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Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo.

Paranjape SA, Chan O, Zhu W, Horblitt AM, McNay EC, Cresswell JA, Bogan JS, McCrimmon RJ, Sherwin RS - Diabetes (2010)

Bottom Line: However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression.Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist.Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA. sachin.paranjape@yale.edu

ABSTRACT

Objective: Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention.

Research design and methods: Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions.

Results: As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist.

Conclusions: Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

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Related in: MedlinePlus

Effect of circulating insulin on plasma glucagon, epinephrine, and C-peptide responses to an equivalent fall in plasma glucose produced by infusion of insulin or phloridzin. The absence of an elevation in circulating insulin magnified the glucagon response, despite identical suppression of C-peptide increments of epinephrine. *P < 0.05.
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Figure 2: Effect of circulating insulin on plasma glucagon, epinephrine, and C-peptide responses to an equivalent fall in plasma glucose produced by infusion of insulin or phloridzin. The absence of an elevation in circulating insulin magnified the glucagon response, despite identical suppression of C-peptide increments of epinephrine. *P < 0.05.

Mentions: To test the effects of circulating insulin on glucagon responses to hypoglycemia, we intravenously infused rats with either insulin or phloridzin and allowed plasma glucose to fall to ∼70 mg/dl using the glucose clamp technique. Plasma insulin declined with phloridzin (7 ± 1 to 4 ± 1 μU/ml) and rose with insulin (8 ± 1 to 151 ± 21 μU/ml) infusion, but plasma glucose was identically reduced in both groups (Fig. 1). The exogenous glucose infusion rate (GIR) to maintain identical hypoglycemia was, however, markedly higher with insulin hypoglycemia compared with phloridzin (8.7 ± 0.3 vs. 0.5 ± 0.1 mg/kg/min; insulin vs. phloridzin P < 0.01). Glucagon levels increased during both phloridzin-induced (33 ± 12 baseline to 777 ± 122 ng/l) and insulin-induced (55 ± 10 to 178 ± 45 ng/l) hypoglycemia (P < 0.01), however, the magnitude of the rise was fourfold to fivefold greater in the absence of systemic hyperinsulinemia. This difference occurred despite identical 70–90% decreases in C-peptide levels and comparable increases in plasma catecholamines (Fig. 2). To evaluate whether the phloridzin infusion might act directly to stimulate glucagon secretion, we administered phloridzin while maintaining euglycemia using a variable glucose infusion. Under these conditions, plasma glucagon remained unchanged (38 ± 12 baseline vs. peak levels of 55 ± 11 ng/l during clamp, n = 6; P = not significant [NS]), suggesting the lack of a direct effect on α-cell secretion. Because these studies do not distinguish between the relative contribution of intraislet and hypothalamic insulin to the disparate glucagon response, additional studies were conducted to manipulate VMH insulin action under hyperinsulinemic and hypoinsulinemic hypoglycemia.


Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo.

Paranjape SA, Chan O, Zhu W, Horblitt AM, McNay EC, Cresswell JA, Bogan JS, McCrimmon RJ, Sherwin RS - Diabetes (2010)

Effect of circulating insulin on plasma glucagon, epinephrine, and C-peptide responses to an equivalent fall in plasma glucose produced by infusion of insulin or phloridzin. The absence of an elevation in circulating insulin magnified the glucagon response, despite identical suppression of C-peptide increments of epinephrine. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874714&req=5

Figure 2: Effect of circulating insulin on plasma glucagon, epinephrine, and C-peptide responses to an equivalent fall in plasma glucose produced by infusion of insulin or phloridzin. The absence of an elevation in circulating insulin magnified the glucagon response, despite identical suppression of C-peptide increments of epinephrine. *P < 0.05.
Mentions: To test the effects of circulating insulin on glucagon responses to hypoglycemia, we intravenously infused rats with either insulin or phloridzin and allowed plasma glucose to fall to ∼70 mg/dl using the glucose clamp technique. Plasma insulin declined with phloridzin (7 ± 1 to 4 ± 1 μU/ml) and rose with insulin (8 ± 1 to 151 ± 21 μU/ml) infusion, but plasma glucose was identically reduced in both groups (Fig. 1). The exogenous glucose infusion rate (GIR) to maintain identical hypoglycemia was, however, markedly higher with insulin hypoglycemia compared with phloridzin (8.7 ± 0.3 vs. 0.5 ± 0.1 mg/kg/min; insulin vs. phloridzin P < 0.01). Glucagon levels increased during both phloridzin-induced (33 ± 12 baseline to 777 ± 122 ng/l) and insulin-induced (55 ± 10 to 178 ± 45 ng/l) hypoglycemia (P < 0.01), however, the magnitude of the rise was fourfold to fivefold greater in the absence of systemic hyperinsulinemia. This difference occurred despite identical 70–90% decreases in C-peptide levels and comparable increases in plasma catecholamines (Fig. 2). To evaluate whether the phloridzin infusion might act directly to stimulate glucagon secretion, we administered phloridzin while maintaining euglycemia using a variable glucose infusion. Under these conditions, plasma glucagon remained unchanged (38 ± 12 baseline vs. peak levels of 55 ± 11 ng/l during clamp, n = 6; P = not significant [NS]), suggesting the lack of a direct effect on α-cell secretion. Because these studies do not distinguish between the relative contribution of intraislet and hypothalamic insulin to the disparate glucagon response, additional studies were conducted to manipulate VMH insulin action under hyperinsulinemic and hypoinsulinemic hypoglycemia.

Bottom Line: However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression.Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist.Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA. sachin.paranjape@yale.edu

ABSTRACT

Objective: Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention.

Research design and methods: Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions.

Results: As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist.

Conclusions: Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

Show MeSH
Related in: MedlinePlus