Loss of glucose sensing with vagal neurocircuits contributes to glycemic dysregulation and gastrointestinal dysfunction in a mouse model of Type 2 diabetes
Diabetic gastroparesis, (delayed gastric emptying associated with other upper gastrointestinal (GI) symptoms such as early satiety, fullness, abdominal pain, nausea and bloating) is experienced by up to 65% of patients with Type 2 diabetes. Despite the annual US economic cost of diabetic gastroparesis (estimated at approximately $3.5 billion) and the considerable impact upon the quality of life of patients, the pathophysiology of diabetic gastroparesis remains to be elucidated fully. Although the GI tract possesses intrinsic neural plexuses that allow a significant degree or autonomy over GI functions, the parasympathetic nervous system, via the vagus nerve, exerts a finely-tuned and complex influence over GI functions including motility, tone and emptying. Studies in both humans and animal models have demonstrated that vagal control of the stomach and upper GI tract is modulated by physiological fluctuations in glycemic levels and is compromised by hyperglycemia and long-standing diabetes; the mechanism by which this maladaptation occurs has not been investigated. Our preliminary evidence has led to the novel central hypothesis that loss of glucose sensing within vagal neurocircuits precedes, and may even contribute to, the development of glycemic dysregulation and GI dysfunction. In the present study, we will use a congenic strain of mice, the NONcNZO10/LtJ mouse that was developed to mimic human obesity-induced Type 2 diabetes and metabolic syndrome. This mouse provides an excellent (though to date unstudied) translational model in which a multi-system disease such as diabetes can be investigated on complex autonomic outcomes such as gastrointestinal functions. To investigate the pathophysiology of diabetic gastroparesis, we will use a variety of techniques to correlate the time-course and onset of disrupted vagal neural signaling with dysregulated gastric functions. We anticipated that the results from the present proposal will provide information regarding the temporal nature of diabetes-induced dysregulation within vagal neurocircuits controlling GI functions as well as the insights into the mechanism behind these alterations

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