SPARC is required for the maintenance of glucose homeostasis and insulin secretion in mice

Abstract

Obesity, metabolic syndrome, and type 2 diabetes, three strongly interrelated diseases, are associated to increased morbidity and mortality worldwide. The pathogenesis of obesity-associated disorders is still under study. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein expressed in many cell types including adipocytes, parenchymal, and non-parenchymal hepatic cells and pancreatic cells. Studies have demonstrated that SPARC inhibits adipogenesis and promotes insulin resistance; in addition, circulating SPARC levels were positively correlated with body mass index in obese individuals. Therefore, SPARC is being proposed as a key factor in the pathogenesis of obesity-associated disorders. The aim of this study is to elucidate the role of SPARC in glucose homeostasis. We show here that SPARC null (SPARC−/−) mice displayed an abnormal insulin-regulated glucose metabolism. SPARC−/− mice presented an increased adipose tissue deposition and an impaired glucose homeostasis as animals aged. In addition, the absence of SPARC worsens high-fat diet-induced diabetes in mice. Interestingly, although SPARC−/− mice on high-fat diet were sensitive to insulin they showed an impaired insulin secretion capacity. Of note, the expression of glucose transporter 2 in islets of SPARC−/− mice was dramatically reduced. The present study provides the first evidence that deleted SPARC expression causes diabetes in mice. Thus, SPARC deficient mice constitute a valuable model for studies concerning obesity and its related metabolic complications, including diabetes.

SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β cells

“…Our results were consistent with a recent study demonstrating that SPARC is necessary for insulin secretion in mouse β cells and that sparc −/− mice displayed glucose intolerance and diabetes in an age-dependent manner 22 . Moreover, Glucose transporter 2 (Glut2) expression in β cells is also reduced in sparc −/− mice 22 , which was in agreement with our cDNA microarray and RT-qPCR data showing induction of Glut2 by SPARC in Min6 cells (Fig. 3 A and Fig.…”

“…2 A, overexpression of SPARC in Min6 cells induced up-regulation of Glut2 mRNA expression. Glut2 protein has been shown to be reduced in the islets from sparc−/− mice 22 . Meanwhile, although expression levels of several other β-cell genes were altered in microarray data, these changes were not confirmed by RT-qPCR experiment (Fig.…”

“…SPARC is expressed in the stromal cells of mouse primary islets that can be detected by Western blot, and plays a role in reducing IGF-1-induced islet survival 21 . sparc −/− mice on high-fat diet showed an impaired insulin secretion capacity and a dramatically reduced expression of glucose transporter 2 in the islets 22 . SPARC-deficient mice exhibited impaired glucose tolerance 22 , 23 , and one of the underlying mechanism is reduced insulin secretion 22 .…”

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans

“…The secreted protein acidic and rich in cysteine ( SPARC) gene product modulates the interaction between the extracellular matrix and surrounding cells and is highly expressed in fibrotic tissues [79]. Fibrosis is a clinical feature of hypertension, and both human and animal models support a relationship between SPARC and type 2 diabetes pathogenesis [80, 81]. While intronic, annotation of SPARC rs4958487 suggests that it is a significant eQTL in tibial artery (GTEx p = 7.0x10 -11 ) and coronary artery (GTEx p = 5.0x10 -7 ) tissues among others, with the A allele associated with higher SPARC expression compared with the G ancestral allele.…”

Modeling Diet‐Induced Metabolic Syndrome in Rodents

“…[92] Hence, to obtain more significant differences in the parameters related to glucose homeostasis, insulin sensitivity, and lipid profile, the studies indicate that the animals should be exposed to diets for longer periods, with better results obtained between 12 and 24 weeks. [45,88,[92][93][94][99][100][101][102] Conversely, very long periods of diet exposure, that is, over 32 weeks, appear not to promote higher significant differences in the impairment of the animals' metabolic parameters compared to 12-24 weeks of exposure and seem to be less efficient in the development of MetS in mice (Table 4). [95][96][97][98]103] Van der Heijden et al evaluated C57BL/6J male mice fed with HFD (45% kcal from fat) for 24, 40, or 52 weeks and showed a rapid increase in body weight, which was significant from 12 weeks following a diet onward.…”