quantify in an unequivocal way the capability of an individual person to get rid of fixed glucose load under the influence of identical insulin stimuli during steady-state conditions [18].

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2. Risk factors for insulin resistance

A number of risk factors are found for insulin resistance, together with being overweight or obese or pursuing a sedentary lifestyle [19]. Numerous genetic constituents can elevate the chances for the same, and there are some particular medical circumstances correlated with insulin resistance [19].

The National Institute of Diabetes and Digestive and Kidney Diseases has specified several hazard factors:

  1. Age of 45 or more.

  2. Native Alaskan, Asian American, American Indian, African American, Native Hawaiian, or Latino/Hispanic ethnicity.

  3. Having abnormal health states such as increased systolic/diastolic pressure and increased levels of cholesterol.

  4. Having gestational diabetes history.

  5. Having a history stroke or heart disease [19].

  6. In addition, some medications and other health conditions can raise the risk [19].

2.1 Types of people more likely to develop insulin resistance

Individuals who have hereditary factors or lifestyle-related factors are bound to have in their later life insulin resistance or prediabetes [20]. Hazard factors incorporate:

  • Overweight or obesity.

  • Age 45 or more.

  • Having a parent, sibling, or sister with diabetes.

  • African American, Alaskan Native, American Indian, Asian American, Hispanic/Latino, Native Hawaiian, or Pacific Islander American ethnicity.

  • Physical idleness.

  • Health conditions, for example, hypertension and high cholesterol levels.

  • A history of gestational diabetes.

  • A history of coronary illness or stroke.

  • Polycystic ovary disorder, also known as PCOS.

  • Individuals who have metabolic disorder—hypertension, irregular cholesterol levels, and enormous waist size—are bound to have prediabetes.

  • Hormonal imbalances, for example, Cushing’s disorder and acromegaly.

  • Sleep issues, particularly rest apnea.

In spite of the fact that you cannot change hazard factors, for example, family ancestry, age, or ethnicity, you can change lifestyle factors such as eating, physical activity, and weight. These ways of life changes can bring down your odds of creating insulin resistance or prediabetes [21].

There are a number of other hazard factors that are firmly connected to insulin resistance; however, these factors are yet to give clear answers about how much these variables might be a reason for the same.

The variables include:

  • Abundance of fat

  • Having hypertension or hypercholesterolemia

  • Having a nearby relative with type 2 diabetes

  • History of gestational diabetes

  • Having potential to develop type 2 diabetes

2.2 Diet

The food that we take are regularly seen as a conspicuous reason for diabetes and frequently supposed as a reason.

Many studies have shown that our diet can have an effect in type 2 diabetes; however, it is one factor among numerous others, and speculations ought not be drawn without the thought of other contributing variables.

2.3 Contributions of genetics

Research has revealed various factors, which are related with an elevated danger of diabetes. There are various elements which can impact our plasma glucose, as well as taking into consideration where we disperse fat in our body and how efficiently our muscles allow glucose to enter from the blood.

It is a well-known fact that genes help control and regulate every metabolic activity in the body, and mutations, in genes, which have influence in the digestion and absorption process can cause problem with controlling blood glucose level. To date scientists have distinguished more than 60 genes related with type 2 diabetes mellitus (T2DM).

2.4 Medication

Corticosteroids treat mainly inflammatory disorders, as rheumatoid joint inflammation, lupus, and hypersensitivities. Normal steroids incorporate hydrocortisone and prednisone. Be that as it may, steroid creams (for a rash) or inhalers (for asthma) aren’t an issue.

Medications that treat nervousness, attention deficit hyperactivity disorder (ADHD), sorrow, and other emotional well-being issues can incorporate clozapine, olanzapine, risperidone, and quetiapine:

  • Contraception pills

  • Medications that treat hypertension, for example, beta-blockers and thiazide diuretics

  • Statins to bring down cholesterol

  • Adrenaline for serious hypersensitive responses

  • High doses of asthma medications or medications that you infuse for asthma treatment

  • Isotretinoin for skin breakout

  • Tacrolimus, which you get after an organ transplant

  • A few meds that treat human immunodeficiency virus (HIV) and hepatitis

  • Pseudoephedrine, a decongestant in some cold and influenza prescriptions

  • Niacin or vitamin B3

Alongside these hazard factors, different things that may add to insulin resistance incorporate:

  • Antihypertensive agents such as β-blockers, diuretics, oral contraceptives, corticosteroids, nicotinic acid, and antipsychotic agents are said to increase insulin resistance [22, 23]; in addition, many anti-retroviral protease inhibitors utilized to treat human immunodeficiency virus infection also cause insulin resistance. The mechanisms of actions vary: β-blockers impede the secretion of insulin from the pancreas by blocking the β-adrenoceptors, depletion of the blood levels of potassium is the main action of thiazide diuretics, counter-regulatory hormonal activity is the main action of oral contraceptives and corticosteroids, and loss of peripheral subcutaneous fat with partial lipodystrophy (with resultant accumulation of truncal adipose tissue) is the main action of HIV-1 protease inhibitors. All these ultimately lead to insulin resistance [24].

