Brainstem Mechanism of the Vagal Loss in Type 2 Diabetes
Vagal deterioration is an integral part in the development of type 2 diabetic (T2D) complications. Brainstem thyrotropin-releasing hormone (TRH) plays an important role in the regulation and dysregulation of vagal efferent functions. The TRH-synthesizing raphe nuclei project to the dorsal vagal complex (DVC). TRH analog microinjected into the DVC or injected intracisternally (ic) induces potent vagally mediated stimulation of gastric acid secretion/contractility, pancreatic insulin secretion, and decreases heart rate. Disturbances in the vagal-activating function of TRH were found in a polygenetic T2D model, the Goto-Kakizaki (GK) rats. Brainstem TRH and TRH receptor 1 in the DVC are decreased in GK rats. After ic TRH analog, GK rats showed an absence of the vagal mediated gastric acid response, potentiated hyperglycemic response with reduced insulin secretion, and acute congestive heart failure due to constantly hypertensive and tachycardic responses with a lack of vagal counterregulation. This proposal is to test the Hypothesis that genetic- and diet-related neurodegeneration in the DVC leads to TRH dysregulation and vagal deterioration in T2D. Normal diet-fed (ND) Wistar, high fat-fed (HFD) Wistar and ND T2D GK rats will be used. In Aim I, real-time PCR, Western blotting and immunohistochemistry will be performed to assess markers of neurodegeneration/apoptosis/insulin resistance, gene expression of neuropeptides, transmitters and receptors, and enzymes involved in neuronal metabolism in the DVC of ND Wistar rats, HFD Wistar rats and GK rats. In Aim II, functional studies will be performed to assess insulin secretion after DVC microinjection of TRH analog, to assess whether there is a reduced vagal responsiveness to TRH action on the DVC in HFD Wistar rats and T2D GK rats. In addition, TRH signal transduction mediators in the DVC will be studied after ic TRH analog in these rat models. Significance: the proposed studies will lead to a better understanding of the mechanisms responsible for the vagal loss in T2D, and provide fundamental knowledge for establishing brainstem TRH as a potential target to prevent and treat diabetes and its multisystemic complications.

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