Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo

Gem-deficient mice were glucose intolerant.

<p><b>A</b>) Eight (8) week old Gem^−/− mice had impaired glucose homeostasis on glucose tolerance testing (GTT). <b>B</b>) Glucose tolerance was also significantly worse in 12 week old Gem^−/− mice. <b>C</b>) Glucose stimulated insulin secretion in vivo was impaired in Gem^−/− mice. <b>D</b>) Whole body insulin sensitivity was un-altered in Gem^−/− mice, as indicated by insulin tolerance tests. <b>E</b>) Insulin release in isolated islets was impaired in Gem^−/− mice. <b>F</b>) Glucose stimulated increase in ATP content was normal in Gem^−/− mice. Error bars indicate ±1SEM. * = p&lt;0.05, ** = p&lt;0.01, *** = p&lt;0.001.</p

Gem-deficient mice have impaired calcium flux.

<p><b>A</b>) Gem^+/+ islets exposed to 11.1 mM glucose establish regular calcium oscillations. <b>B</b>) In contrast, islets from Gem^−/− mice have impaired oscillations. <b>C</b>) The calculated calcium at 11.1 mM glucose is significantly lower in Gem^−/− islets. Error bars indicate ±1SEM. * = p&lt;0.05.</p

Calcium oscillations are slower in Gem^−/− mice.

<p><b>A</b>) Wild-type mice (Gem^+/+) have normal amplitude and frequency of calcium oscillations after exposure to 11.1 mM glucose. <b>B</b>) In contrast, Gem^−/− islets display smaller amplitude oscillations of lower frequency. <b>C</b>) Oscillation cycle time was slower in Gem-null islets. Error bars indicate ±1SEM. ** = p&lt;0.01.</p