INTRODUCTION — The brain relies almost exclusively on glucose as a fuel, but it cannot synthesize or store glucose to a substantial degree. As a result, adequate uptake of glucose from the plasma is essential for normal brain function and survival. Given the survival value of maintenance of the plasma glucose concentration, it is not surprising that very effective physiologic and behavioral mechanisms have evolved that normally prevent or rapidly correct hypoglycemia. As a result, hypoglycemia is an uncommon clinical event except in patients who use drugs that lower glucose levels, particularly those with diabetes who use insulin, a sulfonylurea, or a glinide. In addition to being at increased risk for hypoglycemia, patients with diabetes treated with insulin often have impaired neurohumoral responses to and few early symptoms of low blood glucose concentrations [1-4].
This topic will review glucose metabolism and the response to hypoglycemia in healthy individuals and in patients with diabetes. The therapeutic approach to hypoglycemia in patients with diabetes is discussed separately. (See "Hypoglycemia in adults with diabetes mellitus".)
REGULATION OF GLUCOSE HOMEOSTASIS — In healthy individuals, the extracellular supply of glucose is carefully regulated primarily by insulin and glucagon (figure 1) [1-4]. As plasma glucose concentrations rise after a meal, glucose enters the pancreatic beta cells. In these cells, the enzyme glucokinase, which phosphorylates glucose to glucose-6-phosphate, acts as the glucose sensor, initiating a sequence of events leading to entry of calcium and insulin release. (See "Pancreatic beta cell function".)
Insulin acts to restore normoglycemia primarily through the following two mechanisms:
●Reduction of hepatic glucose production – Insulin decreases hepatic glucose production by diminishing both glycogenolysis and gluconeogenesis. It does so indirectly by diminishing delivery of the gluconeogenic precursors (eg, lactate, glycerol, and alanine and other amino acids) to the liver via its antiglycolytic, antilipolytic, and antiproteolytic actions. Insulin also inhibits glucagon secretion by direct inhibition of the glucagon gene in the pancreatic alpha cells, which further diminishes hepatic glucose production. (See "Insulin action", section on 'Insulin and glucose metabolism'.)
●Promotion of glucose uptake in peripheral tissues – Insulin increases glucose uptake by skeletal muscle and adipose tissue by translocating glucose transporters from an intracellular pool to the cell surface.
The net effect of these responses is inhibition of hepatic glucose production and increased peripheral utilization of the glucose load that is not taken up by the liver. As a result, plasma glucose concentrations normally return to baseline values within several hours.
RESPONSE TO HYPOGLYCEMIA IN HEALTHY INDIVIDUALS — In the fasting state, when glucose cannot be obtained from intestinal absorption, glucose counterregulatory mechanisms prevent or rapidly correct falling plasma glucose concentrations (figure 1 and table 1) [1-4]. There is a hierarchy among the defense mechanisms, and in individuals without diabetes, the glycemic thresholds for activation of these defenses are reproducible. The counterregulatory hormonal responses begin well before the onset of symptoms of hypoglycemia.
Counterregulatory hormones
●The first defense against hypoglycemia is a decrease in insulin secretion as plasma glucose concentrations decline within the physiologic range (starting at an arterialized venous plasma glucose threshold of 80 to 85 mg/dL [4.4 to 4.7 mmol/L]) [5].
●The second defense is an increase in glucagon secretion. Glucagon acts only on the liver, increasing glucose production by stimulating both glycogenolysis and gluconeogenesis from alanine, among other amino acids, and glycerol. A normally functioning liver is necessary for an adequate response to glucagon. The glycemic threshold for glucagon secretion is 70 to 75 mg/dL (3.9 to 4.2 mmol/L) [5,6].
