title: Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders.
abstract: Dysregulation of endoplasmic reticulum (ER) Ca(2+) homeostasis triggers ER stress leading to the development of insulin resistance in obesity and diabetes. Impaired function of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) has emerged as a major contributor to ER stress. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel allosteric activator, CDN1163, which markedly lowered fasting blood glucose, improved glucose tolerance, and ameliorated hepatosteatosis but did not alter glucose levels or body weight in lean controls. Importantly, CDN1163-treated ob/ob mice maintained euglycemia comparable with that of lean mice for >6 weeks after cessation of CDN1163 administration. CDN1163-treated ob/ob mice showed a significant reduction in adipose tissue weight with no change in lean mass, assessed by magnetic resonance imaging. They also showed an increase in energy expenditure using indirect calorimetry, which was accompanied by increased expression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue. CDN1163 treatment significantly reduced the hepatic expression of genes involved in gluconeogenesis and lipogenesis, attenuated ER stress response and ER stress-induced apoptosis, and improved mitochondrial biogenesis, possibly through SERCA2-mediated activation of AMP-activated protein kinase pathway. The findings suggest that SERCA2b activation may hold promise as an effective therapy for type-2 diabetes and metabolic dysfunction.
authors.affiliation: From the Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Soojeong
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutical Science, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064-3095.
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.affiliation: Departments of Medicine and Neuroscience and Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Wilson
authors.initials: W
authors.lastname: Hsieh
authors.affiliation: Departments of Medicine and Neuroscience and Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shin
authors.affiliation: Celladon Corporation, San Diego, California 92130-3579.
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Zsebo
authors.affiliation: Departments of Medicine and Neuroscience and Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
authors.affiliation: From the Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: From the Cardiovascular Research Institute and Diabetes Obesity and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, djamel.lebeche@mssm.edu.
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D001678:Organelle Biogenesis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D001786:Blood Glucose; C000609635:CDN1163; D007004:Hypoglycemic Agents; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: AMP-activated kinase (AMPK); Ca2+ homeostasis; SERCA2b; diabetes; endoplasmic reticulum stress (ER stress); glucose metabolism; hepatosteatosis; insulin sensitivity; lipid metabolism; mitochondria efficiency