The physiologic counterregulatory response to hypoglycemia involves neuroendocrine, ANS, and metabolic processes. This includes the suppression of insulin release as well as secretion of glucagon and pancreatic polypeptide from the pancreas, epinephrine from the adrenal medullae, norepinephrine from sympathetic postganglionic nerve terminals and adrenal medulla, cortisol from the adrenal cortex, and growth hormone from the anterior pituitary gland (11-13). In humans, inhibition of insulin secretion is the initial defense against a falling glucose and occurs at a plasma glucose concentration of about 80 mg/dL. The brain is one of the first organs affected and is most vulnerable to any glucose deprivation.
In adults with T1DM, insulin levels do not decrease as glucose levels fall, because of persistent absorption of exogenous insulin. The lack of decline in plasma insulin concentrations as glucose levels fall constitutes the first deficit in the defense against hypoglycemia in T1DM.
Next to respond in the acute defense against hypoglycemia are glucagon and epinephrine. These hormones begin to rise at glucose levels just below 70 mg/dL. Glucagon (secreted from pancreatic alpha cells) is a rapid-acting stimulus that facilitates hepatic glucose production. Glucagon acts directly on the liver to (i) convert glycogen to glucose (increasing hepatic glycogenolysis) and (ii) by promoting gluconeogenesis, (providing available 3-carbon glucose substrates such as lactate, pyruvate, alanine, and glycerol). This glucagon-stimulated increase in glucose production and thus the increased plasma glucose concentration lasts only for 2 to 3 hours (14).
The glucagon secretory response to hypoglycemia is irreversibly lost in patients with T1DM greater than 5-years duration (3-9). Hence, epinephrine (not glucagon) constitutes the main defense against hypoglycemia in these patients (3-9). As long as this mechanism is intact, epinephrine can adequately compensate for the glucagon deficiency.
Epinephrine sharply increases EGP during hypoglycemia. Secreted by the adrenal medullae, epinephrine binds to multiple receptors and causes an array of hemodynamic and metabolic effects. Through its actions (direct and indirect) on diverse target tissues, the hormone stimulates both glucose production and the limitation of glucose utilization by mainly beta adrenergic receptors in humans (1-3,7-9).
Epinephrine increases hepatic glucose production by direct stimulation of hepatic glycogenolysis. It also increases plasma glucose via hepatic gluconeogenesis; this process occurs mostly through an indirect mechanism, which consists of mobilization of lactate, alanine, glycerol (as gluconeogenic substrates), and nonesterified fatty acids (which provide energy for the process) (15-18). Another important physiologic function of epinephrine is its ability to limit glucose utilization in insulin-sensitive tissues (i.e., skeletal muscle). The epinephrine-stimulated increase in glucose production and glycogenolysis is relatively transient. However, because epinephrine also reduces glucose clearance, the hyperglycemic effect of the hormone is more persistent (8).
During hypoglycemia, norepinephrine is released from the adrenal medullae and through spillover from the sympathetic nervous system. Norepinephrine results in net vasoconstriction with increases in diastolic as well as systolic blood pressure. This effect differs from epinephrine, where there is net vasodilatation with increases in systolic blood pressure but decreases in diastolic blood pressure. Otherwise, norepinephrine, produces metabolic hyperglycemic effects through mechanisms analogous to those of epinephrine (3,7-9), as discussed above.
The increased sympathetic nervous system response is primarily responsible for the activation of lipolyis that results in release of free fatty acids (FFA) and glycerol. The elevated FFA levels result in significant glucose sparing as tissues can oxidize FFA instead of glucose. The inverse relationship that exists between fatty acid oxidation and glucose oxidation in insulin-sensitive tissues (including muscle) occurs by the inhibition of pyruvate dehydrogenase activity. Glycerol also becomes an important substrate for gluconeogenesis during prolonged hypoglycemia. Thus, it has been estimated that the increased lipolysis contributes up to 25% of the total defense against hypoglycemia (3,7-9).
Cortisol and growth hormone increase glucose production and restrain glucose disposal during hypoglycemia. However, these hormones have little or no role in the defense against acute hypoglycemia but become more important during prolonged hypoglycemia (9). Their effects do not become evident until 3 to 4 hours of prolonged hypoglycemia. The metabolic counterregulatory actions of cortisol and growth hormone are similar and include stimulation of gluconeogenesis and inhibition of glucose uptake. However, their effects are limited, having only approximately 20% compared to that of epinephrine (9).
Cortisol limits glucose utilization in muscle and other tissues through both direct and indirect actions. The latter occurs as a result of cortisol-stimulated lipolysis. Cortisol inhibits protein synthesis and promotes protein breakdown with increases of gluconeogenic precursors including lactate, alanine, and other amino acids from muscle and glycerol from fat. In addition to stimulating hepatic gluconeogenesis, cortisol also promotes glycogen
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