Our ten-year study of nondiabetic animals and humans shows that the glucagon response to insulin-induced hypoglycemia (IIH) is autonomically mediated. Since this specific glucagon response is lost early in type 1 diabetes, an early autonomic defect may be responsible. Our recent preliminary data demonstrate an early, marked and selective damage to islet sympathetic nerve terminals in BB diabetic rats. Therefore, our first specific aim is to relate the time course and magnitude of this nerve terminal damage to impaired glucagon responses in BB diabetic rats. Islet sympathetic nerve terminals will be visualized by dual immunohistochemistry for vesicular monoamine transporter 2 (VMAT2) and glucagon. Our second specific aim is to prevent the loss of the glucagon response to IIH by preventing nerve terminal damage using nerve growth factor (NOF) to treat BB rats before the onset of their diabetes. Our third specific aim is to reproduce the loss of the glucagon response to IIH in diabetes resistant BB rats by a combination of nerve terminal damage induced by 6-hydroxydopamine (6-OHDA) and islet B-cell loss induced by streptozotocin(STZ). Since nerve terminal damage impairs the responsiveness of neuronal cell bodies to activation, our fourth specific aim is to determine the magnitude of this impaired responsiveness in BB diabetic rats and its contribution to the loss of the glucagon response to IIH. The response of these neurons will be assessed by counting those that express nuclear Fos. Thus, celiac ganglia (CG) Fos expression will be assessed in response to clamped IIH before and during the first week of BB diabetes and in diabetic rats pretreated with either systemic NGF or ganglionic NGF induced by viral transfection. The final specific aim is to determine the contributions of nerve terminal damage, islet B-cell loss and loss of ganglionic NGF to this impaired responsiveness. Thus, diabetes resistant BB rats will receive a combination of 6-OHDA and STZ and the CG Fos responses to clamped IIH will be measured. Finally, ganglionic levels of NGF will be measured by ELISA in this and previous experiments to directly relate them to the impaired responsiveness. Together these experiments will determine the timing, magnitude and location (nerve terminals or cell bodies) of islet sympathetic dysfunction in BB diabetic rats and its contribution to the loss of the glucagon response to IIH.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Jones, Teresa L Z
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University of Washington
Internal Medicine/Medicine
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Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J et al. (2017) Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure. Diabetes 66:823-834
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