Causes of hypoglycemia in diabetic patients.
Abstract
Blood glucose levels may vary during the day, when this variation goes below a specific limit, hypoglycemia occurs. Hypoglycemia is often associated with reductions in quality of life and even the risk of death. Moreover, hypoglycemia is correlated with physical and/or psychological morbidity. It is usually a result of the complex interaction between hyperinsulinemia and the compromised physiological and behavioral responses attempting to reduce glucose levels. Nevertheless, several conditions can cause hypoglycemia, both in diabetic and non-diabetic patients. Mutually, diabetic and non-diabetic hypoglycemia is common in terms of several medications, alcohol ingestion, critical illnesses, and non-B cell tumors.
Keywords
- hypoglycemia
- diabetes
- drug-induced hypoglycemia
- nondiabetic hypoglycemia
1. Introduction
Glucose is the main source of energy for your body and brain. It can be synthesized de novo or taken from food. Insulin helps to keep blood glucose at normal levels, so your body can work efficiently. Insulin’s task is to help glucose to enter your cells and produce energy. If your glucose level is too low, hypoglycemia may occur [1].
Hypoglycemia is defined as a low plasma glucose level of less than 50 mg/dL, thus exposing the subject to potential harm. It is associated with several signs—palpitation, sweating, tremors (adrenergic response), dysarthria, confusion, epilepsy, visual disturbances, and coma (neuroglycopenic response) [2, 3, 4]. These affect patients’ quality of life and can even increase the risk of death, particularly in diabetic patients. Furthermore, hypoglycemia is often associated with physical and psychological morbidity (such as generalized worry and mood disturbance) [3, 5]. In diabetic patients, the complex interaction between hyperinsulinemia and the compromised physiological and behavioral responses to reduced glucose levels can lead to hypoglycemia [6].
Diabetes—particularly with the use of insulin or sulfonylurea, that is, insulin secretagogue treatment, is the classical cause of hypoglycemia. Moreover, diverse causes are also common, such as medications, alcoholism, critical illness, cachectic state, cortisol insufficiency, gastric or bariatric surgery, pancreas transplantation, glucagon deficiency, dietary toxins, and various conditions (sepsis, starvation, severe excessive exercise), and insulinoma [3, 7, 8]. Not to mention the non-classical causes that may include congenital hyperinsulinism, insulin receptor mutation, inborn errors of metabolism, and non-islet-cell tumor [9].
The primary cause of hypoglycemia is a complex interaction between hyperinsulinemia and compromised physiologic and behavioral responses to reducing glucose levels (Figure 1).
2. Diabetic hypoglycemia
Diabetic hypoglycemia is both a physiologic and a clinical condition that is associated with increased mortality and morbidity in both type 1 and type 2 diabetes. Hypoglycemia has proven to have detrimental complications for diabetic patients in both the short and long term [10]. There are several causes of hypoglycemia in diabetic patients, including age, renal insufficiency or end-stage renal disease, pregnancy, and polypharmacy of diabetic medications [10, 11], as shown in (Table 1).
Drugs Insulin or insulin secretagogue Alcohol ACEi Β-blockers NSAIDs Antimalarials Antibiotics (ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin, antiarrhythmics (like quinine, quinidine)) Psychotropic medications | Insulin related causes Absolute insulin excess Relative insulin excess
|
Malabsorption Celiac disease Pancreatic exocrine insufficiency | Diabetes complications Gastroparesis Neuropathy |
Hormone deficiency Cortisol Growth hormone Glucagon Epinephrine Hypopituitarism | Concurrent illness Renal disease Hepatic disease Cardiac failure Sepsis |
Non-islet cell tumor | Psychological Fear of hypoglycemia Depression Cognitive impairment |
2.1 Etiology
2.1.1 Drug induced
As mentioned before, hypoglycemia is well known to be associated with diabetes. The risk of hypoglycemia is manifested as a limiting factor and a barrier to optimal treatment and glucose control of type 1 and type 2 diabetes. Although the risk of hypoglycemia is more common in type 1 diabetes, it is prominent in type 2 diabetes with the use of an insulin secretagogue (such as sulfonylurea and glinides) and insulin [6, 10, 12]. Other types of antidiabetic medications have a low incidence of hypoglycemia.
