Diabetes suppresses sympathetic neurotransmission and thereby glucagon secretion

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DESCRIPTION (provided by applicant): We have previously shown in non-diabetic animals and humans that the majority of the glucagon response to both moderate and marked insulin-induced hypoglycemia is mediated by the autonomic nervous system. This autonomic activation is caused by central neuroglucopenia and includes activation of pancreatic sympathetic nerves, which directly stimulate glucagon secretion. Very recent data demonstrate that activation of sympathetic nerves can be markedly suppressed by even short-term diabetic hyperglycemia: in vitro, high glucose impairs the activation of the nicotinic acetylcholine receptor (nAChR) that is required for neurotransmission across a prototypic sympathetic ganglion. In vivo, our preliminary data demonstrate marked suppression of nicotinic activation of the sympathetic neurons that project to the pancreatic islet Such data may explain why the glucagon response to insulin-induced hypoglycemia is lost in animals so soon after the development of non-autoimmune diabetes, despite the absence of structural neuropathies at this early stage of the disease. Therefore, the overall goal of this project is to determine the relationship of diabetic hyperglycemia to this suppression of sympathetic ganglionic neurotransmission and to determine the contribution of this suppression to impaired glucagon responses in diabetes. Our first Specific Aim is to determine the magnitude and duration of diabetic hyperglycemia needed to suppress ganglionic neurotransmission in the sympathetic-islet pathway and the ability of interventions to prevent or reverse that suppression. We will activate nicotinic acetylcholine receptors on the sympathetic neurons in the celiac ganglion and compare their fos mRNA responses between non-diabetic and diabetic animals. We will vary the magnitude of diabetic hyperglycemia, without insulin, by increasing urinary glucose excretion with a new SGLT2 inhibitor, dapagliflozin. We will vary the duration of diabetic hyperglycemia simply by adjusting the length of the experiment. To determine how long it takes to reverse the hyperglycemia- induced suppression of sympathetic ganglionic neurotransmission, we will restore euglycemia, without insulin, by infusing leptin into the cerebral ventricles of STZ diabetic rats. To prevent hyperglycemia-induced suppression of sympathetic ganglionic neurotransmission, we will use the Wallerian Degeneration Slow (Wlds) rat which our new Preliminary Data show to be resistant to this form of neural dysfunction. Our second Specific Aim will systematically examine the functional consequences of suppressed ganglionic neurotransmission for the impaired glucagon responses seen in diabetes. First we will prevent hyperglycemia- induced suppression of sympathetic ganglionic neurotransmission by using Wlds rats to demonstrate that it normalizes the glucagon response to the preganglionic nerve stimulation. Second, we will also evaluate the efficacy of antioxidant treatment to both reverse this suppression of sympathetic ganglionic neurotransmission and to restore this glucagon response. We will use these approaches to determine the specific contribution of that suppressed sympathetic activation makes to the overall impairment of the alpha cell's response to insulin- induced hypoglycemia, since the diabetes-induced impairment of this glucagon response may be due to multiple factors.