Regulating Glucagon Signaling Essential in Preventing Type II Diabetes

A recent paper described the molecular mechanism that regulates the gluconeogenetic pathway that generates glucose from noncarbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids.

Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when glucose levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High blood glucose levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at a stable level. Global control of gluconeogenesis is mediated by glucagon (released when blood glucose is low); it triggers phosphorylation of enzymes and regulatory proteins by Protein Kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis.

In a paper published in the April 8, 2012, online edition of the journal Nature investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) showed that in mice glucagon stimulated CREB (cAMP response element-binding) coactivator CRTC2 ( CREB regulated transcription coactivator 2) dephosphorylation in liver cells by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase. Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic pathway.

"In insulin-resistant type II diabetic individuals, the CRTC2 switch is turned on too strongly because the insulin signal is not getting through," said senior author Dr. Marc Montminy, professor of peptide biology at the Salk Institute for Biological Studies. "As a result, the liver produces too much glucose and the level of glucose in the blood stream is too high. Over a period of 10 to 20 years, the abnormal elevation of glucose leads to chronic complications including heart disease, blindness, and kidney failure. If you control these switches, you can control the production of glucose, which is really at the heart of the problem of type II diabetes. We obviously have a lot of work to do to find out whether such a strategy might work in humans."

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Salk Institute for Biological Studies