Increasing the Decrement in Insulin Secretion Improves Glucagon Responses to Hypoglycemia in Advanced Type 2 Diabetes

Abstract

OBJECTIVE -In advanced ␤-cell failure, counterregulatory glucagon responses may be impaired due to a reduced decrement in insulin secretion during the development of hypoglycemia. The present studies were therefore undertaken to test the hypothesis that these may be improved by increasing this decrement in insulin secretion.RESEARCH DESIGN AND METHODS -Twelve subjects with type 2 diabetes who have been insulin requiring were studied as a model of advanced ␤-cell failure. Glucagon responses were examined during a 90-min hypoglycemic clamp (ϳ2.8 mmol/l) on two separate occasions. On one occasion, tolbutamide was infused for 2 h before the clamp so that the decrement in insulin secretion during the induction of hypoglycemia would be increased. On the other occasion, normal saline was infused as a control.RESULTS -Before the hypoglycemic clamp, infusion of tolbutamide increased insulin secretion ϳ1.9-fold (P Ͻ 0.001). However, during hypoglycemia, insulin secretion decreased to similar rates on both occasions (P ϭ 0.31) so that its decrement was approximately twofold greater following the tolbutamide infusion (1.63 Ϯ 0.20 vs. 0.81 Ϯ 0.17 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001). This was associated with more than twofold-greater glucagon responses (42 Ϯ 11 vs. 19 Ϯ 8 ng/l, P Ͻ 0.002) during the hypoglycemic clamp but unaltered glucagon responses to intravenous arginine immediately thereafter (449 Ϯ 50 vs. 453 Ϯ 50 ng/l, P ϭ 0.78).CONCLUSIONS -Increasing the decrement in insulin secretion during the development of hypoglycemia improves counterregulatory glucagon responses in advanced ␤-cell failure. These findings further support the concept that the impaired counterregulatory glucagon responses in advanced ␤-cell failure may at least partially be due to a reduced decrement in insulin secretion. Diabetes Care 28:2691-2696, 2005I ncreased secretion of glucagon is considered most important for counterregulation of hypoglycemia. Epinephrine responses, although normally not critical, become critical when glucagon secretion is deficient (1). Counterregulation of hypoglycemia is markedly impaired when both glucagon and epinephrine responses are compromised (1). Defective glucagon responses to hypoglycemia, as they occur in type 1 diabetes and markedly insulindeficient type 2 diabetes, therefore play an important role in the pathophysiology of glucose counterregulation.Growing evidence suggests that a decrease in insulin secretion may be an important signal for the increased glucagon secretion during hypoglycemia as originally proposed by Samols et al. (2). Absence or a marked reduction in this signal may therefore be a plausible explanation for the impaired glucagon responses in type 1 diabetes and advanced type 2 diabetes. For example, Robertson's group (3,4) showed that both normal isolated human and rat islets and islets from streptozotocin-administered rats (which characteristically do not release glucagon when exposed to a very low glucose concentration) can respond to glucose deprivation by releasing glucagon if they are f...

Sleep Loss Alters Basal Metabolic Hormone Secretion and Modulates the Dynamic Counterregulatory Response to Hypoglycemia

“…This finding is particularly surprising in conjunction with the attenuated decrease in C-peptide levels during hypoglycemia, which reflects that the suppression of endogenous insulin secretion is reduced. Because the acute reduction in ␤-cell insulin secretion during hypoglycemia is a crucial signal for counterregulatory ␣-cell glucagon release (27)(28)(29)(30), glucagon levels should be expected to be attenuated rather than enhanced in the presence of markedly elevated C-peptide levels during hypoglycemia. Hence, our data point to a differential influence of SD on ␣-and ␤-cell secretory activity and presumably also on the interplay between both cell types.…”

Mechanisms of Hypoglycemia-Associated Autonomic Failure in Diabetes

“…Third, because there is a glucagon response to administered amino acids in patients with type 1 diabetes, 5,19,20 loss of the glucagon response to hypoglycemia must be the result of reduced signaling of functional alpha cells to secrete glucagon during hypoglycemia. Fourth, because insulin normally regulates glucagon secretion in a reciprocal fashion in humans [20][21][22][23][24][25] and laboratory animals, it follows that loss of beta-cell insulin secretion would result in loss of the signal of a decrease in insulin to increase alpha-cell glucagon secretion, despite a low glucose level in the alpha cells (Fig. 3).…”

Reversal of Defective Glucagon Responses to Hypoglycemia in Insulin-Dependent Autoimmune Diabetic BB Rats

“…Safety concerns preclude the use of systemic infusions of insulin to reproduce the switch-off signal because of the high systemically circulating insulin concentrations that would be needed to mimic the levels delivered from the ␤-cell to the ␣-cell. However, Israelian et al (17) recently published data that may be relevant because they involved insulin-requiring type 2 diabetic patients. In this work glucagon responses during hypoglycemic clamps were studied on two separate occasions in 12 subjects.…”