Diabetes mellitus is associated with severe debilitating complications which include a Diabetic Autonomic Neuropathy (DAN) characterized by decreased autonomic responsiveness of the heart. Approximately 50% of patients with diabetes for 10 years or more demonstrate DAN. Type I diabetics with evidence of DAN demonstrate a fivefold higher 5 year mortality and increased incidence of sudden death than those without DAN. Parasympathetic stimulation has been shown to protect the heart from the development of arrhythmias especially in the setting of myocardial infarction. Thus the increased incidence of sudden death in the diabetic population might reflect a predisposition to fatal arrhythmias in the presence of parasympathetic dysfunction. Parasympathetic response of the heart involves the interaction of the M2 muscarinic receptor, Gai2, and the inward rectifying K channel, (GIRK1)2/(Girk4)2 which stimulates IKACh and a decrease in beat rate and Gai2 and adenlyate cyclase which decreases the force of contraction. Insulin regulates levels of sterol response element binding proteins (SREBPs), which play a role in the control of cholesterol, fatty acid, and glucose metabolism. Preliminary data suggest that compared to non-diabetic WT, the type I diabetic Akita mouse demonstrates a decreased response to parasympathetic signaling and develops life threatening arrhythmias following myocardial infarction which are reversed by the muscarinic agonist carbamylcholine. Using this mouse 4 hypotheses will be tested: 1)that the Akita mouse is a model for DAN; demonstrates parasympathetic dysfunction, decreased IKACh decreased inhibition of 3-adrenergic stimulation of the heart 2) that hypoinsulinemia in diabetes results in a decrease in the expression of M2, Gai2, and GIRK1 in response to a decrease in SREBP 3) that the Type I diabetic Akita mouse is an animal model for the development of spontaneous life threatening arrhythmias following Ml and that parasympathetic dysfunction of DAN predisposes the heart to the development of arrhythmias and 4) that therapeutic interventions that increase SREBP such as insulin therapy or HMG-CoA reductase inhibitors increase M2, Gai2, and GIRK1 expression, reverse parasympathetic dysfunction and decrease the incidence of post Ml VT. This model offers a unique opportunity for new insights into mechanism and therapy of DAN and its relationship to arrhythmia and sudden death. ? ? ?
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