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 language | English (US) |
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Pages (from-to) | 2424-32 |
Number of pages | 9 |
Journal | Diabetes |
Volume | 61 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2012 |
Externally published | Yes |
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