Glucose Modulation of Vagal Sensory Signaling is Compromised in a Mouse Model of Type 2 Diabetes

Abstract

Studies in both humans and animal models have demonstrated that vagal control of the upper gastrointestinal (GI) tract is compromised by hyperglycemia and diabetes; the mechanism by which this maladaptation occurs has not been investigated fully. The aim of the present study was to investigate whether disrupted glucose sensing within vagal neurocircuits precedes, and may even contribute to, the development of glycemic dysregulation. The NONcNZO10/LtJ (NON) mouse is a congenic strain developed to mimic human obesity-induced Type 2 diabetes and metabolic syndrome. After being weaned onto a 10-11% fat diet, male NON mice develop Type 2 diabetes spontaneously. To measure the ability of glucose to modulate glutamate release from the central terminals of vagal afferents, whole cell patch clamp recordings were made from second order nucleus of the tractus solitarius (NTS) neurons in thin brainstem slices. The table below summarizes the effects of glucose on mEPSC frequency in control and in NON mice before (prediabetes), during the transition towards (transition) and after the development of diabetes expressed as a percentage of the frequency in control (5mM) extracellular glucose. Glucose Control (n=5) Pre-diabetes (n=3) Transition (n=3) Diabetes (n=4) 1mM 66.5±3.3%* 82±21.3% 110±4% 100±7% 5mM 100±0% 100±0% 100±0% 100±0% 10mM 157±15.9%* 119±4% 93±6% 101±6% 20mM 180±17.9%* 125±9%* 94±3% 96±10% These results suggest that the ability of extracellular glucose to modulate vagal afferent signaling is compromised even prior to the development of diabetes. Since the NON mouse strain mimics human obesity-induced Type 2 diabetes, it may provide an excellent model in which to investigate the pathophysiology of dysregulated vago-vagal reflex control of the gastrointestinal tract.