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Loss of Beta-Cell EPAC2A Activity Linked to Development of Type II Diabetes

By BiotechDaily International staff writers
Posted on 25 Apr 2013
Diabetes researchers have discovered how the protein EPAC2A (guanine nucleotide exchange factors for Ras-like small GTPases) affects glucose metabolism and how loss of this protein activity may contribute to the development of type II diabetes.

Incretin hormone action on beta cells stimulates in parallel two different intracellular cyclic AMP-dependent signaling branches mediated by PKA (protein kinase A) and EPAC2A. Both pathways contribute towards potentiation of glucose-stimulated insulin secretion. However, the overall functional role of EPAC2A in beta cells as it relates to in vivo glucose homeostasis has not been well understood.

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta-cells of the islets of Langerhans after eating, even before blood glucose levels become elevated. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. Furthermore, they also inhibit glucagon release from the alpha cells of the islets of Langerhans. The two main candidate molecules that fulfill criteria for an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).

In the current study, investigators at Johns Hopkins University (Baltimore, MD, USA) examined the interaction between incretins and EPAC2A. To do this they genetically engineered a line of mice lacking the gene for EPAC2A production.

Results published in the April 11, 2013, online edition of the journal Diabetes revealed that EPAC2A deficiency did not impact glucose-stimulated insulin secretion in the knockout mice under normal conditions. However, when the mice were exposed to diet-induced insulin resistance or incretin hormone stimulation of beta cells, EPAC2A was required for the increased beta-cell response to secretory demand. Under these circumstances, EPAC2A was required for potentiating the early dynamic increase in islet calcium levels after glucose stimulation, which is reflected in potentiated first phase insulin secretion.

“It is as if during these extreme conditions, the body calls upon EPAC2 as backup to help it balance insulin supply and demand,” said senior author Dr. Mehboob Hussain, associate professor of pediatrics, medicine, and biological chemistry at Johns Hopkins University. “Drugs that precision-target failing pancreatic cells and restore or boost their function have become the holy grail of diabetes research. We believe that our finding establishes a pathway to do just that.”

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