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

Abstract

OBJECTIVEInsulin released by the β-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 METHODSInitially 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 μU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a γ-aminobutyric acid A (GABAA) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions.RESULTSAs 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 GABAA receptor agonist.CONCLUSIONSTogether, these data suggest that insulin's inhibitory effect on α-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.

Evidence for Central Regulation of Glucose Metabolism

“…These effects were blocked by coinfusion of PI3K inhibitors into the ICV. Further studies also showed that intrahypothalamic insulin administration suppressed pancreatic glucagon release under hypoglycemic clamp conditions in rats (25).…”

Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

“…For example, insulin acts indirectly via insulin receptors expressed on the ventromedial hypothalamus to modulate peripheral glucose homoeostasis in addition to its direct action on target tissues (Diggs-Andrews et al 2010, Paranjape et al 2010. We therefore proposed the hypothesis that the inhibitory effect of SST on insulin release may similarly be at least partly dependent on central activation of SSTRs by SST.…”

Peripheral glucose homeostasis: does brain insulin matter?

“…Loss of insulin signaling in neurons expressing Glut4 markedly increases hyperglycemia in mice with peripheral insulin resistance (18). Furthermore, in nondiabetic rats, acute blockade of insulin signaling within the ventromedial hypothalamus, a key glucose-sensing region, immediately stimulates glucagon secretion (7). Impaired insulin secretion also appeared in preliminary studies using virus-induced knockdown of ventromedial hypothalamus InsR (R.S.…”

“…Further improvements of INS1 cells in terms of insulin content and secretion were then obtained with clonal selection techniques to obtain a cell line called 823/13 (6). In work going on in parallel, the oncogene simian virus 40 large tumor antigen (SV40LT) was first used to make cells with β cell characteristics when HIT cells were generated from infected isolated islets from hamsters (7). Work in mice with the same oncogene then led to the generation of βTC cells (8) and MIN6 cells (9), which remain among the most widely used rodent pancreatic β cell lines today.…”

“…The brain is an insulin-sensitive organ; various studies have shown that insulin action in the brain affects energy and glu-cose homeostasis, neuroendocrine function, reward, memory, and learning (3,6,7). Neurons in many areas of the brain express insulin receptors (InsRs), and insulin, acting on these receptors, causes activation of PI3K and MAPK signaling pathways (8,9).…”