Our ten-year study of nondiabetic animals and humans shows that the glucagon response to insulin-induced hypoglycemia (IIH) is largely autonomically mediated. Since this specific glucagon response is lost early in type 1 diabetes, an early autonomic defect may be responsible. Indeed, we demonstrated an early sympathetic islet neuropathy (eSIN) in BB diabetic rats, diabetic NOD mice and now in human subjects with type 1 diabetes.
Specific Aim #1 : Determine if the loss of islet sympathetic nerves in human type 1 diabetes relates to their impaired glucagon responses. We will quantify the loss of islet nerves in autopsy samples from type 1 diabetic humans and determine if an impairment in this sympathetic A-cell pathway relates to the impairment of their glucagon response to IIH.
Specific Aim #2 : Determine if injury to the peri-islet Schwann cells (pSC), which protect and sustain islet sympathetic nerves, is the mechanism by which eSIN occurs. First, we will relate differing degrees of pSC injury to islet nerve loss in non-obese diabetic (NOD) mice. Second, we will administer glial toxins to determine if chemical injury to pSC causes nerve loss. Third, we will determine if this nerve loss is sufficient to impair the function of the sympathetic A-cell pathway. Finally, we will determine if this mechanism is islet- specific or autoimmune-specific by repeating these studies in the submandibular gland of the NOD mouse Specific Aim #3: Determine if restoring the islet nerves in BB diabetic rats corrects their impaired glucagon response to IIH. We will restore islet innervation by use of viral vectors encoding nerve growth factor while suppressing recurrent autoimmune attack on the islets and their ingrowing nerves. We will measure glucagon responses to IIH both before and after the reinnervation of the islets. Significance: Establishing that eSIN impairs the glucagon response to IIH and that reinnervation of the islet restores this response will provide new insight into the mechanism by which this response is lost in type 1 diabetes. Restoring the glucagon response to IIH will allow more intensive treatment of patients with type 1 diabetes which will in turn help prevent the long-term complications of this disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK050154-09A1
Application #
7141870
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
1996-12-19
Project End
2010-07-31
Budget Start
2006-09-30
Budget End
2007-07-31
Support Year
9
Fiscal Year
2006
Total Cost
$272,200
Indirect Cost
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108
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; 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; 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; 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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