Drug-induced hypoglycemia is not limited to antidiabetic medication use; other medications can also induce hypoglycemia. The most common non-antihyperglycemic medications that are correlated with hypoglycemia are angiotensin-converting enzyme inhibitors (ACEi), beta-blockers (BB), non-steroidal anti-inflammatory drugs (NSAIDs), antimalarials, antiarrhythmics (such as quinine and quinidine), psychotropic medications antibiotics, for example, (cotrimoxazole, ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin). In addition, Clarithromycin has also been implicated in many hypoglycemia cases, and the risk of hypoglycemia is exceptionally high in the concomitant use of repaglinide [3, 11, 13]. A systematic review conducted in 2008 and included 448 references assessed 164 drugs associated with hypoglycemia [14], the most commonly mentioned drugs to be linked with hypoglycemia were—quinolones, pentamidine, quinine, beta-blockers, angiotensin-converting enzyme inhibitors (ACEI), and IGF.
2.1.2 Insulin-related causes
2.1.2.1 Absolute insulin excess
Both absolute and relative insulin excess is a major cause of hypoglycemia. Absolute insulin excess occurs due to excessive insulin doses, wrong time of injection, wrong insulin type, and decreased insulin clearance as in renal failure and ill-timed. Therefore, the antidiabetic regimen should be adjusted according to a review of blood glucose patterns. In addition, understanding the pharmacokinetic profile of different types of insulin is a key to dosing insulin safely [6, 8, 10, 15].
2.1.2.2 Relative insulin excess
The relative insulin excess occurs due to:
Decreased exogenous glucose delivery
The risk of hypoglycemia is increased during overnight fasting and with exercise. A new exercise routine, duration, intensity, and inadequate energy intake can increase insulin sensitivity and glucose utilization. The glucose utilization/insulin dose mismatch can increase the risk of hypoglycemia. It is worth mentioning that insulin doses on days of planned exercise should be well-controlled. Patients need to associate the meal with inulin injection and need to understand how the carbohydrates in their diet affect blood glucose [9, 12, 16]. Inherently, delayed meals, inadequate carbohydrate intake, and skipping meals or snacks can increase the risk of hypoglycemia [17].
Increased insulin sensitivity
The body’s insulin sensitivity following weight loss or improved glycemic control often increases during midnight [6, 8].
Decreased endogenous glucose production
The effects of alcohol on blood glucose levels depend on the amount of alcohol consumption and the fed status of the individual. Acute alcohol intake after a fasting state (3–4 days) can induce severe hypoglycemia even in a healthy individual. Alcohol intake has an inhibitory effect on gluconeogenesis [13].
2.1.3 Diabetic complications (gastroparesis, neuropathy)
Gastroparesis, that is, delayed gastric emptying, is common autonomic neuropathy in patients with long-standing diabetes. It results in poor glycemic control and poor nutrition, and dehydration, resulting in frequent hypoglycemia episodes, hospitalizations, and poor quality of life [18, 19]. Neuropathy is also associated with hypoglycemia, particularly hypoglycemia-associated autonomic failure (HAAF). HAAF is a situation in which there is an absence or reduction of insulin secretion, enhancement of glucagon secretion, and/or a defective glucose counter-regulation by epinephrine. These factors induce hypoglycemia by reducing sympathetic neural activity and neurogenic symptoms [20].
2.1.4 Malabsorption (Celiac disease, pancreatic exocrine insufficiency)
Celiac disease is a chronic autoimmune disorder that destructs the small intestine, so the patient is unable to take nutrients in. It is prevalent in type 1 diabetes and causes episodes of hypoglycemia. Pancreatic exocrine insufficiency, which is characterized by a deficiency of exocrine pancreatic enzymes, is also associated with type I and II diabetes.
2.1.5 Hormone deficiency (cortisol, growth hormone, hypopituitarism, glucagon, and epinephrine deficiency in insulin-deficient diabetes)
The hormonal deficiency was found to be associated with hypoglycemia. Cortisol and growth hormone deficiencies, for instance, cause a reduction in gluconeogenesis and increased glucose utilization leading to hypoglycemia. Moreover, isolated glucagon deficiency can also result in hypoglycemia if insulin secretion is not suppressed and the counter-regulatory hormone epinephrine secretion is decreased. Studies also found that hypopituitarism may present with life-threatening hypoglycemia [21].
2.1.6 Concurrent illness (renal, hepatic, or cardiac failure, sepsis)
Hypoglycemia developing secondary to an underlying illness is associated with increased nutritional body demand due to increased metabolic response in critically ill patients. Endogenous glucose production is rapidly reduced in hepatic diseases and liver cirrhosis [22].
