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

32 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 (US)
Pages (from-to)2424-32
Number of pages9
JournalDiabetes
Volume61
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

Keywords

  • Animals
  • Calcium-Binding Proteins/genetics
  • Glucose/pharmacology
  • Glucose Intolerance/genetics
  • Glucose Transporter Type 4/metabolism
  • Insulin/metabolism
  • Insulin Resistance/genetics
  • Insulin Secretion
  • Islets of Langerhans/drug effects
  • Mice
  • Mice, Knockout
  • Munc18 Proteins/metabolism
  • Muscle, Skeletal/drug effects
  • Nerve Tissue Proteins/genetics
  • Qa-SNARE Proteins/metabolism

Fingerprint

Dive into the research topics of 'Doc2b is a key effector of insulin secretion and skeletal muscle insulin sensitivity'. Together they form a unique fingerprint.

Cite this