The goal of this proposal is to investigate the role of the autonomic nervous system in the production of the counterregulatory hormonal response, especially glucagon, to mild and moderate hypoglycemia as well as the response of the hormones during moderate exercise in normal and diabetic dogs. This information is potentially clinically important because patients with insulin-dependent diabetes have decreased counterregulatory responses and poor recovery from treatment-induced hypoglycemia and some are prone to exercise-induced hypoglycemia. This proposal examines the mechanisms for the impairment of this hypoglycemic response and the investigator hypothesizes that impaired activation of pancreatic nerves in diabetics significantly contributes to these problems and that demonstration of such a neural role may influence the approach to their treatment. The first part of the proposal, Specific Aims 1 to 3, propose to determine the role of the autonomic input to the islet to stimulate glucagon secretion during hypoglycemia. They propose the measure the norepinephrine spillover from the pancreas of conscious dogs using chronically implanted pancreatic venous catheters to confirm pancreatic nerve activation during moderate hypoglycemia. They also propose to test the hypothesis that hypoglycemia associated autonomic failure (HAAF) impairs the glucagon response by decreasing the activation of these nerves in non-diabetic dogs. They will then investigate the role of either HAAF in newly diabetic dogs, or chronic severe hyperglycemia, in longer term diabetic dogs assuming that neural disfunction will occur and thereby impaired glucagon response to hypoglycemia.
In Specific Aim 1, the effect of prior hypoglycemia on the activation of pancreatic nerves will be examined and it will be determined if there is a reduction of autonomic input and whether this is associated with impaired glucagon responses in non-diabetic dogs. The effect of hyperinsulinemia as opposed to hypoglycemia will be examined. In addition, the effect of glucocorticoids will be evaluated. Then the autonomic activation induced by the first hypoglycemic event will be blocked to assess whether subsequent impairment is mediated by this response. They will then assess whether localized islet hypoglycemia might mediate the impairment of glucagon responses during HAAF.
In Specific Aim 2, similar effects will be evaluated in newly diabetic dogs induced by alloxan but in particular the effect of local insulin deficiency will also be evaluated.
In Specific Aim 3, the model will be a chronically hyperglycemia diabetic dog undergoing similar evaluation. In addition, the effects of chronic hyperglycemia on the local stimulation (electric) of the peripheral parasympathetic neural pathway will be examined and the effect of autonomic agonists will be explored. In the second part of the proposal described in Specific Aim 4, they will document the degree of activation of the parasympathetic nerves during exercise and block retineural activation to quantify its role in mediating exercise-induced decrease of insulin and increase of glucagon secretion. Both pancreatic norepinephrine spillover and galanin spillover will be evaluated in normal and chronically diabetic dogs. In addition, local pancreatic sympathetic neurotransmitter release will be blocked with bretylium in order to assess its role in the pancreatic hormone response to exercise.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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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
Schools of Medicine
United States
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