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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 local blockade of VMH insulin during insulin-induced hypoglycemia (above) and VMH delivery of insulin during phloridzin-induced hypoglycemia (below) on GIR, peak glucagon, C-peptide, and epinephrine levels. Blockade of VMH insulin action reduced GIRs and amplified glucagon responses during systemic insulin infusion, whereas VMH insulin microinjection during phloridzin infusion increased GIR and suppressed glucagon responses. (All values ± SEM, *P < 0.05.)
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Figure 3: Effect of local blockade of VMH insulin during insulin-induced hypoglycemia (above) and VMH delivery of insulin during phloridzin-induced hypoglycemia (below) on GIR, peak glucagon, C-peptide, and epinephrine levels. Blockade of VMH insulin action reduced GIRs and amplified glucagon responses during systemic insulin infusion, whereas VMH insulin microinjection during phloridzin infusion increased GIR and suppressed glucagon responses. (All values ± SEM, *P < 0.05.)

Mentions: To investigate whether the observed disparate glucagon responses to hypoglycemic stimuli could at least in part be attributed to differences in the exposure of the VMH to insulin, we microinjected specific anti-insulin or control (noninsulin binding) affibodies bilaterally into the VMH to locally bind and reduce local insulin levels during a 6 mU/kg/min hyperinsulinemic hypoglycemic clamp. Blockade of insulin action within the VMH reduced by 50% the GIR required to maintain the same hypoglycemic plateau compared with microinjection of a control affibody (4.4 ± 0.4 anti-insulin affibody vs. 8.7 ± 0.3 mg/kg/min control, P < 0.05). This effect was associated with a 2.5-fold greater glucagon increase in rats that received the VMH anti-insulin affibody (430 ± 95 anti-insulin affibody vs. 178 ± 45 ng/l control affibody; P < 0.05). In contrast, blockade of insulin within the VMH had no effect on the suppression of either C-peptide or catecholamine levels during hypoglycemia, suggesting that insulin acts directly on the VMH to selectively suppress glucagon secretion independent of intraislet insulin or input from circulating catecholamines (Fig. 3).


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 local blockade of VMH insulin during insulin-induced hypoglycemia (above) and VMH delivery of insulin during phloridzin-induced hypoglycemia (below) on GIR, peak glucagon, C-peptide, and epinephrine levels. Blockade of VMH insulin action reduced GIRs and amplified glucagon responses during systemic insulin infusion, whereas VMH insulin microinjection during phloridzin infusion increased GIR and suppressed glucagon responses. (All values ± SEM, *P < 0.05.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: Effect of local blockade of VMH insulin during insulin-induced hypoglycemia (above) and VMH delivery of insulin during phloridzin-induced hypoglycemia (below) on GIR, peak glucagon, C-peptide, and epinephrine levels. Blockade of VMH insulin action reduced GIRs and amplified glucagon responses during systemic insulin infusion, whereas VMH insulin microinjection during phloridzin infusion increased GIR and suppressed glucagon responses. (All values ± SEM, *P < 0.05.)
Mentions: To investigate whether the observed disparate glucagon responses to hypoglycemic stimuli could at least in part be attributed to differences in the exposure of the VMH to insulin, we microinjected specific anti-insulin or control (noninsulin binding) affibodies bilaterally into the VMH to locally bind and reduce local insulin levels during a 6 mU/kg/min hyperinsulinemic hypoglycemic clamp. Blockade of insulin action within the VMH reduced by 50% the GIR required to maintain the same hypoglycemic plateau compared with microinjection of a control affibody (4.4 ± 0.4 anti-insulin affibody vs. 8.7 ± 0.3 mg/kg/min control, P < 0.05). This effect was associated with a 2.5-fold greater glucagon increase in rats that received the VMH anti-insulin affibody (430 ± 95 anti-insulin affibody vs. 178 ± 45 ng/l control affibody; P < 0.05). In contrast, blockade of insulin within the VMH had no effect on the suppression of either C-peptide or catecholamine levels during hypoglycemia, suggesting that insulin acts directly on the VMH to selectively suppress glucagon secretion independent of intraislet insulin or input from circulating catecholamines (Fig. 3).

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