●The third defense is an increase in epinephrine secretion. Acting via beta-2-adrenergic receptors, epinephrine increases glucose production primarily from the liver and, to a lesser extent, from the kidneys. It also promotes lipolysis in adipose tissue, increasing the delivery of gluconeogenic substrates from the periphery. In addition, epinephrine inhibits glucose utilization by skeletal muscle and adipose tissue, and, via alpha-2-receptors, may further inhibit insulin secretion. As with glucagon, a normally functioning liver is necessary for an adequate epinephrine-induced increase in hepatic glucose production. The glycemic threshold for epinephrine secretion is 65 to 70 mg/dL (3.6 to 3.9 mmol/L) [5,6].
●Cortisol and growth hormone contribute only if hypoglycemia persists for several hours. These hormones limit glucose utilization and enhance hepatic glucose production. The glycemic threshold for cortisol and growth hormone secretion are 60 to 65 mg/dL (3.3 to 3.6 mmol/L) [5,6].
Interaction between insulin and glucagon — The secretion of insulin and glucagon are closely coupled, both anatomically and physiologically within the pancreatic islet. In the earliest stages (within minutes) of a decreasing plasma glucose concentration within the physiologic range, reduced insulin secretion is the most important regulatory hormone response, and increased glucagon secretion is the most important counterregulatory hormone response. This coordinated primary pancreatic islet response normally ensures that fasting glucose does not fall below approximately 70 mg/dL (3.9 mmol/L), as the decreased insulin-to-glucagon ratio to which the liver is exposed promotes an increase in hepatic glucose production calibrated to prevent or correct low blood glucose.
Insulin, perhaps among other beta cell secretory products acting within the islet, normally restrains glucagon secretion, and diminished insulin (or other beta cell secretory products) within the islet provides an obligate paracrine signal to the alpha cell to secrete glucagon during the development of hypoglycemia [7]. This effect is lost in insulin-deficient diabetes. (See "Pancreatic beta cell function".)
Behavioral defenses — The initial autonomic (neurogenic) symptoms of sweating, anxiety, palpitations, hunger, and tremor occur as the plasma glucose concentration falls below 55 mg/dL (3.1 mmol/L) [1-6]. These symptoms trigger the critical behavioral defense (ie, ingestion of food) and are signaled largely by increased sympathetic neural activity. Together with the increase in epinephrine secretion, this sympathetic neural activity and its associated symptoms constitute the sympathoadrenal response to hypoglycemia.
Hypoglycemia can also cause cognitive dysfunction, which occurs in healthy individuals at plasma glucose concentrations below 50 mg/dL (2.8 mmol/L). Cognitive dysfunction can impair behavioral defenses. More severe neurologic symptoms, including obtundation, seizures, and coma, occur with progressive hypoglycemia. Profound and prolonged hypoglycemia can cause brain death.
RESPONSE TO HYPOGLYCEMIA IN DIABETES
Impairment of behavioral and counterregulatory responses — Hypoglycemia in insulin- or insulin secretagogue-treated patients with diabetes is typically the result of the interplay between absolute or relative therapeutic insulin excess and compromised physiologic and behavioral defenses against falling plasma glucose concentrations.
Insulin — The protective response to hypoglycemia is impaired in many patients with diabetes (table 1) [1-3,8]. The first defense, the ability to suppress insulin exposure, cannot occur in patients with absolute beta cell failure, ie, those with type 1 diabetes and longstanding type 2 diabetes. Therefore, inhibition of hepatic glucose production continues. Thus, the main defense against hypoglycemia is increased release of counterregulatory hormones (glucagon and epinephrine), which raise plasma glucose concentrations by stimulating glucose production, and, for epinephrine, by antagonizing the insulin-induced increase in glucose utilization.
Glucagon — For type 1 diabetes, the glucagon response to hypoglycemia is nearly uniformly lost within a few years of diagnosis, whereas the progressive loss of this response occurs more slowly in type 2 diabetes [1-3,8-11]. The diminished glucagon response is the result of beta cell loss and failure with consequent loss of the hypoglycemia-induced decline in intra-islet insulin. This decline normally stimulates alpha cell glucagon secretion during hypoglycemia via a paracrine mechanism within the islet [3,12,13]. Individuals with advanced beta cell loss still have intact glucagon responses to other stimuli such as amino acids.