2.5 Lifestyle factors

Many hormones can instigate insulin resistance, prominent among them being human placental lactogen, growth hormone, and cortisol [25]. Counteraction of insulin is done by cortisol and can cause elevated hepatic gluconeogenesis, decreasing peripheral use of glucose and elevating insulin resistance [26]. Cortisol does this by diminishing the translocation of glucose transporters (especially GLUT4) to the respective cell membrane [27, 28]. This is based on the noteworthy augmentation in the sensitivity of insulin in humans after doing bariatric surgery and surgical removal of the duodenum in rats [29]; it has been speculated that some substance is manufactured in the mucosa of duodenum, which gives a signal to the body cells to become insulin resistant. With removal of the producing tissue, cessation of the signal occurs, and reverting back of the body cells to normal insulin sensitivity is seen. No such particular substance has been discovered as yet, and the certainty of such a substance remains speculative. Leptin is a hormone derived from the adipocytes and ob gene [30] whose role is the regulation of hunger by forewarning the body when it is full [31]. Researches have depicted that dearth of leptin leads to severe obesity and is intensely associated with insulin resistance [32].

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3. Pathogenesis

Four major metabolic abnormalities characterize type 2 diabetes mellitus: impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction [33, 34, 35]. In spite of the fact that there is considerable authentication that three of these idiosyncrasies exist in most people before the commencement of diabetes, the concatenation with which they evolve and their corresponding contributions to the advancement from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT), and ultimately to type 2 diabetes [36, 37, 38], cannot be confirmed for sure even though some detailed longitudinal studies have provided some information [39, 40, 41, 42, 43, 44]. Contemporaneous comprehension of the pathogenesis of type 2 diabetes is established on a wide-reaching number of cross-sectional [45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57] and prospective [58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72] studies. The evolution (and subsequent progress) of type 2 diabetes mellitus is delineated by a gradual degeneration of glucose tolerance over several years [33, 34, 35, 36, 37, 38]. Prospective and cross-sectional data demonstrate that defects in insulin secretion, body weight gain, insulin action, and an elevation in endogenous glucose output are cardinal in this decline [45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56]. The pathogenetic history of diabetes—the corporeal chain of events with which these metabolic aberrations evolve in relation to one another throughout the various stages of the illness—remains unrevealed. Many authors have suggested that a flaw in insulin activity is the principal aberration in the premature stages of the evolution of type 2 diabetes and that secretory dysfunction of insulin takes place only at a later stage.

3.1 Molecular mechanism of insulin resistance in the muscle

Cellular contents of lipids inside myocytes (of muscles) are referred to as intramyocellular lipid (IMCL) and basically reflect intramyocellular triglyceride content. Although IMCL emphatically relates with muscle insulin resistance in inactive people, triglycerides themselves have been disassociated from insulin resistance, recommending that other lipids (e.g., diacylglycerols, ceramides, and so on) intervene insulin resistance [73]. Various investigations have depicted the interrelationship insulin resistance in muscles and between diacylglycerol (DAG) content. Insulin-animated tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-1-related phospho-inositide 3-kinase (PI3K) actuation were intensely debilitated in skeletal muscle of lipid-injected people [74] and rodents [75, 76]. In rodents, lipids and high-fat intake bring about transient increments in muscle DAG content [75], bringing about continued appearance of protein kinase C-theta (PKCθ) that constrained phosphorylation of IRS-1 by insulin receptor substrate 1 (IRTK). Lipid mixtures in normal human volunteers correspondingly elevated skeletal muscle DAG [77, 78] and caused muscle insulin resistance. The improvement of muscle insulin resistance can prompt metabolic ailment. This has been seen in hereditary mouse models of particular muscle insulin resistance [79], which are inclined to hepatic steatosis [75] and increased adiposity [77]. In young, lean, and people with skeletal muscle insulin resistance, ingested glucose is not taken up by muscle and gets occupied to the liver, where it becomes substrate for liver once more by lipogenesis, increasing liver triglyceride; furthermore, plasma triglyceride increase results in decreasing plasma high-density lipoprotein (HDL) levels [80]. Nonalcoholic fatty liver disease (NAFLD) is unequivocally connected with hepatic insulin resistance. In patients with lipodystrophy, ectopic lipid accumulation in the liver and skeletal muscle was related with extreme hepatic and muscle insulin resistance [81]. Leptin treatment diminished the consumption of calorie, settled hepatic steatosis, and improved insulin activity [82]. Lipodystrophic mice have a comparable phenotype, and fat transplantation protected these mice by permitting redistribution of lipids from ectopic destinations to transplanted fat tissue and standardization of insulin activity [83]. Mice overexpressing lipoprotein lipase in the liver cause hepatic steatosis and liver-explicit insulin resistance [84]. In rodents and mice, high-fat eating regimens lead to hepatic steatosis and hepatic insulin resistance. In this way, these considerations show that ectopic lipid in the liver is explicitly related with hepatic insulin resistance. Magkos et al. showed that hepatic DAG content (not hepatic ceramide content) was the best indicator of hepatic insulin resistance in obese people [85]. There are a few conditions wherein hepatic steatosis shows up disassociated from hepatic insulin resistance. A typical single-nucleotide polymorphism (rs738409, I48M) in the lipid bead protein-like phospholipase domain-containing protein 3 [patatin-like phospholipase domain-containing A3 gene (PNPLA3), likewise called adiponutrin (ADPN)] has been related with expanded hepatic steatosis, but not insulin resistance [86, 87, 88]. Along these lines, occasions of obvious disassociation of hepatic steatosis and hepatic insulin opposition might be clarified by a superior comprehension of the subcellular conveyance of DAG [89]. Ceramides are additionally bioactive lipid particles that are embroiled in the advancement of insulin resistance. Increments in hepatic and muscle ceramide content have been related with insulin resistance in rodents, and inhibitors of ceramide blend can forestall insulin resistance [90, 91]. In any case, a disassociation between ceramide substance and tissue insulin resistance has been revealed in numerous investigations [85, 92, 93], and the fundamental component connecting ceramides to insulin resistance has not been completely finalized. As of late, some investigations analyzed how a particular ceramide species, C16:0, resists mitochondrial oxidation, permitting triglyceride to accumulate and cause insulin resistance [94, 95]. Despite the fact it has not been concluded, it is conceivable that the equal relationship between C16:0 ceramide and mitochondrial oxidation could additionally cause increments DAG and impede insulin action.

