Elimination of Hypoglycemia From the Lives of People Affected by Diabetes

Iatrogenic hypoglycemia is a problem for people affected by diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes, and it is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the vascular benefits of glycemic control. And, it compromises defenses against subsequent falling plasma glucose concentrations and therefore causes a vicious cycle of recurrent hypoglycemia. Hypoglycemia in diabetes is fundamentally iatrogenic, the result of therapeutic hyperinsulinemia caused by treatment with a sulfonylurea, a glinide, or insulin. But because of the effectiveness of the normal glucose counterregulatory mechanisms, hypoglycemia is typically the result of the interplay of therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations in people with diabetes (1). The compromised physiological defenses include loss of the normal decrements in insulin, increments in glucagon, and increments in epinephrine as glucose levels fall in absolute endogenous insulin deficient diabetes (1). Loss of decrements in insulin and of increments in glucagon develop early in people with type 1 diabetes but only later in people with type 2 diabetes. In view of increasing evidence that -cell insulin secretion normally restrains -cell glucagon secretion (2) and that a decrease in insulin normally signals an increase in glucagon secretion during hypoglycemia (3), loss of both the insulin and the glucagon responses is plausibly attributable to -cell failure (1). That construct fits nicely with the fact that iatrogenic hypoglycemia becomes a major problem early in people with type 1 diabetes but only later in people with type 2 diabetes (1). Given the evidence that insulin also acts on the hypothalamus to restrain glucagon secretion, there may also be a central nervous system component to the loss of the glucagon response (4). However, that cannot be the sole explanation since the denervated (transplanted) human pancreas and the denervated dog pancreas (as well as the perfused pancreas and perifused islets) release glucagon in response to low glucose concentrations in the absence of innervation (1). In any event, people with absolute endogenous insulin deficient diabetes are largely dependent on epinephrine for defense against falling glucose levels. However, the increments in epinephrine are often attenuated. That is a critical component of the pathophysiology of glucose counterregulation in diabetes. In the setting of absent insulin and glucagon responses, attenuated increments in epinephrine cause the clinical syndrome of defective glucose counterregulation with a 25-fold or greater increased risk of severe hypoglycemia (1). Attenuated increments in sympathoadrenal, largely sympathetic neural, activation cause the clinical syndrome of hypoglycemia unawareness with a sixfold increased risk of severe hypoglycemia (1). The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia (as well as sleep or prior exercise) causes both defective glucose counterregulation (by reducing the epinephrine response to subsequent hypoglycemia in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by reducing the sympathoadrenal response to subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia (1). Perhaps the most compelling evidence for the clinical impact of HAAF is the fact that hypoglycemia unawareness and to some extent the attenuated epinephrine component of defective glucose counterregulation are reversed after as little as 2–3 weeks of scrupulous avoidance of hypoglycemia in most affected subjects (5–8). The mechanism(s) of the attenuated central nervous system-mediated sympathoadrenal response to falling glucose levels, the key feature of HAAF in type 1 diabetes and advanced type 2 diabetes, is not known (1). Much of the relevant investigative focus has been on the hypothalamus and its environs in experimental animals (e.g., ref. 9). However, recent studies in humans have raised the possibility that a cerebral network, operating through the thalamus, may be involved in the pathogenesis of HAAF (10–12). The current clinical approach to minimizing the risk of iatrogenic hypoglycemia includes 1) acknowledging the problem in subjects at risk, 2) applying the principles of aggressive glycemic therapy, and 3) addressing the risk factors for hypoglycemia (1). With respect to the latter, a history of hypoglycemia unawareness should prompt a 2to 3-week period of scrupulous avoidance of hypoglycemia with the anticipation that awareness will return (1,5–8). Given the vascular benefits of glycemic control, mean glycemia as close to the nondiabetic range as can be safely maintained is generally in the best interest of people with diabetes (1). During effective therapy with lifestyle changes or with glucose-lowering drugs other than a sulfonylurea, a glinide, or insulin, the glycemic goal might be a normal A1C. But such therapies are seldom effective over a lifetime of diabetes. During therapy with a sulfonylurea, a glinide, or insulin, the glycemic goal might be an A1C 7%. The latter can sometimes be safely achieved From the Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri. Corresponding author: Philip E. Cryer, [email protected]. DOI: 10.2337/db10-1359 © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 39. COMMENTARY