title: SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion.
abstract: Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin-related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse β-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO-1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes.
authors.affiliation: Univ. of Chicago, Chicago, IL 60637, USA. srajan@uchicago.edu
authors.forename: Sindhu
authors.initials: S
authors.lastname: Rajan
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Torres
authors.forename: Michael S
authors.initials: MS
authors.lastname: Thompson
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
mesh_terms: D000818:Animals; D019921:Biotinylation / Q000502:physiology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D031541:Fluorescence Resonance Energy Transfer; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D054795:Incretins / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics* / Q000502:physiology*; D013268:Stimulation, Chemical; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D018076:DNA, Complementary; D054795:Incretins; D007328:Insulin; D008565:Membrane Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D052216:Glucagon-Like Peptide 1; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D006152:Cyclic GMP; D005947:Glucose