3.2 Insulin resistance in the adipose tissue

Some of the actions of insulin on adipose tissue are (1) stimulation of uptake of glucose and biosynthesis of triglyceride and (2) suppression of triglyceride hydrolysis-cum release of free fatty acids (FFA) and glycerol into the blood [96, 97]. It has been seen that adipose tissue insulin resistance (Adipo-IR), which means diminished suppression of lipolysis when high insulin levels are present, is interlinked with glucose intolerance, and increased plasma FFA amounts have also shown to diminish insulin signaling in muscles, endorse gluconeogenesis in the liver, and diminish glucose-activated insulin response [97, 98, 99, 100, 101, 102, 103]. In spite of the fact that the natural history and role of β-cell abnormality (or impairment) and insulin resistance in muscle are firmly established in the evolution of T2DM, the influence of Adipo-IR in the progression from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM) is still not clear. It is possible to quantitate palmitate turnover by the utilization of tracers [104, 105, 106] which can also provide the release rate of glycerol [107, 108] to furnish a lipolysis index. Tracer turnover (i.e., labeled palmitate or glycerol) or FFA suppression during insulin infusion (euglycemic-hyperinsulinemic clamp) or oral glucose tolerance test (OGTT) has led to the development of a number of indices of Adipo-IR [109]. Gastaldelli et al. [104] confirmed that fasting Adipo-IR index can be considered as a reliable index of insulin resistance in the fat cell when considered over the entire spectrum from NGT to T2DM. There has been consistent demonstration of weakened suppression of plasma FFA and also glycerol and 14C-palmitate turnover with the stepped hyperinsulinemic clamp [106, 110, 111] (i.e., adipocyte insulin resistance) in persons having T2DM. Therefore a decline in insulin secretion/insulin resistance (disposition) index has been seen with progression from lean NGT to obese NGT to IGT [112]. A decline in the secretion from β-cell of insulin is also interlinked with an elevation in the fasting Adipo-IR. Therefore, it can be said that the fasting adipocyte insulin resistance index (fasting FFA × fasting insulin) increases in a forward-looking, innovative manner over the stretch of glucose tolerance, extending from NGT to T2DM, and furnishes a reliable index of fat cell sensitivity to the actions of insulin [113, 114, 115]. In contradiction, there is increment of adipocyte insulin resistance index during OGTT (from NGT to IGT) and decrease with advancement of IGT to T2DM; this is due to gradual deficiency of the secretion of insulin in this group having diabetes. In conclusion, the gradual decrease in β-cell function that progresses from NGT is interlinked with a gradual elevation in fasting Adipo-IR and FFA [104].

Fat insulin resistance is the failure of insulin to activate fat glucose transport, advance lipid take-up, and diminish lipolysis. While diminished fat glucose take-up is exhibited in both in vivo and in vitro models, metabolic effect of hindered insulin-intervened glucose take-up in fat tissue is not well explained. For instance, the loss of fat GLUT4 in mice does not modify adiposity or, on the other hand, how weight gain prompts insulin resistance in skeletal muscle and liver [116]. Glucose transport into fat cells initiates starch reaction component restricting protein (ChREBP), which may affect fat lipid digestion [117]. Adipocytes discharge explicit unsaturated fats that are related with increased insulin affectability, as palmitoleate [118, 119] or monomethyl chain unsaturated fats [120].