Epinephrine — In the setting of absent insulin and glucagon responses, patients are dependent upon epinephrine to protect against hypoglycemia. However, the epinephrine response to hypoglycemia also becomes attenuated in many patients, at least in part because of recent antecedent hypoglycemia [1,2,10,14]. In a systematic review of 63 studies, the calculated median glycemic thresholds for activation of epinephrine was somewhat lower in individuals with type 1 diabetes than in those without diabetes (61 versus 68 mg/dL [3.4 versus 3.8 mmol/L]) [9]. An attenuated epinephrine response causes defective glucose counterregulation, which is associated with a 25-fold or greater increased risk of severe hypoglycemia [15,16].
Autonomic symptoms — An attenuated autonomic (largely sympathetic neural) symptom response causes impaired awareness of hypoglycemia, which is associated with a sixfold increased risk of severe hypoglycemia [17]. A complete absence of autonomic symptom recognition, or hypoglycemia unawareness, is associated with a 20-fold increased risk of severe hypoglycemia [18]. In a systematic review of 63 studies that employed hyperinsulinemic stepped-hypoglycemic clamps, the median glycemic thresholds for autonomic and neuroglycopenic symptoms were somewhat lower in patients with type 1 diabetes (54 versus 61 mg/dL [3.0 versus 3.4 mmol/L] for both symptom sets) [9].
Hypoglycemia-associated autonomic failure — The concept of hypoglycemia-associated autonomic failure (HAAF) in type 1 diabetes [10] and longstanding (absolute endogenous insulin-deficient) type 2 diabetes [11] posits that recent, antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation and impaired awareness of hypoglycemia and thus promotes a vicious cycle of recurrent hypoglycemia (algorithm 1) [1,2,4]. It does so by shifting the glycemic thresholds for activation of the sympathoadrenal epinephrine and autonomic symptom responses to subsequent hypoglycemia to lower plasma glucose concentrations. This shift, as well as a reduced magnitude of response, causes defective glucose counterregulation by reducing epinephrine in the setting of absent insulin and glucagon responses at a given level of hypoglycemia. It also causes impaired awareness of hypoglycemia by reducing the autonomic symptom response. Sleep and prior exercise can cause a similar phenomenon of attenuated sympathoadrenal epinephrine and autonomic symptom responses to subsequent hypoglycemia and feed the cycle of recurrent hypoglycemia in diabetes [1,2].
Mechanism — The precise mechanisms that underlie the key feature of HAAF (ie, the attenuated sympathoadrenal epinephrine and autonomic symptom responses to falling plasma glucose concentrations) are unknown [1,2,4]. One hypothesis is that hypoglycemia-induced alterations in hypothalamic functions, or even a cerebral network, reduce the sympathoadrenal response to subsequent hypoglycemia [4]. Another hypothesis is that an increase in cortisol (or some other stress-related factor) during hypoglycemia causes a reduced sympathoadrenal response to subsequent hypoglycemia. An impaired epinephrine response can develop independent of an impairment in autonomic symptoms [19], an effect possibly explained by a hypoglycemia-induced reduction in the secretory capacity of adrenal chromaffin cells as demonstrated in a mouse model [20].
HAAF is a functional disorder distinct from classical diabetes-related autonomic neuropathy, the result of nerve fiber loss. Nonetheless, the sympathoadrenal epinephrine response to a given level of hypoglycemia is reduced further in patients with autonomic neuropathy [21,22].
Type 1 versus type 2 — Although it was originally developed in type 1 diabetes [10], the concept of HAAF also applies to patients with type 2 diabetes treated with intensive (basal/bolus) insulin regimens (table 1) [11]. Endogenous insulin secretion decreases progressively over time in type 2 diabetes [23]. As patients with type 2 diabetes develop absolute insulin deficiency and become dependent on exogenous insulin, insulin secretion does not decrease and glucagon secretion does not increase when plasma glucose concentrations fall. Furthermore, antecedent hypoglycemia reduces the sympathoadrenal epinephrine and autonomic symptom responses to subsequent falling glucose levels in type 2 diabetes [11].
