Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects.
Bottom Line: However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood.Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway.This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.
Affiliation: From the Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.Show MeSH
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Mentions: Glucose triggers calcium entry and insulin secretion via its oxidative phosphorylation in the mitochondria and the generation of ATP, leading to closure of KATP channels. We hypothesized that the defect in glucose-induced calcium dynamics reflected a defect in mitochondrial metabolism. To test this idea, we examined insulin secretion from βLKB islets in response to mitochondrial fuels. Perifusion of islets with glutamine (which can enter the TCA cycle through activity of glutamate dehydrogenase) did not increase insulin secretion at low glucose levels in both βLKB and control islets. However, glutamine combined with leucine, an activator of glutamate dehydrogenase (40), did trigger insulin secretion at low glucose (Fig. 3A), and this response was stronger in βLKB islets compared with controls. Surprisingly, control experiments where leucine was added alone revealed a similar increase in insulin secretion. The response to leucine alone was higher in βLKB than in control islets, and the magnitude of the effect was similar to that seen in response to glucose (Fig. 3B).
Affiliation: From the Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.