The Role of Colonic Short Chain Fatty Acids in Glucose Homeostasis

Abstract

The incidence of diabetes, now the 7th leading cause of death in the US, is rising worldwide. Hyperglycemia is a hallmark characteristic of diabetes, resulting in elevated blood glucose levels, due, in part, to chronic elevations in endogenous hepatic glucose production (GP). Normally, small intestinal nutrient-sensing mechanisms trigger negative feedback loops to inhibit GP, thereby maintaining proper glucose regulation. Macronutrients stimulate secretion of gut peptides, which can activate a gut-brain-liver axis to lower hepatic GP. More recently the gut microbiota has been implicated as a salient contributor to energy and glucose homeostasis, with prebiotic, non-digestible carbohydrate treatment, improving glucose tolerance in humans and rodents. One potential mechanism may be through the production of short chain fatty acids (SCFA), which are bacterial breakdown products of non-digestible dietary fibers occurring mainly in the large intestine. SCFAs are known to improve glucose and energy homeostasis but the exact mechanisms remain unknown. SCFAs increase gut peptide release and, therefore, have the potential to activate colonic sensing mechanisms to regulate glucose homeostasis following a meal. However, no one has assessed the postprandial production kinetics of SCFAs nor has anyone tested whether large intestinal SCFAs can lower hepatic glucose production. To examine this, we performed a fasting-refeeding study in both chow and HFD-fed rats and found that refeeding produced significant rises in postprandial large intestinal SCFA concentrations in chow, but not HFD fed rats. Furthermore, decreased postprandial SCFA levels were associated with increased adiposity and glucose intolerance. Utilizing pancreatic basal insulin euglycemic clamps we determined that the colonic administration of either 10mM or 100mM acetate, butyrate, or propionate, which are the 3 main SCFAs, were each able to decrease hepatic glucose production through a GLP-1R mediated neuronal gut-brain-liver axis, facilitated by celiac and hepatic vagal signaling pathways. Collectively, this work demonstrates the glucoregulatory signaling capacity of colonic SCFAs and that HFD induced impairments in postprandial SCFA rises may contribute to glucose dysregulation.