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4. Methods for diagnosis

4.1 Fasting insulin levels

A fasting serum insulin amount of more than 25 mU/L or in other sense 174 pmol/L designates insulin resistance. The same amounts pertain to 3 hours after taking the last meal [121].

4.2 Glucose tolerance testing

While performing a glucose tolerance test (GTT), a patient who is fasting is given a 75 g of glucose orally. Then plasma glucose levels are continuously monitored (along with urine glucose) for a period of 2 hours.

The elucidation of the test is established on the guidelines of the World Health Organization (WHO). After a period of 2 hours, a plasma glucose amount of less than 7.8 mmol/L (140 mg/dL) is regarded as normal, and a plasma glucose amount of between 7.8 and 11.0 mmol/L (140 to 197 mg/dL) is regarded as impaired glucose tolerance (IGT), and a plasma glucose amount of greater than or equal to 11.1 mmol/L (200 mg/dL) is regarded as diabetes mellitus. Extension of the testing (for several more hours) may reveal a hypoglycemic “dip” that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

4.3 Using the hyperinsulinemic euglycemic clamp

“Hyperinsulinemic euglycemic clamp” is also known as the gold standard for investigating and quantifying insulin resistance. It is so-called because it calculates the level of glucose obligatory to reimburse for an elevated insulin level without giving rise to hypoglycemia [122]. It is a kind of glucose clamping technique. The test is seldom carried out in clinical settings but is utilized in medical research [123]. The process takes around 2 hours. Insulin is infused through a peripheral vein. The rate is of infusion is 10–120 mU per m2/minute. With the intention to recompense for the infusion of insulin, 20% glucose is infused to sustain blood glucose levels between 5 and 5.5 mmol/L. The blood sugar levels every 5 to 10 minutes, to determine the rate of infusion of glucose [123]. The determination of insulin sensitivity is made by the rate of glucose infusion in the last 30 minutes of the test. If greater levels (7.5 mg/min or greater) are required, the patient is considered as insulin sensitive. Low levels such as 4.0 mg/min or lower than that designates that the body is resistant to actions of insulin. Levels between 4.0 and 7.5 mg/min are not conclusive and indicate “impaired glucose tolerance,” which is a premature gesticulation of insulin resistance [123, 127]. This basic method may be modified significantly by the utilization of glucose tracers.

4.4 Modified insulin suppression test

Gerald Reaven developed the modified insulin suppression test at Stanford University. The test corresponds well with the euglycemic clamp, with minute operator-dependent error. Particularly, this test has been utilized in research correlating to the metabolic syndrome [123]. A 25 μg of octreotide (Sandostatin) is given to the patient in 5 mL of normal saline over a period of 3–5 minutes through intravenous infusion (IV) as a primary bolus. Subsequently, the patient is continuously infused with an IV infusion of somatostatin (0.27 μg/m2/min) to repress internal glucose and insulin secretion. Next, 20% glucose and insulin are infused at varying rates of 32 and 267 mg/m2/min. Plasma glucose is monitored at 0, 30, 60, 90 minutes, and lastly at 120 minutes and subsequently after each 10 minutes for the final 30 minutes of the study. The averages of these final four values are utilized to ascertain the steady-state plasma glucose level (SSPG). People having an SSPG greater than 150 mg/dL are contemplated to have insulin resistance [45].

4.5 Homeostatic model assessment (HOMA)

By this method it is possible to quantify insulin resistance. Also, pancreatic beta-cell function can be possibly elucidated:

HOMAIR=Glucose×Insulin22.5E1

and

HOMAβ=20×InsulinGlucose3.5%E2

where glucose is in mmol/L.

Also,

HOMAIR=Glucose×Insulin%405E3

and

HOMAβ=360×Insulin%Glucose63E4

where glucose is in mg/dL.

Note: insulin is taken in μU/mL; both glucose and insulin are taken during fasting; IR means insulin resistance; HOMA-β is the percentage of beta cell function [124, 125, 126, 127, 128].

4.6 Quantitative insulin sensitivity check index (QUICKI) method for insulin assessment

QUICKI is obtained utilizing the inverse of the addition of the logarithms of the fasting insulin and fasting glucose:

1/logfasting insulinμU/mL+logfasting glucosemg/dLE5

The QUICKI method corresponds well with glucose clamp researches (r = 0.78) and is very good for the measurement of insulin sensitivity (IS), which is derived by utilizing the reciprocal quantity of insulin resistance (IR).

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5. Conclusions

From the time insulin resistance was discovered, the cellular and molecular mechanisms were the considerations for which drugs were tried for diabetes mellitus. Considering the cellular mechanisms of insulin resistance which are mostly concerned with plasma cell membrane glycoprotein-1 (PC-1), also termed as ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), the mechanism is really complex. The full understanding of the cellular mechanisms will permit the development of novel targets for various treatment modalities. From the therapeutic point of view, we need to have a clear knowledge about the cellular mechanism of insulin resistance in order to treat and also to prevent the occurrence of diabetes from prediabetic stage. From recent studies, it is evident that insulin resistance can be stopped or reversed if the pathophysiology is clear. It is the necessity to implement a huge global strategic plan for identifying and preventing/treatment of insulin resistance in the prediabetic stage.

