Insulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog

Abstract

In the present study, we examined how the arterial insulin level alters the ␣-cell response to a fall in plasma glucose in the conscious overnight fasted dog. Each study consisted of an equilibration (؊140 to ؊40 min), a control (؊40 to 0 min), and a test period (0 to 180 min), during which BAY R 3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally to decrease glucose output in each of four groups (n ‫؍‬ 5). In group 1, saline was infused. In group 2, insulin was infused peripherally (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ), and the arterial plasma glucose level was clamped to the level seen in group 1. In group 3, saline was infused, and euglycemia was maintained. In group 4, insulin (3.6 pmol ⅐ kg ؊1 ⅐ min ؊1 ) was given, and euglycemia was maintained by glucose infusion. In group 1, drug administration decreased the arterial plasma glucose level (mmol/l) from 5.8 ؎ 0.2 (basal) to 5.2 ؎ 0.3 and 4.4 ؎ 0.3 by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels (pmol/l) and the hepatic portalarterial difference in plasma insulin (pmol/l) decreased (P < 0.01) from 78 ؎ 18 and 90 ؎ 24 to 24 ؎ 6 and 12 ؎ 6 over the first 30 min of the test period. The arterial glucagon levels (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) rose from 43 ؎ 5 and 5 ؎ 2 to 51 ؎ 5 and 10 ؎ 5 by 30 min (P < 0.05) and to 79 ؎ 16 and 31 ؎ 15 (P < 0.05) by 90 min, respectively. In group 2, in response to insulin infusion, arterial insulin (pmol/l) was elevated from 48 ؎ 6 to 132 ؎ 6 to an average of 156 ؎ 6. The hepatic portal-arterial difference in plasma insulin was eliminated, indicating a complete inhibition of endogenous insulin release. The arterial glucagon level (ng/l) and the hepatic portalarterial difference in plasma glucagon (ng/l) did not rise significantly (40 ؎ 5 and 7 ؎ 4 at basal, 44 ؎ 4 and 9 ؎ 4 at 90 min, and 44 ؎ 8 and 15 ؎ 7 at 180 min). In group 3, when euglycemia was maintained, the insulin and glucagon levels and the hepatic portal-arterial difference remained constant. In group 4, the arterial plasma glucose level remained basal (5.9 ؎ 1.1 mmol/l) throughout, whereas insulin infusion increased the arterial insulin level to an average of 138 ؎ 6 pmol/l. The hepatic portal-arterial difference in plasma insulin was again eliminated. Arterial glucagon level (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) did not change significantly (43 ؎ 2 and 9 ؎ 2 at basal, 39 ؎ 3 and 9 ؎ 2 at 90 min, and 37 ؎ 3 and 7 ؎ 2 at 180 min). Thus, a difference of ϳ120 pmol/l in arterial insulin completely abolished the response of the ␣-cell to mild hypoglycemia. Diabetes 51:3033-3042, 2002

Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo

“…The current data suggest that the decrease in glucose provoked by systemic insulin administration may be not only perceived as a signal of metabolic deprivation but also seen as a signal of concomitant food availability, thereby resulting in a muted or maladaptive glucagon response. It is noteworthy that a similar enhancement of glucagon secretion has been reported with drug-induced insulin-independent decrements in blood glucose in the dog, which was attributed to suppression of intraislet insulin, but that is equally consistent with the loss of the central inhibitory actions of insulin (47). One might speculate that the loss of glucagon response to hypoglycemia in type 1 diabetic patients lacking endogenous insulin might result in part from the simultaneous increase in insulin levels both in the VMH and locally in the islet caused by exogenous insulin administration.…”

Counterregulatory deficits occur within 24 h of a single hypoglycemic episode in conscious, unrestrained, chronically cannulated mice

“…Although the frequency and total number of hormone samples in our experiments were insufficient to derive a precise glycemic threshold, correlation of hormone levels against blood glucose indicated that epinephrine, corticosterone, and glucagon increased in mice at glucose levels that were close to 80 mg/dl. This level is notably higher than the 60 -70 mg/dl threshold reported for responses of these counterregulatory hormones to insulininduced hypoglycemia in humans and dogs (25,39) and suggests that the same blood glucose level may not represent the same stimulus severity in all species. We did not observe hypoglycemia-induced increases in plasma norepinephrine, but elevated norepinephrine is not a consistent feature of counterregulation in other species (14,29,(37)(38)(39).…”

Glucagon secretion and autonomic signaling during hypoglycemia in late pregnancy

“…Redundant mechanisms appear to control glucagon secretion in the normal state. The alpha cell is able to respond sensitively to the glycemic level in hypoglycemia, but this ability is ablated in the presence of even very mild hyperinsulinemia (29). The decrement in intraislet insulin that occurs during hypoglycemia is reported to be related to the magnitude of the glucagon response (3,23,33,36).…”