Abstract
SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. Here, we showed that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. Overexpression of SPARC down-regulated RGS4, a negative regulator of β-cell M3 muscarinic receptors. Conversely, knockdown of SPARC up-regulated RGS4 in Min6 cells. RGS4 was up-regulated in islets from sparc −/− mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Furthermore, inhibition of RGS4 restored GSIS in the islets from sparc −/− mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M-stimulated insulin secretion. Phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 abolished SPARC-induced down-regulation of RGS4. Taken together, our data revealed that SPARC promoted GSIS by inhibiting RGS4 in pancreatic β cells.
Highlights
SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown
The early β-cell dysfunction is manifested as impaired glucose-stimulated insulin secretion (GSIS), and loss of first phase GSIS can be detected in the earliest stages of type 2 diabetes[1,3]
Consistent with the findings above, we found that up-regulation of RGS4 mRNA and down-regulation of Glut[2] mRNA expressions in the islet of sparc −/− mice compared to wild type (WT) mice (Fig. S2B)
Summary
SPARC-deficient mice have been shown to exhibit impaired glucose tolerance and insulin secretion, but the underlying mechanism remains unknown. We showed that SPARC enhanced the promoting effect of Muscarinic receptor agonist oxotremorine-M on insulin secretion in cultured mouse islets. RGS4 was up-regulated in islets from sparc −/− mice, which correlated with decreased glucose-stimulated insulin secretion (GSIS). Inhibition of RGS4 restored GSIS in the islets from sparc −/− mice, and knockdown of RGS4 partially decreased the promoting effect of SPARC on oxotremorine-M-stimulated insulin secretion. Acetylcholine, which is released from intrapancreatic nerve endings, stimulates insulin secretion through binding and activation of M3 muscarinic receptor, resulting in increased intracellular calcium concentration in β cells during food ingestion[24]. Mice selectively lacking M3 muscarinic receptor in pancreatic β cells displayed impaired glucose tolerance and a dramatic reduction in insulin secretion, demonstrating that M3 muscarinic csu.edu.cn
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