Doc2b is a key effector of insulin secretion and skeletal muscle insulin sensitivity

Latha Ramalingam, Eunjin Oh, Stephanie M. Yoder, Joseph T. Brozinick, Michael A. Kalwat, Alexander J. Groffen, Matthijs Verhage, Debbie C. Thurmond

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Exocytosis of intracellular vesicles, such as insulin granules, is carried out by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) and Sec1/Munc18 (SM) proteins. An additional regulatory protein, Doc2b (double C2 domain), has recently been implicated in exocytosis from clonal β-cells and 3T3-L1 adipocytes. Here, we investigated the role of Doc2b in insulin secretion, insulin sensitivity, and the maintenance of whole-body glucose homeostasis. Doc2b heterozygous (Doc2b+/-) and homozygous (Doc2b-/-) knockout mice exhibited significant whole-body glucose intolerance and peripheral insulin resistance, compared with wild-type littermates. Correspondingly, Doc2b+/-and Doc2b-/- mice exhibited decreased responsiveness of pancreatic islets to glucose in vivo, with significant attenuation of both phases of insulin secretion ex vivo. Peripheral insulin resistance correlated with ablated insulin-stimulated glucose uptake and GLUT4 vesicle translocation in skeletal muscle from Doc2b-deficient mice, which was coupled to impairments in Munc18c-syntaxin 4 dissociation and in SNARE complex assembly. Hence, Doc2b is a key positive regulator of Munc18c-syntaxin 4-mediated insulin secretion as well as of insulin responsiveness in skeletal muscle, and thus a key effector for glucose homeostasis in vivo. Doc2b's actions in glucose homeostasis may be related to its ability to bind Munc18c and/or directly promote fusion of insulin granules and GLUT4 vesicles in a stimulus-dependent manner.

Original languageEnglish
Pages (from-to)2424-2432
Number of pages9
JournalDiabetes
Volume61
Issue number10
DOIs
StatePublished - Oct 2012

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