Loss of liver kinase B1 (LKB1) in beta cells enhances glucose-stimulated insulin secretion despite profound mitochondrial defects

Avital Swisa, Zvi Granot, Natalia Tamarina, Sophie Sayers, Nabeel Bardeesy, Louis Philipson, David J. Hodson, Jakob D. Wikstrom, Guy A. Rutter, Gil Leibowitz, Benjamin Glaser, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

35 Scopus citations

Abstract

The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper β cell polarity and restricts β cell size, total β cell mass, and glucosestimulated insulin secretion (GSIS). However, the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remain incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro and cannot be explained by altered cell polarity, increased β cell number, or increased insulin content. Increased secretion does require membrane depolarization and calcium influx but appears to rely mostly on a distal step in the secretion pathway. 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. Thus LKB1 is essential for mitochondrial homeostasis in β cells and in parallel is a powerful negative regulator of insulin secretion. 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.

Original languageAmerican English
Pages (from-to)20934-20946
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number34
DOIs
StatePublished - 21 Aug 2015

Bibliographical note

Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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