References

  1. 1. Wang G. Raison d’etre of insulin resistance: The adjustable threshold hypothesis. Journal of the Royal Society. 2014;11(101):20140892. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223910
  2. 2. Diagnosis and Classification of Diabetes Mellitus. American Diabetes Association Diabetes Care. Jan 2014;37(Suppl 1):S81-S90. DOI: 10.2337/dc14-s081
  3. 3. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutrition and Metabolism. 2005;2(1):5. DOI: 10.1186/1743-7075-2-5
  4. 4. Hu F. Obesity Epidemiology. New York: Oxford University Press, Inc.; 2008. pp. 283-285. ISBN: 978-0-19-971847-4. Available from: https://books.google.com/books?id=rv42OY9QLkMC&pg=PA283 [Accessed: 20 April 2013]
  5. 5. Smith TA, Biing-Hwan L, Jonq-Ying L. Taxing Caloric Sweetened Beverages: Potential Effects on Beverage Consumption, Calorie Intake, and Obesity, ERR-100. U.S. Department of Agriculture, Economic Research Service. July 2010
  6. 6. Gallagher J. Fasting Diet ‘Regenerates Diabetic Pancreas’ (Health and Science Reporter, BBC News Website). BBC. 2017. Available from: https://www.bbc.com/news/health-39070183 [Accessed: 06 August 2018]
  7. 7. Sakzewski E. Fasting Diet Could Regenerate Pancreas and Reverse Diabetes, Researchers Say. ABC. 2017. Available from: http://www.abc.net.au/news/2017-02-26/fasting-diet-could-reverse-diabetes-and-regenerate-the-pancreas/8304426 [Accessed: 06 August 2018]
  8. 8. Yalow RS, Berson SA. Immunoassay of endogenous plasma insulin in man. The Journal of Clinical Investigation. 1960;39:1157-1175
  9. 9. Yalow RS, Berson SA. Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immuno-assay technic. Diabetes. 1960;9:254-260
  10. 10. Kahn CR, Neville DM Jr, Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. The Journal of Biological Chemistry. 1973;248:244-250
  11. 11. Goldfine ID, Kahn CR, Neville DM Jr, Roth J, Garrison MM, Bates RW. Decreased binding of insulin to its receptors in rats with hormone induced insulin resistance. Biochemical and Biophysical Research Communications. 1973;53:852-857
  12. 12. Mantzoros CS, Flier JS. Insulin resistance: The clinical spectrum. Advances in Endocrinology and Metabolism. 1995;6:193-232
  13. 13. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: Pathophysiology and advances in treatment. Nature Reviews. Endocrinology. 2011;7:137-150
  14. 14. Buchanan KD, McKiddie MT. Factors determining the plasmainsulin response to oral glucose in diabetes mellitus. Diabetes. 1967;16:466-471
  15. 15. Chiles R, Tzagournis M. Excessive serum insulin response to oral glucose in obesity and mild diabetes. Diabetes. 1970;19:458-464
  16. 16. Hales CN, Randle PJ. Effects of low-carbohydrate diet and diabetes mellitus on plasma concentrations of glucose, non-esterified fatty acids, and insulin during oral glucose tolerance. Lancet. 1963;1:790-794
  17. 17. Reaven GM, Miller R. Study of the relationship between glucose and insulin responses to an oral glucose load in man. Diabetes. 1968;17:560-569
  18. 18. Shen S-W, Reaven GM, Farquhar JW. Comparison of impedance to insulin-mediated glucose uptake in normal subjects and diabetic subjects and in subjects with latent diabetes. The Journal of Clinical Investigation. 1970;49:2151-2160
  19. 19. Insulin Resistance & Prediabetes. National Institute of Diabetes and Digestive and Kidney Diseases; 2018. Available from: https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance
  20. 20. Available from: https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes/prediabetes-insulin-resistance
  21. 21. Available from: https://www.diabetes.co.uk/causes-of-type2-diabetes.html
  22. 22. Bressler P, De Fronzo RA. In: Alberti KGMM, Zimmet P, Defronzo RA, Keen H, editors. International Textbook of Diabetes Mellitus (2nd ed). New York: John Wiley & Sons; 1997. p. 213-254
  23. 23. Ananth J, Parameswaran S, Gunatilake S. Side effects of atypical antipsychotic drugs. Current Pharmaceutical Design. 2004;10:2219-2229
  24. 24. Chen D, Misra A, Garg A. Lipodystrophy in human immunodeficiency virus-infected patients. The Journal of Clinical Endocrinology and Metabolism. 2002;87:4845-4856
  25. 25. Newbern D, Freemark M. Placental hormones and the control of maternal metabolism and fetal growth. Current Opinion in Endocrinology, Diabetes, and Obesity. 2011;18(6):409-416. DOI: 10.1097/MED.0b013e32834c800d
  26. 26. Brown TA, Bracken SJ. USMLE Step 1 Secrets in Color 4th Edition. Saunders; 3 edition (September 6, 2012). ISBN-10: 0323085148
  27. 27. King MW. Lange Q&A USMLE Step 1. 6th ed. New York: McGraw-Hill Medical; 2005. p. 82. ISBN: 978-0-07-144578-8
  28. 28. Piroli GG, Grillo CA, Reznikov LR, Adams S, McEwen BS, Charron MJ, et al. Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology. 2007;85(2):71-80. DOI: 10.1159/000101694
