TCF7L2 expressed in the pancreatic beta cells plays a crucial role in glucose metabolism through regulation of the beta cell mass.

The solventogenic sol operon consisting of bld, ctfA, ctfB, and adc was cloned from Clostridium saccharoperbutylacetonicum strain N1-4. These genes share as high as 95-98% similarity with the corresponding sol genes of Clostridium beijerinckii NCIMB 8052. The N1-4 sol gene cluster was transcribed in a polycistronic manner under the control of two promoters, and its transcription was highly induced during solventogenesis. Strain DGN3-4, the degenerated strain derived from N1-4, maintained the sol genes, but transcription of the DGN3-4 sol operon was hardly induced during solventogenesis. A substance extracted from the culture supernatants of wild-type N1-4 allowed us to induce transcription of the sol operon in DGN3-4. These results suggest that the degeneration is caused by the incompetence of the induction mechanism of the sol operon, and that transcription might be under the control of a quorum-sensing mechanism.

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.

A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1␤ (ERO1␤) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic ␤ cells. It has recently been demonstrated that ERO1␤ promotes insulin biogenesis in ␤ cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1␤ is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1␤ expression is paradoxically decreased in ␤ cells despite the indications of increased ER stress. However, overexpression of ERO1␤ in ␤ cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1␤ overexpression caused ER stress in the ␤ cells. Insulin contents were decreased in the ␤ cells that overexpressed ERO1␤, leading to impaired insulin secretion in response to glucose stimulation. These data indicate the importance of the fine-tuning of the ER redox state, the disturbance of which would compromise the function of ␤ cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus.

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Aims/hypothesis Recently, incretin-related agents have been reported to attenuate insulin resistance in animal models, although the underlying mechanisms remain unclear. In this study, we investigated whether anagliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor, attenuates skeletal muscle insulin resistance through endothelial nitric oxide synthase (eNOS) activation in the endothelial cells. We used endothelium-specific Irs2-knockout (ETIrs2KO) mice, which show skeletal muscle insulin resistance resulting from a reduction of insulin-induced skeletal muscle capillary recruitment as a consequence of impaired eNOS activation. Methods In vivo, 8-week-old male ETIrs2KO mice were fed regular chow with or without 0.3% (wt/wt) DPP-4 inhibitor for 8 weeks to assess capillary recruitment and glucose uptake by the skeletal muscle. In vitro, human coronary arterial endothelial cells (HCAECs) were used to explore the effect of glucagon-like peptide 1 (GLP-1) on eNOS activity. Results Treatment with anagliptin ameliorated the impaired insulin-induced increase in capillary blood volume, interstitial insulin concentration and skeletal muscle glucose uptake in ETIrs2KO mice. This improvement in insulin-induced glucose uptake was almost completely abrogated by the GLP-1 receptor (GLP-1R) antagonist exendin-(9-39). Moreover, the increase in capillary blood volume with anagliptin treatment was also completely inhibited by the NOS inhibitor. GLP-1 augmented eNOS phosphorylation in HCAECs, with the effect completely disappearing after exposure to the protein kinase A (PKA) inhibitor H89. These data suggest that anagliptin treatment enhances insulin-induced capillary recruitment and interstitial insulin concentrations, resulting in improved skeletal muscle glucose Hiroyuki Sato, Naoto Kubota and Tetsuya Kubota contributed equally to this work. Electronic supplementary material The online version of this article

In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.