As kidneys play a major role in metabolizing insulin, reabsorption and synthesizing glucose, and excretion of different metabolites of hypoglycemic medications. Therefore, kidney impairment will prohibit all these processes leading to hypoglycemia. On the other hand, the counter-regulatory response to hypoglycemia may be defective due to uremia and associated anorexia [21]. On the other hand, in uremia, gluconeogenesis from the kidney and liver is reduced. Hypoglycemia can also occur in acute renal failure and end-stage renal disease (ESR), this is due to reduced renal insulinase-mediated insulin clearance.
Furthermore, severe cardiac failure and hepatic congestion may contribute to lower glucose output from the liver and reduce its intestinal absorption. While hypoglycemia in sepsis and adrenal insufficiency develops due to increased serum cortisol levels [4]. In literature, hypoglycemia in sepsis is often related to strict glycemic control protocols for stress hyperglycemia [23, 24, 25, 26, 27].
2.1.7 Psychological
2.1.7.1 Fear of hypoglycemia
The fear of hypoglycemia is common in patients with diabetes. It influences the quality and health outcomes. It can also increase the risk of poor metabolic control [28].
2.1.7.2 Depression
In diabetic patients with depression, hypoglycemia can occur frequently as a result of poor adherence to medications, diet, physical activity, smoking cessation, poor self-care, and blood glucose monitoring [29].
3. Non-diabetic hypoglycemia
3.1 Non-diabetic hypoglycemia: overview
Non-diabetic hypoglycemia (hypoglycemia without diabetes) is a rare condition, it comes from having too much insulin in the blood, leading to low blood glucose levels. It can occur in pre-diabetes, sepsis, and critical organ failure including renal or hepatic failure. It also rarely occurs in cortisol deficiency [8], and β-cell tumors due to endogenous hyperinsulinism [8, 31, 32, 33]. Moreover, hypoglycemia can be accidental, surreptitious, or even malicious [34].
Hypoglycemia can occur post-bariatric surgery, that is, gastric bypass surgery, or even due to an autoimmune disease [8, 32, 33]. Table 2 demonstrates the causes of hypoglycemia in nondiabetic patients.
Drugs Salicylates Sulfa drug antibiotics Pentamidine Quinine | Hormone deficiency Cortisol Growth hormone Glucagon Epinephrine Hypopituitarism |
Critical illness Renal failure Hepatic failure Cardiac failure Sepsis Inanition | Endogenous hyperinsulinism Insulinoma Nesidioblastosis Post-gastric bypass surgery |
Non-islet cell tumor | Insulin autoimmune hypoglycemia Antibody to insulin Antibody to the insulin receptor |
Intentional/accidental Surreptitious Malicious Factitious | Infancy and childhood Preterm Infants of DM mother Maternal drugs-sulphonylureas Rh incompatibility Beckwith-Wiedemann syndrome Exchange transfusions Enzyme defects-glycogen storage the disease I, III, VI. |
3.2 Differential diagnosis
Whipple’s triad (low plasma glucose level, clinical signs or symptoms of hypoglycemia, and resolution of signs or symptoms when the plasma glucose level increases) should be documented prior to initiating an evaluation [35].
When the patient is either looking ill or medicated, the initial diagnosis should focus on the possibility of drug involvement, critical conditions, hormone deficiency, or non-islet cell tumor hypoglycemia. If the patient seems well in the absence of any of the fore-mentioned etiologies, the focus should be on the possibility of having endogenous hyperinsulinism due to insulinomas, functional β-cell disorders, or insulin autoimmune conditions. In addition to the possibility of accidental, surreptitious, or malicious hypoglycemia [35, 36]. Hypoglycemia in patients post-bariatric surgery is increasingly recognized as the frequency of these operations has grown in the last few decades [36].
3.3 Etiology
3.3.1 Drug-induced
Fasting hypoglycemia is found to be associated with several medications, such as salicylates pain killers, antibiotic sulfa drugs, pentamidine, and quinine antimalarial medications [1].
3.3.2 Critical illnesses
Dysglycemia, in the form of hyperglycemia, hypoglycemia, and/or marked glucose variability, is a characteristic feature of critical illness in both diabetic and non-diabetic patients [37]. It can increase morbidity and mortality [38]. Among hospitalized patients, serious illnesses, such as renal, hepatic, or cardiac failure; sepsis; and inanition are the only drugs to cause hypoglycemia.
3.3.2.1 Sepsis
Sepsis is one of the main causes of death across the world and is considered the most familiar cause of death among intensive care unit (ICU) patients [39]. The mortality rate due to sepsis ranges from 15 to 56% [40]. Not to mention that patients with sepsis usually report variable types of dysglycemia due to the changes in endocrine metabolism in sepsis, which affects the stability of the internal environment and worsens their general condition [41].
