title: Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects.
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 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 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.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Swisa
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Granot
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tamarina
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sayers
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637.
authors.forename: Louis
authors.initials: L
authors.lastname: Philipson
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Unit of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 77 Stockholm, Sweden.
authors.forename: Jakob D
authors.initials: JD
authors.lastname: Wikstrom
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, SW7 2AZ, London, United Kingdom.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
authors.affiliation: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yuvald@ekmd.huji.ac.il.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000819:agonists / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000633:toxicity; D046509:Tissue Culture Techniques
chemical_list: D007328:Insulin; D011994:Recombinant Proteins; D013629:Tamoxifen; D018698:Glutamic Acid; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: KATP channel; calcium channel; insulin secretion; liver kinase B1 (LKB1); mitochondria; mitochondrial metabolism; pancreatic islet