Search

Genome-wide association studies have identified several gene polymorphisms, including UBE2E2 , associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E 2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cell–specific UBE2E2 -transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In TG mice, suppressed proliferation of β-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21 , resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in β-cells play an important role in regulating glucose homeostasis and β-cell mass. [ABSTRACT FROM AUTHOR]

Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs. [ABSTRACT FROM AUTHOR]

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation. [ABSTRACT FROM AUTHOR]

Glucokinase (Gck) is known to function as a glucose sensor for insulin secretion. Mice with β-cell-specific haploinsufficiency of glucokinase gene (Gck+/-) fed a standard-chow diet exhibit impaired insulin secretion to glucose. After 4 weeks on a high-fat (HF) diet wild-type mice maintained normal glucose tolerance, whereas Gck+/- developed severe diabetes, despite the presence of a similar degree of insulin resistance. We here investigated the effects of small-molecular glucokinase activator (GKA) on glucose metabolism in wild-type mice and Gck+/- in response to HF-diet-induced insulin resistance. We analyzed three mouse groups, namely wild-type mice on the HF diet (W), Gck+/- on the HF diet (G), and Gck+/- treated with GKA mixed in the HF diet (A). After 10 weeks on the above diets, we investigated body weight, fat mass, liver weight, liver triglyceride content, serum triglyceride and ALT levels in these mice. We also performed glucose tolerance test (OGTT and IVGTT) and histological analysis to assess β-cell mass. After 10 weeks on the above diets, there were no differences in body weight among the three mouse groups (W: 39.8 ± 1.5 g, G: 40.9 ± 1.3 g, A: 42.0 ± 1.8 g). Fat mass, liver weight, serum triglyceride and ALT levels were also indistinguishable among these mice. Fed glucose levels decreased shortly after the GKA treatment in A compared with G. In fact, after 10 weeks' GKA treatment, A had blood glucose level significantly lower than G (W: 129.2 ± 12.2 mg/dl, G: 202.8 ± 18.1 mg/di, A: 77.0 ± 6.6 mg/dl, A vs. G: p<0.01). Moreover, GTT revealed that A had better glucose tolerance and higher serum insulin level 1 min after an intravenous glucose load than G. Histological analysis revealed that A had maximum islet diameter similar to W and larger than G, although statistically not significant (W: 111.3 ± 3.3 µn, G: 105.6±2.5 µm, A: 112.9±3.3 µm, G vs. W: p=0.17, A vs. G: p=0.07). These results suggest that GKA is able to improve glucose metabolism on the HF diet in mice with β-cell-specific haploinsufficiency of glucokinase gene. [ABSTRACT FROM AUTHOR]

Endothelial cells are considered to be essential for normal pancreatic β-cell function. The current study attempted to demonstrate the role of insulin receptor substrate-2 (Irs2) in endothelial cells with regard to insulin secretion. Endothelial cell-specific Irs2 knockout (ETIrs2KO) mice exhibited impaired glucose-induced, arginine-induced, and glucagon-induced insulin secretion and showed glucose intolerance. In batch incubation and perifusion experiments using isolated islets, glucose-induced insulin secretion was not significantly different between the control and the ETIrs2KO mice. In contrast, in perfusion experiments, glucose-induced insulin secretion was significantly impaired in the ETIrs2KO mice. The islet blood flow was significantly impaired in the ETIrs2KO mice. After the treatment of these knockout mice with enalapril maleate, which improved the islet blood flow, glucose-stimulated insulin secretion was almost completely restored to levels equal to those in the control mice. These data suggest that Irs2 deletion in endothelial cells leads to a decreased islet blood flow, which may cause impaired glucose-induced insulin secretion. Thus, Irs2 in endothelial cells may serve as a novel therapeutic target for preventing and ameliorating type 2 diabetes and metabolic syndrome., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)