  29. 29. Garrido-Sanchez L, Murri M, Rivas-Becerra J, Ocaña-Wilhelmi L, Cohen RV, Garcia-Fuentes E, et al. Bypass of the duodenum improves insulin resistance much more rapidly than sleeve gastrectomy. Surgery for Obesity and Related Diseases. 2012;8(2):145-150. DOI: 10.1016/j.soard.2011.03.010
  30. 30. Friedman JM. Obesity in the new millennium. Nature. 2000;404(6778):632-634. DOI: 10.1038/35007504
  31. 31. Flier JS. Clinical review 94: What’s in a name? In search of leptin’s physiologic role. The Journal of Clinical Endocrinology and Metabolism. 1998;83(5):1407-1413. DOI: 10.1210/jcem.83.5.4779
  32. 32. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. Unraveling the central nervous system pathways underlying responses to leptin. Nature Neuroscience. 1998;1(6):445-450. DOI: 10.1038/2164
  33. 33. Weir GC, Leahy JL. Pathogenesis of non-insulin-dependent (type II) diabetes mellitus. In: Kahn CR, Weir GE, editors. Joslin’s Diabetes Mellitus. 13th ed. Philadelphia, PA: Lea & Febiger; 1994. pp. 240-264
  34. 34. Bogardus C. Metabolic abnormalities in the development of noninsulin-dependent diabetes mellitus. In: LeRoith D, Taylor SI, Olefski JM, editors. Diabetes Mellitus. Vol. 459. Philadelphia, PA: Lippincot-Raven Publishers; 1996
  35. 35. DeFronzo RA. Lilly Lecture 1987. The triumvirate: B-cell, muscle, liver. A collision responsible for NIDDM. Diabetes. 1988;37:667-687
  36. 36. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-1057
  37. 37. World Health Organization. Diabetes mellitus: Report of a WHO Study Group. In: World Health Organization Technical Report Series. Vol. 17. 1985. p. 45. Available from: https://apps.who.int/iris/handle/10665/39592
  38. 38. American Diabetes Association. Report of an expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1998;21(Suppl. 1):S5-S19
  39. 39. Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607
  40. 40. DeFronzo RA. Pathogenesis of type 2 diabetes: Metabolic and molecular implications for identifying diabetes genes. Diabetes Reviews. 1997;5:177-269
  41. 41. DeFronzo RA, Bonadonna RC, Ferrannini E. The pathogenesis of NIDDM. A balanced overview. Diabetes Care. 1992;15:318-368
  42. 42. Groop LC, Widen E, Ferrannini E. Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus: Errors of metabolism or of methods? Diabetologia. 1993;36:1326-1331
  43. 43. Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes. 1994;43:735-740
  44. 44. Ferrannini E. Insulin resistance vs. insulin deficiency in noninsulin-dependent diabetes mellitus: Problems and prospects. Endocrine Reviews. 1998;19:477-490
  45. 45. Reaven GM, Olefsky JM. Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects and patients with chemical diabetes. Diabetologia. 1977;13:201-206
  46. 46. Reaven GM, Hollenbeck CB, Chen YDI. Relationship between glucose tolerance, insulin secretion, and insulin action in nonobese individuals with varying degrees of glucose tolerance. Diabetologia. 1989;32:52-55
  47. 47. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott DM. Relationships between insulin secretion, insulin action and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. The Journal of Clinical Investigation. 1984;74:1238-1246
  48. 48. Cerasi E, Luft R, Efendic S. Decreased sensitivity of the pancreatic beta cells to glucose in prediabetic and diabetic subjects. A glucose dose-response study. Diabetes. 1972;21:224-234
  49. 49. Eriksson J et al. Early metabolic defects in persons at increased risk for non-insulin dependent diabetes mellitus. The New England Journal of Medicine. 1989;321:337-343
  50. 50. Pimenta W et al. Insulin secretion and insulin deficiency in people with impaired glucose tolerance. Diabetic Medicine. 1996;13:S33-S36
  51. 51. Yoneda H et al. Analysis of early-phase insulin responses in nonobese subjects with mild glucose intolerance. Diabetes Care. 1992;15:1517-1521
  52. 52. O’Rahilly SP et al. Beta-cell dysfunction, rather than insulin insensitivity, is the primary defect in familial type 2 diabetes. Lancet. 1986;2:360-364
  53. 53. Kosaka K, Kuzuya T, Hagura R, Yoshinaga H. Insulin response to oral glucose load is consistently decreased in established non-insulin dependent diabetes mellitus: The usefulness of decreased early insulin response as a predictor of diabetes mellitus. Diabetic Medicine. 1996;13:S109-S119
  54. 54. Pimenta W et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. Journal of the American Medical Association. 1995;273:1855-1861
  55. 55. Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents. A cross-sectional study. Diabetes. 1997;46:1001-1009
  56. 56. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes. 1992;41:1575-1586
  57. 57. Zimmet P, Whitehouse S, Alford F, Chisholm D. The relationship of insulin response to a glucose stimulus over a wide range of glucose tolerance. Diabetologia. 1978;15:23-27
  58. 58. Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. Diabetologia. 1996;39:1201-1207
