Glycans in metabolic origins of common disease (106.3)

Abstract

Acquired alterations of protein glycosylation can cause disease. For example, the GnT‐4a enzyme produces an N‐glycan linkage essential for pancreatic beta cell glucose transport, glucose‐stimulated insulin secretion (GSIS), and physiological glucose tolerance. Acquired deficiency of GnT4a occurs in Type 2 diabetes (T2D) and in the obesity‐associated mouse model of T2D. Beta cell glucose transporters lacking GnT‐4a glycosylation are internalized and degraded, resulting in glucose intolerance, loss of GSIS, and insulin resistance. Enforced beta cell‐specific GnT‐4a expression protects obese mice from diabetes in large part by maintaining glucose transporters at the plasma membrane. A computational model of glucose transport was recently developed that identified a metabolic threshold crossed in T2D whereby diminished glucose transport disrupts glycolysis. These findings have provided a foundation for novel approaches to prevent obesity‐associated diabetes. Yet it is unclear why species have conserved a mechanism eliminating pancreatic beta cell glucose transport and impairing cellular functions. It is known that fasting leads to glucose intolerance and the loss of GSIS. We have hypothesized that beta cell GnT‐4a function may be diminished during fasting as an advantageous response to impending starvation. Metabolic parameters measured during fasting indicate that down modulation of GnT‐4a is an advantageous mechanism of thrift to prolong survival during famine. When induced over long periods of time during nutrient and lipid excess as in obesity, this mechanism becomes pathogenic and causes diabetes.