A dominant role for glucose in β cell compensation of insulin resistance
Gordon C. Weir, Susan Bonner-Weir
Gordon C. Weir, Susan Bonner-Weir
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):81-83. https://doi.org/10.1172/JCI30862.
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Commentary

A dominant role for glucose in β cell compensation of insulin resistance

Abstract

Increased insulin secretion and expansion of pancreatic β cell mass work together to maintain normal glucose levels when insulin resistance develops. Changes in glucose concentration have long been known to have profound effects upon the rates of insulin secretion and β cell mass, but various other agents can also cause changes, raising questions about which mechanisms are dominant. Evidence favoring a dominant role for glucose is provided by Terauchi et al. in this issue of the JCI (see the related article beginning on page 246). Mice haploinsufficient for β cell glucokinase (Gck) were unable to increase their β cell mass in response to insulin resistance produced by high-fat feeding. Gck is known to be the glucose sensor for glucose metabolism in β cells. The study also provides strong evidence that insulin receptor substrate 2 (Irs2), which is known to have major effects on β cell growth and survival, is a key downstream mediator of the effects of glucose found in this study.

Authors

Gordon C. Weir, Susan Bonner-Weir

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Figure 1

The pathway from glucose metabolism to increased β cell mass through enhanced β cell replication and survival.

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The pathway from glucose metabolism to increased β cell mass through enh...
Glucose enters the β cell via glucose transporter 2 (Glut2; also known as Slc2a2) and is phosphorylated to glucose-6-phosphate (G6P) by the rate-limiting enzyme of glycolysis, Gck. Further metabolism of glucose increases the expression of Irs2, possibly through CREB phosphorylation at residue Ser133 as a result of increased cytosolic calcium levels generated via voltage-dependent calcium channels (VDCCs), the ER, and mitochondria. The calcium effect is likely mediated by calmodulin-dependent protein kinases (CaMKs). Calcium can also increase cAMP levels in β cells. Increased Irs2 activity can then activate a signalling cascade that leads to β cell replication (via FoxO1 nuclear exclusion) and β cell survival (via PKB/Akt). This pathway can be augmented by cAMP signaling through GLP1 receptors (Glp1r). The contributions of the insulin and Igf1 receptors (Insr and Igf1r, respectively) are likely to be permissive. P, phosphate group.