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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK050154-05A1S1
Application #
6571313
Study Section
Metabolism Study Section (MET)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
1996-12-19
Project End
2005-06-30
Budget Start
2001-09-20
Budget End
2002-06-30
Support Year
5
Fiscal Year
2002
Total Cost
$25,000
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Mundinger, Thomas O; Mei, Qi; Foulis, Alan K et al. (2016) Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves. Diabetes 65:2322-30
Mundinger, Thomas O; Taborsky Jr, Gerald J (2016) Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation. Diabetologia 59:2058-67
Mundinger, Thomas O; Cooper, Ellis; Coleman, Michael P et al. (2015) Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses. Am J Physiol Endocrinol Metab 309:E246-55
Meek, Thomas H; Dorfman, Mauricio D; Matsen, Miles E et al. (2015) Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia. Diabetes 64:2376-87
Taborsky Jr, G J; Mei, Q; Hackney, D J et al. (2014) The search for the mechanism of early sympathetic islet neuropathy in autoimmune diabetes. Diabetes Obes Metab 16 Suppl 1:96-101
Taborsky Jr, Gerald J; Mei, Qi; Bornfeldt, Karin E et al. (2014) The p75 neurotrophin receptor is required for the major loss of sympathetic nerves from islets under autoimmune attack. Diabetes 63:2369-79
Meek, Thomas H; Wisse, Brent E; Thaler, Joshua P et al. (2013) BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production. Diabetes 62:1512-8
Meek, Thomas H; Matsen, Miles E; Dorfman, Mauricio D et al. (2013) Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. Endocrinology 154:3067-76
Taborsky Jr, Gerald J; Mundinger, Thomas O (2012) Minireview: The role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology 153:1055-62

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