Compared with type 1 diabetes [10], the features of HAAF develop later in the natural history of type 2 diabetes [1,2,11]. This different temporal pattern of the pathophysiology of glucose counterregulation likely explains why iatrogenic hypoglycemia is relatively uncommon early in the course of type 2 diabetes (even during treatment with insulin), when the glucoregulatory defenses are intact, but occurs more frequently as patients approach the insulin-deficient end of the spectrum of type 2 diabetes, when the defenses become compromised.
Nocturnal hypoglycemia — Most episodes of severe hypoglycemia occur during sleep. Nocturnal hypoglycemia is frequent, even with the use of continuous subcutaneous insulin infusion (CSII) or a basal-bolus regimen with insulin analogs [24]. Sleep is typically the longest interprandial period and time interval between blood glucose measurements, and it usually coincides with the time of maximal insulin sensitivity. Furthermore, sympathoadrenal responses to hypoglycemia are diminished during sleep; therefore, people with diabetes are less able to defend against hypoglycemia and less likely to be awakened by autonomic symptoms [25,26]. Continuous glucose monitoring (CGM) alerts and alarms help to reduce, but do not eliminate, nocturnal hypoglycemia and only modestly improve glucose counterregulation in individuals affected by HAAF [27]. As discussed earlier, even asymptomatic nocturnal hypoglycemia impairs defenses against subsequent hypoglycemia.
The notion that nocturnal hypoglycemia causes hyperglycemia the following morning (the Somogyi hypothesis) has been discredited [28,29]. The opposite is typically found, namely, a direct relationship between the overnight blood glucose nadir and the following morning blood glucose value; thus, patients with morning hyperglycemia typically have high, not low, blood glucose concentrations at night. The most common causes of morning hyperglycemia are nocturnal growth hormone secretion [30] and hypoinsulinemia.
Strategies to prevent nocturnal hypoglycemia and the best solution for morning hyperglycemia are discussed separately. (See "Hypoglycemia in adults with diabetes mellitus" and "Management of blood glucose in adults with type 1 diabetes mellitus".)
Exercise — Exercise increases glucose utilization by skeletal muscle and, therefore, can cause hypoglycemia in patients with insulin-deficient diabetes who have near normal or moderately elevated plasma glucose levels at the start of exercise. In addition, as noted earlier, exercise, like hypoglycemia, can cause HAAF hours later (algorithm 1) [1,2]. Hypoglycemia can be prevented by frequent blood glucose monitoring or CGM and, when indicated, reduced insulin doses, carbohydrate ingestion, or both prior to exercise. (See "Exercise guidance in adults with diabetes mellitus".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)
SUMMARY
●Clinical relevance of hypoglycemia – Hypoglycemia is an uncommon clinical event except in patients who use drugs that lower plasma glucose concentrations, specifically insulin, a sulfonylurea, or a glinide. It is the limiting factor in the glycemic management of diabetes. (See 'Introduction' above and "Hypoglycemia in adults with diabetes mellitus".)
●Physiologic response to hypoglycemia – Glucose counterregulatory mechanisms and behavioral defenses normally prevent or rapidly correct hypoglycemia (figure 1 and table 1). (See 'Response to hypoglycemia in healthy individuals' above.)
●Altered physiologic response in individuals with diabetes – The protective response to hypoglycemia is impaired in most patients with type 1 diabetes and in many patients with longstanding (absolute endogenous insulin-deficient) type 2 diabetes (table 1). (See 'Response to hypoglycemia in diabetes' above.)
●Hypoglycemia-associated autonomic failure – Hypoglycemia, even if asymptomatic, causes a vicious cycle of recurrent hypoglycemia by causing hypoglycemia-associated autonomic failure (HAAF), the clinical syndrome of defective glucose counterregulation and impaired awareness of hypoglycemia (algorithm 1). (See 'Hypoglycemia-associated autonomic failure' above.)
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