Sepsis patients are often complicated by hypoglycemia as has been approved by multiple large-scale randomized controlled trials (RCTs). Although such protocols have not been approved to improve patient mortality, rather they possibly increase the risk of hypoglycemia [41]. While there is a dearth of studies on the effects of spontaneous hypoglycemia in patients with sepsis, its occurrence leads to increased mortality and elevated lactate levels in patients with sepsis [41].
In septic patients, increased glucose utilization is induced by cytokine production in macrophage-rich tissues, such as the liver, spleen, and lung. Hypoglycemia develops if glucose production fails to keep pace. Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion, in combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia.
3.3.2.2 Hepatic failure
The liver as a metabolic organ plays an important role in glucose metabolism. It regulates the blood glucose level mainly through glycogenolysis and gluconeogenesis. Hepatic impairment is well known to correlate with poor blood glucose regulation [42]. The presence of liver impairment or hepatocellular damage can lead to a disturbance of the metabolic function of the liver causing an imbalance in blood glucose levels. Rapid and extensive hepatic destruction, such as toxic hepatitis, for example, causes fasting hypoglycemia due to the lack of endogenous glucose production.
3.3.2.3 Renal failure
Patients with end-stage kidney disease frequently experience variable glycemic disturbances, with the common incidence of both hypoglycemia and hyperglycemia. The risk of hypoglycemia is increased in critically ill renal patients and having chronic kidney disease is a known risk factor for developing hypoglycemia [43, 44]. Multiple mechanisms are involved in hypoglycemia development in kidney disease patients, including impaired gluconeogenesis process run by the kidney, impaired insulin clearance by the kidney, and impaired insulin degradation due to uremia.
Other mechanisms of developing hypoglycemia in kidney disease also include increased erythrocyte glucose uptake during hemodialysis, impaired counter-regulatory hormone responses (cortisol, growth hormone), and nutritional deprivation [45, 46, 47, 48, 49]. Moreover, insulin sensitivity may improve in uremic patients after starting renal replacement therapy increases the risk of hypoglycemia in renal replacement patients [50]. In contrast, the risk of hypoglycemia is reduced with starting hemodialysis due to the addition of glucose to the dialysis solution [51].
3.3.2.4 Cardiac failure
Severe heart failure is sometimes associated with hypoglycemia. However, the exact mechanism is yet to be determined. Several mechanisms have been suggested including impaired gluconeogenesis due to hepatic congestion and the reduced glycogen stores from either inadequate intake or reduced gastrointestinal absorption [52, 53, 54].
3.3.2.5 Inanition
Inanition is a well-known cause of hypoglycemia. During starvation, a catabolic state occurs when the body shifts from predominately carbohydrate metabolism to that of fat and protein, the brain then starts conversing and utilizing alternative substrates, such as lactate, pyruvate, and ketone bodies with only a modest counter-regulatory neuroendocrine and autonomic nervous system response.
The refeeding syndrome (RFS) can occur after starvation and energy replenishment. This can be defined as severe electrolyte and metabolic abnormalities in undernourished patients after the introduction of nutrients [55, 56, 57]. Multiple organ systems including cardiac, respiratory, neurologic, and hematologic can be affected by the RFS and are occasionally associated with postprandial hypoglycemia [55, 58].
3.3.3 Hormone deficiencies
Increased cortisol and growth hormone (GH) secretion are involved in the defense mechanism against prolonged hypoglycemia. When these defenses fail to refute the hypoglycemia episode, plasma glucose levels will continue to fall [35].
Chronic cortisol deficiency is typically associated with anorexia and weight loss, likely leading to glycogen depletion. Cortisol deficiency is also associated with impaired gluconeogenesis and low levels of gluconeogenic precursors causing the substrate limited gluconeogenesis, in the setting of glycogen depletion, which leads to hypoglycemia.
Growth hormone deficiency can cause hypoglycemia in young children. In addition to extended fasting, high rates of glucose utilization, such as during exercise and in pregnancy, or low rates of glucose production, such as post-alcohol consumption, can precipitate hypoglycemia in adults with previously undiagnosed hypopituitarism [59].