  59. 59. Wilson PW, McGee DL, Kannel WB. Obesity, very low density lipoproteins, and glucose intolerance over 14 years. The Framingham Study. American Journal of Epidemiology. 1981;114:697-704
  60. 60. Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetes mellitus in the Pima Indians: Incidence, risk factors and pathogenesis. Diabetes/Metabolism Reviews. 1990;6:1-27
  61. 61. Ohlson LD et al. The influence of body fat distribution on the incidence of diabetes mellitus. 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes. 1985;34:1055-1058
  62. 62. Lillioja S et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin dependent diabetes mellitus. Prospective studies of Pima Indians. The New England Journal of Medicine. 1993;329:1988-1992
  63. 63. Martin BC et al. Role of glucose and insulin resistance in development of type 2 diabetes. Results of a 25-year follow-up study. Lancet. 1992;340:925-929
  64. 64. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type 2 diabetes in the offspring of diabetic parents. Annals of Internal Medicine. 1990;113:909-915
  65. 65. Saad MF et al. A two-step model for development of non-insulin dependent diabetes mellitus. The American Journal of Medicine. 1991;90:229-235
  66. 66. Charles MA et al. Risk factors for NIDDM in white population: Paris prospective study. Diabetes. 1991;40:796-799
  67. 67. Chen KW et al. Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM. Diabetes Care. 1995;18:747-753
  68. 68. Nagi DK et al. Early and late insulin response as predictors of NIDDM in Pima Indians with impaired glucose tolerance. Diabetologia. 1995;38:187-192
  69. 69. Warram JH, Sigal RJ, Martin BC, Krolewski AS, Soeldner JS. Natural history of impaired glucose tolerance: Follow-up at Joslin Clinic. Diabetic Medicine. 1996;13:S40-S45
  70. 70. Efendic S, Luft R, Wajngot A. Aspects of the pathogenesis of type 2 diabetes. Endocrine Reviews. 1984;5:395-410
  71. 71. Lundgren H, Bengtsson C, Blohme G, Lapidus L, Waldenstroem J. Fasting serum insulin concentration and early insulin response as risk determinants for developing diabetes. Diabetic Medicine. 1990;7:407-413
  72. 72. Kadowaki T et al. Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia. 1984;26:44-49
  73. 73. Yu C et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity muscle. The Journal of Biological Chemistry. 2002;277(52):50230-50236
  74. 74. Dresner A et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. The Journal of Clinical Investigation. 1999;103(2):253-259
  75. 75. Yu C et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. The Journal of Biological Chemistry. 2002;277(52):50230-50236
  76. 76. Griffin ME et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signalling cascade. Diabetes. 1999;48(6):1270-1274
  77. 77. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes. 2002;51(7):2005-2011
  78. 78. Szendroedi J et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(26):9597-9602
  79. 79. Kim JK et al. Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. The Journal of Clinical Investigation. 2001;108(1):153-160
  80. 80. Petersen KF et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(31):12587-12594
  81. 81. Petersen KF et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. The Journal of Clinical Investigation. 2002;109(10):1345-1350
  82. 82. Petersen KF et al. Leptin reverses insulin resistance and hepatic steatosis in patient with severe lipodystrophy. The Journal of Clinical Investigation. 2002;109(10):1465-1474
  83. 83. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. The Journal of Biological Chemistry. 2000;275(12):8456-8460
  84. 84. Kim JK et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(13):7522-7527
  85. 85. Magkos F et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology. 2012;142(7):1444-1446
  86. 86. Romeo S et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics. 2008;40(12):1461-1465
  87. 87. Smagris E et al. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology. 2015;61(1):108-118
  88. 88. Peter A et al. PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans. Diabetologia. 2014;57(10):2103-2107
  89. 89. Coate KC et al. Hepatic glucose uptake and disposition during short-term high-fat vs. high fructose feeding. American Journal of Physiology. Endocrinology and Metabolism. 2014;307(2):E151-E160
  90. 90. Holland WL et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated fat-, and obesity-induced insulin resistance. Cell Metabolism. 2007;5(3):167-179
  91. 91. Ussher JR et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes. 2010;59(10):2453-2464
  92. 92. Kumashiro N et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(39):16381-16385
  93. 93. Perry RJ et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metabolism. 2013;18(5):740-748
  94. 94. Raichur S et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metabolism. 2014;20(4):687-695
  95. 95. Turpin SM et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metabolism. 2014;20(4):678-686
