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: To clarify how βLKB islets secrete more insulin in response to glucose, we perturbed steps in the triggering pathway for insulin secretion. Treatment with diazoxide, a KATP channel opener, completely abolished glucose-stimulated secretion in perifused βLKB islets (Fig. 2A). This suggested that closure of KATP channels and membrane depolarization are essential for enhanced secretion in the mutants. However, when channels were forced to open with diazoxide and KCl was added, βLKB islets secreted more insulin than controls, consistent with the findings in Fig. 1E. Thus in the face of a similar degree of membrane depolarization, βLKB islets secrete more insulin, indicating enhancement of secretion at a distal step of the pathway (Fig. 2A). Furthermore, treatment with glyburide (forcing the closure of KATP channels) led to higher insulin secretion from cultured βLKB islets both at basal (2.8 mm) and stimulating (16.7 mm) glucose concentrations (Fig. 2B). In addition, in vivo administration of a high dose of glyburide boosted plasma insulin levels to a higher degree in βLKB mice compared with controls (data not shown). This further indicates a component boosting GSIS downstream to membrane depolarization.
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.