Abstract
Defective glucose-stimulated insulin secretion is the main cause of hyperglycemia in type 2 diabetes mellitus. Mutations in HNF-1alpha cause a monogenic form of type 2 diabetes, maturity-onset diabetes of the young (MODY), characterized by impaired insulin secretion. Here we report that collectrin, a recently cloned kidney-specific gene of unknown function, is a target of HNF-1alpha in pancreatic beta cells. Expression of collectrin was decreased in the islets of HNF-1alpha (-/-) mice, but was increased in obese hyperglycemic mice. Overexpression of collectrin in rat insulinoma INS-1 cells or in the beta cells of transgenic mice enhanced glucose-stimulated insulin exocytosis, without affecting Ca(2+) influx. Conversely, suppression of collectrin attenuated insulin secretion. Collectrin bound to SNARE complexes by interacting with snapin, a SNAP-25 binding protein, and facilitated SNARE complex formation. Therefore, collectrin is a regulator of SNARE complex function, which thereby controls insulin exocytosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Blotting, Northern
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Calcium / metabolism
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Cell Line
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Cloning, Molecular
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DNA, Complementary / metabolism
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Diabetes Mellitus, Type 2 / metabolism*
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Disease Models, Animal
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Exocytosis
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Genes, Reporter
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Glucose / chemistry
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Glucose / metabolism
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Glutathione Transferase / metabolism
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Growth Hormone / metabolism
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Hepatocyte Nuclear Factor 1 / metabolism*
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Humans
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Immunoblotting
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Immunohistochemistry
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Immunoprecipitation
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / metabolism
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Insulinoma
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Islets of Langerhans / cytology
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Transgenic
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Microscopy, Fluorescence
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Microscopy, Immunoelectron
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Models, Genetic
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Molecular Sequence Data
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Nucleic Acid Hybridization
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Oligonucleotide Array Sequence Analysis
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Pancreas / metabolism
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Photons
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Protein Binding
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Rats
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Reverse Transcriptase Polymerase Chain Reaction
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SNARE Proteins / metabolism*
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Time Factors
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Tissue Distribution
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Transcription, Genetic
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Two-Hybrid System Techniques
Substances
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CLTRN protein, human
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DNA, Complementary
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Insulin
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Membrane Glycoproteins
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RNA, Messenger
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RNA, Small Interfering
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SNARE Proteins
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Hepatocyte Nuclear Factor 1
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Growth Hormone
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Glutathione Transferase
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Glucose
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Calcium