Pancreatic sympathetic nerves contribute to increased glucagon secretion during severe hypoglycemia in dogs.

To determine if pancreatic sympathetic nerves can contribute to increased glucagon secretion during hypoglycemia, plasma glucagon and pancreatic glucagon secretion in situ were measured before and during insulin-induced hypoglycemia in three groups of halothane-anesthetized dogs. All dogs were bilaterally vagotomized to eliminate the input from pancreatic parasympathetic nerves. One group of dogs received only vagotomy (VAGX). A second group was vagotomized and adrenalectomized (VAGX + ADX). A third group received vagotomy, adrenalectomy, plus surgical denervation of the pancreas (VAGX + ADX + NERVX) to prevent activation of pancreatic sympathetic nerves. In dogs with VAGX only, hypoglycemia increased plasma epinephrine (Epi), pancreatic norepinephrine (NE) output (+320 +/- 140 pg/min, P < 0.05), arterial plasma glucagon (+28 +/- 12 pg/ml, P < 0.01), and pancreatic glucagon output (+1,470 +/- 370 pg/min, P < 0.01). The addition of ADX eliminated the increase of Epi but did not increase pancreatic NE output (+370 +/- 190 pg/min, P < 0.025), arterial plasma glucagon (+20 +/- 5 pg/ml, P < 0.01), or pancreatic glucagon output (+810 +/- 200 pg/min, P < 0.01). In contrast, the addition of pancreatic denervation eliminated the increase of pancreatic NE output (-20 +/- 40 pg/min, P < 0.05 vs. VAGX), the arterial glucagon (+1 +/- 2 pg/ml, P < 0.01 vs. VAGX), and pancreatic glucagon output responses (+210 +/- 280 pg/min, P < 0.025 vs. VAGX) to hypoglycemia. Thus activation of pancreatic sympathetic nerves can contribute to the increased glucagon secretion during severe insulin-induced hypoglycemia in dogs

Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia

In summary, this article briefly reviews the evidence that three separate autonomic inputs to the islet are capable of stimulating glucagon secretion and that each is activated during IIH. We have reviewed our evidence that these autonomic inputs mediate the glucagon response to IIH, both in non-diabetic animals and humans. Finally, we outline our new preliminary data suggesting an eSIN in an autoimmune animal model of T1DM. We conclude that the glucagon response to IIH is autonomically mediated in non-diabetic animals and humans. We further suggest that at least one of these autonomic inputs, the sympathetic innervation of the islet, is diminished in autoimmune T1DM. These data raise the novel possibility that an autonomic defect contributes to the loss of the glucagon response to IIH in T1DM

Autonomic mechanism and defects in the glucagon response to insulin-induced hypoglycaemia

In summary, this article briefly reviews the evidence that three separate autonomic inputs to the islet are capable of stimulating glucagon secretion and that each is activated during IIH. We have reviewed our evidence that these autonomic inputs mediate the glucagon response to IIH, both in non-diabetic animals and humans. Finally, we outline our new preliminary data suggesting an eSIN in an autoimmune animal model of T1DM. We conclude that the glucagon response to IIH is autonomically mediated in non-diabetic animals and humans. We further suggest that at least one of these autonomic inputs, the sympathetic innervation of the islet, is diminished in autoimmune T1DM. These data raise the novel possibility that an autonomic defect contributes to the loss of the glucagon response to IIH in T1DM

Corelease of galanin and NE from pancreatic sympathetic nerves during severe hypoglycemia in dogs.

To determine whether norepinephrine (NE) and galanin are coreleased during reflex activation of the sympathetic nervous system by hypoglycemia, we administered insulin to halothane-anesthetized (0.8%) dogs and measured the spillover of NE and galanin-like immunoreactivity (GLIR) into pancreatic venous plasma. Insulin injection produced hypoglycemia [plasma glucose (PG) = 34 +/- 3 mg/dl] but did not activate pancreatic noradrenergic (delta pancreatic NE output = +20 +/- 130 pg/min) or galaninergic nerves (delta GLIR output = +40 +/- 50 fmol/min). To determine whether more severe hypoglycemia would activate these nerves, insulin was administered to dogs infused with somatostatin (SS; 2.5 micrograms/min) to block the counterregulatory increase of glucagon secretion. SS reduced the glucagon response to hypoglycemia by greater than 90%, which allowed PG to decrease to 14 +/- 1 mg/dl. Pancreatic NE output increased by 470 +/- 140 pg/min (P less than 0.005); however, pancreatic GLIR output did not increase significantly (delta = +70 +/- 50 fmol/min). When SS was discontinued, pancreatic NE output increased by 490 +/- 200 pg/min (P less than 0.025), and GLIR output increased by an additional +160 +/- 70 fmol/min (P less than 0.025; total delta from baseline = +230 +/- 90 fmol/min, P less than 0.025), suggesting that SS may restrain pancreatic NE and galanin release. Pancreatic NE and GLIR spillover were also increased during severe hypoglycemia when ganglionic neurotransmission was partially impaired with hexamethonium but not when the neural pathway was interrupted by spinal cord transection. We conclude that NE and galanin are coreleased from pancreatic sympathetic nerves when these nerves are centrally activated during severe hypoglycemia in halothane-anesthetized dogs

The canine sympathetic neuropeptide galanin: a neurotransmitter in pancreas, a neuromodulator in liver.

Our laboratory has investigated the role of the neuropeptide galanin in the sympathetic neural control of both the canine endocrine pancreas and liver. Galanin mRNA and peptide were found in the neuronal cell bodies of the celiac ganglion, which projects fibers to both organs. Galanin fibers formed dense networks around the islets. Galanin was released from these nerves and the amount released appeared sufficient to markedly inhibit basal insulin secretion. We therefore propose that galanin is a sympathetic neurotransmitter in canine endocrine pancreas. Galanin was also found in hepatic nerves usually co-localized with tyrosine hydroxylase, a sympathetic marker. Further, intraportal administration of the sympathetic neurotoxin, 6-hydroxydopamine, abolished galanin staining in the hepatic parenchyma. We evaluated the role of galanin in mediating the actions of sympathetic nerves to increase hepatic glucose production and decrease hepatic arterial conductance. Local infusion of synthetic galanin had little effect by itself, but it did potentiate the action of norepinephrine to stimulate hepatic glucose production, demonstrating a neuromodulatory action. In contrast, galanin had no effect on hepatic arterial blood flow. We therefore propose that in the liver galanin functions as a neuromodulator of norepinephrine's metabolic action