  96. 96. Saponaro C, Gaggini M, Carli F, Gastaldelli A. The subtle balance between lipolysis and lipogenesis: A critical point in metabolic homeostasis. Nutrients. 2015;7:9453-9474
  97. 97. Boden G. Obesity and free fatty acids. Endocrinology and Metabolism Clinics of North America. 2008;37:635-646
  98. 98. Allister CA, Liu LF, Lamendola CA, et al. In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans. Journal of Lipid Research. 2015;56:435-439
  99. 99. Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. The Journal of Clinical Investigation. 1996;97:2859-2865
  100. 100. Belfort R, Mandarino L, Kashyap S, et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005;54:1640-1648
  101. 101. Kashyap S, Belfort R, Gastaldelli A, et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52:2461-2474
  102. 102. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. The Journal of Clinical Investigation. 1983;72:1737-1747
  103. 103. Roden M, Stingl H, Chandramouli V, et al. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes. 2000;49:701-707
  104. 104. Gastaldelli A, Gaggini M, DeFronzo RA. Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: Results from the San Antonio Metabolism Study. Diabetes. Apr 2017;66(4):815-822. DOI: 10.2337/db16-1167
  105. 105. Fabbrini E, Magkos F, Conte C, et al. Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects. Journal of Lipid Research. 2012;53:321-324
  106. 106. Groop LC, Bonadonna RC, DelPrato S, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. The Journal of Clinical Investigation. 1989;84:205-213
  107. 107. Robinson C, Tamborlane WV, Maggs DG, et al. Effect of insulin on glycerol production in obese adolescents. The American Journal of Physiology. 1998;274:E737-E743
  108. 108. Gastaldelli A, Casolaro A, Ciociaro D, et al. Decreased whole body lipolysis as a mechanism of the lipid-lowering effect of pioglitazone in type 2 diabetic patients. American Journal of Physiology. Endocrinology and Metabolism. 2009;297:E225-E230
  109. 109. Sondergaard E, Jensen MD. Quantification of adipose tissue insulin sensitivity. Journal of Investigative Medicine. 2016;64:989-991
  110. 110. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: Time for a re-evaluation. Diabetes. 2011;60:2441-2449
  111. 111. Jensen MD, Nielsen S. Insulin dose response analysis of free fatty acid kinetics. Metabolism. 2007;56:68-76
  112. 112. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA, San Antonio Metabolism Study. Beta-cell dysfunction and glucose intolerance: Results from the San Antonio Metabolism (SAM) study. Diabetologia. 2004;47:31-39
  113. 113. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795
  114. 114. Ferrannini E, Natali A, Muscelli E, et al. Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: The RISC Study. Diabetologia. 2011;54:1507-1516
  115. 115. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet. 2014;383:1068-1083
  116. 116. Abel ED et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001;409(6821):729-733
  117. 117. Herman MA et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature. 2012;484(7394):333-338
  118. 118. Stefan N et al. Circulating palmitoleate strongly and independently predicts insulin sensitivity in humans. Diabetes Care. 2010;33(2):405-407
  119. 119. Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134(6):933-944
  120. 120. Su X et al. Adipose tissue monomethyl branched chain fatty acids and insulin sensitivity: Effects of obesity and weight loss. Obesity (Silver Spring). 2015;23(2):329-334
  121. 121. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. The American Journal of Physiology. 1979;237(3):E214-E223. DOI: 10.1152/ajpendo.1979.237.3.e214
  122. 122. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: Advantages, limitations, and appropriate usage. American Journal of Physiology. Endocrinology and Metabolism. 2008;294(1):E15-E26. DOI: 10.1152/ajpendo.00645.2007
  123. 123. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419. DOI: 10.1007/BF00280883
  124. 124. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27(6):1487-1495. DOI: 10.2337/diacare.27.6.1487
  125. 125. Singh B, Saxena A. Surrogate markers of insulin resistance: A review. World Journal of Diabetes. 2010;1(2):36-47. DOI: 10.4239/wjd.v1.i2.36. PMC 3083884
  126. 126. Hermans MP, Levy JC, Morris RJ, Turner RC. Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes. Diabetes. 1999;48(9):1779-1786. DOI: 10.2337/diabetes.48.9.1779
  127. 127. Hermans MP, Levy JC, Morris RJ, Turner RC. Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes. Diabetologia. 1999;42(6):678-687. DOI: 10.1007/s001250051215
  128. 128. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans. The Journal of Clinical Endocrinology and Metabolism. 2000;85(7):2402-2410

Written By

Gaffar S. Zaman

Submitted: 05 November 2019 Reviewed: 18 May 2020 Published: 17 June 2020