Because absence of the glucagon response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia in patients with insulin-deficient diabetes and the mechanism of this defect is unknown, and given evidence in experimental animals that a decrease in intraislet insulin is a signal to increased glucagon secretion, we examined the role of endogenous insulin in the physiological glucagon response to hypoglycemia. We tested the hypothesis that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic-adrenomedullary, sympathetic neural, and parasympathetic neural-response and a low ␣-cell glucose concentration. Twelve healthy young adults were studied on three separate occasions. Insulin was infused in hourly steps in relatively low doses (1.5, 3.0, 4.5, and 6.0 pmol ⅐ kg ؊1 ⅐ min ؊1 ) from 60 through 300 min on all three occasions. Plasma glucose levels were clamped at euglycemia (ϳ5.0 mmol/l, ϳ90 mg/dl) on one occasion and at hourly steps of ϳ4.7, 4.2, 3.6, and 3.0 mmol/l (ϳ85, 75, 65, and 55 mg/dl) from 60 through 300 min on the other two occasions. On one of the latter occasions, the ␤-cell secretagogue tolbutamide was infused in a dose of 1.0 g/h from 60 through 300 min. Hypoglycemia with tolbutamide infusion, compared with similar hypoglycemia alone, was associated with higher (P < 0.0001) C-peptide levels (final values of 1.0 ؎ 0.2 vs. 0.1 ؎ 0.0 nmol/l), higher (P < 0.0001) rates of insulin secretion (final values of 198 ؎ 60 vs. 15 ؎ 4 pmol/min), and higher (P < 0.0001) insulin levels (final values of 325 ؎ 30 vs. 245 ؎ 20 pmol/l) as expected. The glucagon response to hypoglycemia was prevented during tolbutamide infusion (P < 0.0001). Glucagon levels were 17 ؎ 1 pmol/l at baseline on both occasions, 14 ؎ 1 vs. 15 ؎ 1 pmol/l, respectively, during the initial hyperinsulinemic euglycemia, and 15 ؎ 1 vs. 22 ؎ 2 pmol/l, respectively, during hypoglycemia with and without tolbutamide infusion. Autonomic-adrenomedullary (plasma epinephrine), sympathetic neural (plasma norepinephrine), and parasympathetic neural (plasma pancreatic polypeptide)-responses to hypoglycemia were not reduced during tolbutamide infusion. We conclude that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response and a low ␣-cell glucose concentration. Diabetes 51:958 -965, 2002

. Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia. Am J Physiol Endocrinol Metab 282: E770-E777, 2002. First published December 11, 2001 10.1152/ajpendo.00447.2001.-We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of ␣-(1-24)-ACTH (100 g/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to ϳ45 g/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P ϭ 0.004, final plasma epinephrine levels of 489 Ϯ 64 vs. 816 Ϯ 113 pg/ml), sympathetic neural (P ϭ 0.0022, final plasma norepinephrine levels of 244 Ϯ 15 vs. 342 Ϯ 22 pg/ml), parasympathetic neural (P ϭ 0.0434, final plasma pancreatic polypeptide levels of 312 Ϯ 37 vs. 424 Ϯ 56 pg/ml), and neurogenic (autonomic) symptom (P ϭ 0.0097, final symptom score of 7.1 Ϯ 1.5 vs. 10.6 Ϯ 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus. epinephrine; norepinephrine; glucagon; diabetes; hypoglycemia-associated autonomic failure IATROGENIC HYPOGLYCEMIA is the limiting factor in the glycemic management of diabetes (4). It causes recurrent physical morbidity, and often psychosocial morbidity, in most patients with type 1 diabetes mellitus (T1DM) and in many with advanced type 2 diabetes mellitus (T2DM). It sometimes causes chronic disability and even premature death. Furthermore, because it precludes maintenance of true euglycemia over time, iatrogenic hypoglycemia limits full realization of the established microvascular benefits and the potential macrovascular benefits of aggressive glycemic therapy of diabetes (32, 33).Iatrogenic hypoglycemia is typically the result of the interplay of relative or absolute insulin excess and compromised glucose counterregulation in people with diabetes (5). With respect to compromised defenses against developing hypoglycemia, the concept of hypoglycemia-associated autonomic failure (HAAF) (4, 6, 7) posits that episodes of recent antecedent iatrogenic hypoglycemia cause both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by red...