3.3.4 Non-islet cell tumor hypoglycemia (NICTH)
Hypoglycemia due to non-islet cell tumors abbreviated as NICTH is considered to be rare [8, 31, 32, 33]; it is a rare paraneoplastic syndrome encountered in the setting of a wide variety of tumors and is most common in tumors of mesenchymal or hepatic origin [60]. Hypoglycemia in this realm is initially attributed to glucose consumption by the tumor and to tumor secretion of an “insulin-like” factor afterward, this factor is a precursor of IGF-2, called Big-IGF-2. While secretion of Big-IGF2 is the most common cause of NICTH, secretion of somatostatin or IGF1 may also be responsible [61]. Usually, IGF-2-related hypoglycemia manifests when the tumor turns quite large [62, 63].
3.3.5 Endogenous hyperinsulinism
Endogenous hyperinsulinism is a clinical condition that involves excessive insulin secretion and is related in 55% of cases to insulinoma [64]. Nesidioblastosis and insulinoma represent the main cause of endogenous hyperinsulinemic hypoglycemia in infants and apparently healthy adults, respectively [35]. The main pathophysiological feature of endogenous hyperinsulinism is the failure of insulin secretion to fall to very low levels when plasma glucose concentrations fall to hypoglycemic levels; hypoglycemia in this case is a result of low rates of glucose production, rather than high rates of glucose utilization [65]. Nesidioblastosis is a rare cause of persistent hyperinsulinemic hypoglycemia in adults. The hypoglycemia in the case of nesidioblastosis is attributed to β-cell hypertrophy and hyperfunction [66, 67, 68].
Post-prandial hypoglycemia can also be observed after bariatric surgeries, especially the procedures that divert nutrients into the mid-small bowel, such as Roux-en-Y gastric bypass surgery (RYGB), and not fully restrictive procedures like adjustable gastric banding [69]. Post-RYGB surgery hypoglycemia (PGBH) usually occurs between 1 and 8 years after the procedure [70], this might be due to several causes including late dumping syndrome, nesidioblastosis, and insulinoma [71].
3.3.6 Insulin autoimmune hypoglycemia
Hypoglycemia can also be caused by an antibody to insulin or its receptors, a condition known as insulin autoimmune syndrome (IAS) and also known as Hirata’s disease or insulin autoimmune hypoglycemia (IAH). It is essentially a rare autoimmune disorder caused by the spontaneous production of anti-insulin and anti-insulin receptor antibodies which bind insulin/proinsulin and/or insulin receptors and work as insulin-mimetic leading to predominantly postprandial hyperinsulinemic hypoglycemia [9, 72]. Graves’ disease is frequently present in Hirata syndrome and appears to be particularly prevalent in Japan [73].
3.3.7 Intentional/accidental
Hypoglycemia can also happen accidentally and can be surreptitious, malicious, or sometimes fictitious [74]. Pharmacy errors (e.g., substitution of a hypoglycemic drug for another medication) and medical treatment errors can stand behind some accidental intake cases [75].
Intentional hypoglycemia can be surreptitious and this is most commonly seen in people with knowledge of and access to glucose-lowering medications. It can be malicious which is usually accomplished by the administration of insulin or an insulin secretagogue [74]. It also can be fictitious in some cases.
3.3.8 Infancy and childhood
Hyperinsulinemic hypoglycemia (HH), which is characterized by unregulated insulin release, is the most common cause of persistent and severe hypoglycemia in infants and children [76]. This can be transient (associated with risk factors), or permanent (linked to genetic mutations). In the majority of cases (60–70%) hypoglycemia occurs in the first week of life [77, 78], and it carries a considerable risk of neurological damage and developmental delays if diagnosis and treatment were delayed [76].
HH is also classified as primary and secondary HH. The primary HH, which is also known as congenital HH (CHH), where the hypoglycemia is associated with variants in several genes involved in pancreatic development and function. The secondary HH, where hypoglycemia is associated with syndromes, such as intrauterine growth restriction, maternal diabetes, and birth asphyxia [79].
CHI can be classified according to etiology into two types—acquired and genetic. In neonates, acquired forms are usually associated with some conditions, such as perinatal stress or maternal gestational diabetes, and are often transient [80]. Genetic CHI can be caused by single-gene mutations in the insulin secretory pathway or genes causing syndromes with multiple associated factors, such as Beckwith-Wiedemann syndrome or Kabuki syndrome [78].
Hypoglycemia in infants can also be caused by counter-regulatory hormone deficiencies, such as adrenal insufficiency or GH deficiency [80]. In such cases, replacement of the deficient hormones yields a complete resolution of hypoglycemia. Some metabolic disorders, such as fatty acid oxidation disorders and certain glycogen storage disease types, are additional causes of hypoglycemia in infants and children [81].
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