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The tumor suppressor liver kinase B1 (LKB1) is an important regulator of pancreatic beta cell biology. LKB1-dependent phosphorylation of distinct AMPK (adenosine monophosphate-activated protein kinase) family members determines proper beta cell polarity and restricts beta cell size, total beta cell mass, and glucose-stimulated 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 beta 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 beta 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 beta cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in beta cells and in parallel is a powerful negative regulator of insulin secretion. This study shows that beta cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria and without deterioration over months.

Original publication

DOI

10.1074/jbc.M115.639237

Type

Journal article

Journal

J Biol Chem

Publication Date

2015

Volume

290

Pages

20934 - 20946

Keywords

AMP-Activated Protein Kinases/genetics/metabolism Animals Gene Expression Regulation Glucose/*metabolism/pharmacology Glutamic Acid/metabolism Humans Insulin/agonists/*metabolism Insulin Secretion Insulin-Secreting Cells/drug effects/*metabolism/pathology Mice Mice, Transgenic Mitochondria/drug effects/*metabolism/pathology Phosphorylation Protein Serine-Threonine Kinases/deficiency/*genetics Recombinant Proteins/genetics/metabolism Signal Transduction Tamoxifen/toxicity Tissue Culture Techniques KATP channel calcium channel liver kinase B1 (LKB1) mitochondria mitochondrial metabolism pancreatic islet