Hypoglycemia-associated autonomic failure (HAAF)-reduced autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia caused by recent antecedent hypoglycemia-plays a key role in the pathogenesis of defective glucose counterregulation and hypoglycemia unawareness and thus iatrogenic hypoglycemia in type 1 diabetes. On the basis of the findings that cortisol infusion mimics and deficient or inhibited cortisol secretion minimizes this phenomenon, it has been suggested that the cortisol response to antecedent hypoglycemia mediates HAAF. We tested the hypothesis that any stimulus that releases cortisol, such as exercise, reduces autonomic and symptomatic responses to subsequent hypoglycemia. Thirteen healthy young adults (four women) were studied on three occasions in random sequence: 1) cycle exercise (ϳ70% peak oxygen consumption) from 0830 to 0930 h and from 1200 to 1300 h on day 1 and hyperinsulinemic (2.0 mU ⅐ kg ؊1 ⅐ min ؊1 ) stepped hypoglycemic (85, 75, 65, 55, and 45 mg/dl) clamps on day 2, 2) rest on day 1 and identical hypoglycemic clamps on day 2, and 3) hyperinsulinemic-euglycemic clamps. Exercise raised plasma cortisol concentrations to 16.9 ؎ 1.9 (0930 h) and 16.6 ؎ 1.6 g/dl (1300 h) on day 1. Compared with rest on day 1, exercise on day 1 was associated with reduced epinephrine (P ‫؍‬ 0.0113) responses-but not norepinephrine (P ‫؍‬ 0.6270), neurogenic symptom (P ‫؍‬ 0.6470), pancreatic polypeptide (P ‫؍‬ 0.0629), or glucagon (P ‫؍‬ 0.0436, but higher) responses-to hypoglycemia on day 2. However, the effect was small. (The final day 2 hypoglycemia epinephrine values were 765 ؎ 106 pg/ml after rest on day 1 and 550 ؎ 94 pg/ml after exercise on day 1 compared with 30 ؎ 6 pg/ml during euglycemia.) These data are consistent with the hypothesis that the cortisol response to hypoglycemia mediates in part the reduced epinephrine response to subsequent hypoglycemia, one key component of HAAF in type 1 diabetes. However, the small effect suggests that an additional factor or factors may well be involved. These data do not support the hypothesis that the cortisol response to hypoglycemia mediates the reduced neurogenic symptom response to subsequent hypoglycemia, another key component of HAAF in type 1 diabetes. Diabetes 51:1485-1492, 2002 I atrogenic hypoglycemia is the limiting factor, both conceptually and in practice, in the glycemic management of diabetes (1-4). At least in type 1 diabetes, iatrogenic hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological and behavioral defenses against developing hypoglycemia (1,2,5-9). The concept of hypoglycemia-associated autonomic failure (HAAF) in type 1 diabetes (10 -16) posits that recent antecedent iatrogenic hypoglycemia, by reducing the autonomic (including the adrenomedullary epinephrine as well as the sympathetic neural norepinephrine and acetylcholine) responses and the resultant neurogenic symptomatic responses to a given level of subsequent hypoglycemia, cau...

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemicstepped hypoglycemic clamps the day after saline or cortisol (1.3 ؎ 0.2 g ⅐ kg ؊1 ⅐ min (1). It is typically the result of the interplay of relative or absolute insulin excess and compromised physiological and behavioral defenses against developing hypoglycemia in type 1 diabetes (1,2) and advanced type 2 diabetes (1,3). The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural as well as adrenomedullary response and the resulting neurogenic [autonomic] symptom responses to a given level of subsequent hypoglycemia) and thus causes a vicious cycle of recurrent iatrogenic hypoglycemia (1-4). The clinical impact of HAAF, including the finding that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients is well documented (1,4). However, the mediator(s) and mechanisms(s) of HAAF are unknown (1,4).Davis and colleagues have suggested that the cortisol response to antecedent hypoglycemia mediates HAAF (5-7). They found that cortisol infusions, which raised mean plasma cortisol concentrations to ϳ32 g/dl, reduced autonomic neuroendocrine (among other) responses to hypoglycemia the following day in healthy subjects (5); effects on symptom responses were not reported (5). They also found that deficient cortisol secretion (in patients with primary adrenocortical failure) minimized the effects of antecedent hypoglycemia (6). These investigators presented evidence that intracerebroventricular cortisone (7) or cortisol (8), but not dexamethasone (8), reduced plasma epinephrine and norepinephrine responses to subsequent hypoglycemia. They also found that intravenous dehydroepiandrosterone, a putative glucocorticoid antagonist, blocked the effect of antecedent hypoglycemia to reduce these responses t...

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