Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses

Abstract

Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes.

Intrapancreatic Ganglia and Neural Regulation of Pancreatic Endocrine Secretion

“…Patients with type 1 diabetes show a severe loss of islet sympathetic nerves. Moreover, rats with short-term hyperglycemia show a dysfunction in the islet sympathetic innervation from the celiac ganglia, while hyperphagic weaning mice show markedly increased sympathetic innervation compared to control mice (Mundinger et al, 2015, 2016; Tang et al, 2018b).…”

Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation

“…To test which of these two methods gave the best functional estimate of the sympathetic innervation of the islet, we activated the postganglionic nerves innervating the islet in both STZ-diabetic rats [30] and ALX-diabetic mice [20] and measured the resultant glucagon response. We found that the glucagon response was unchanged, not tripled, when compared with that of non-diabetic controls.…”

“…The hyper-response in humans may be due to an upregulation of adrenergic receptors on the alpha cell, secondary to loss of islet sympathetic nerves, but experiments specifically designed to directly test this hypothesis are needed. This glucagon impairment is due neither to loss of beta cells nor to diabetic hyperglycaemia because when both are induced by non-immune, chemical destruction of islet beta cells, which does not cause loss of islet sympathetic nerves, the glucagon response to activation of postganglionic sympathetic axons and terminals is not impaired [20, 30]. In contrast, the glucagon impairment seen in autoimmune diabetes, which does cause the loss of islet sympathetic nerves, is likely due to decreased neurotransmitter release.…”

“…Currently, there are barriers to correctly performing and correctly interpreting such studies In particular, the inhibitory effect of short-term diabetic hyperglycaemia on sympathetic ganglia and the inhibitory effect of exogenous insulin on alpha cell responsiveness must be accounted for. A recent study has shown that even 1 week of severe hyperglycaemia can impair neurotransmission across coeliac ganglia [30]. Since coeliac ganglia project sympathetic nerves to the pancreas [81], such impaired ganglionic neurotransmission results in the impairment of sympathetically mediated glucagon responses when preganglionic nerves are activated [30].…”

“…A recent study has shown that even 1 week of severe hyperglycaemia can impair neurotransmission across coeliac ganglia [30]. Since coeliac ganglia project sympathetic nerves to the pancreas [81], such impaired ganglionic neurotransmission results in the impairment of sympathetically mediated glucagon responses when preganglionic nerves are activated [30]. This implies that previous conclusions that the impaired glucagon response to IIH in diabetic animals is due solely to loss of beta cell switch-off may need to be amended to include the contribution of a previously unrecognised impairment in the sympathetic islet pathway.…”