Aims/hypothesisWe investigated the molecular mechanism by which the human glucagon-like peptide-1 analogue liraglutide preserves pancreatic beta cells in diabetic db/db mice.MethodsMale db/db and m/m mice aged 10 weeks received liraglutide or vehicle for 2 days or 2 weeks. In addition to morphological and biochemical analysis of pancreatic islets, gene expression profiles in the islet core area were investigated by laser capture microdissection and real-time RT-PCR.ResultsLiraglutide treatment for 2 weeks improved metabolic variables and insulin sensitivity in db/db mice. Liraglutide also increased glucose-stimulated insulin secretion (GSIS) and islet insulin content in both mouse strains and reduced triacylglycerol content in db/db mice. Expression of genes involved in cell differentiation and proliferation in both mouse strains was regulated by liraglutide, which, in db/db mice, downregulated genes involved in pro-apoptosis, endoplasmic reticulum (ER) stress and lipid synthesis, and upregulated genes related to anti-apoptosis and anti-oxidative stress. In the 2 day experiment, liraglutide slightly improved metabolic variables in db/db mice, but GSIS, insulin and triacylglycerol content were not affected. In db/db mice, liraglutide increased gene expression associated with cell differentiation, proliferation and anti-apoptosis, and suppressed gene expression involved in pro-apoptosis; it had no effect on genes related to oxidative stress or ER stress. Morphometric results for cell proliferation, cell apoptosis and oxidative stress in db/db mice islets were consistent with the results of the gene expression analysis.Conclusions/interpretationLiraglutide increases beta cell mass not only by directly regulating cell kinetics, but also by suppressing oxidative and ER stress, secondary to amelioration of glucolipotoxicity.

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Type 2 diabetes mellitus is characterized by insulin resistance in various insulin target tissues, such as the liver, adipose tissue, and skeletal muscle, and insufficient insulin secretion from pancreatic β-cells. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are newly developed antidiabetic agents, decrease blood glucose levels by enhancing urinary glucose excretion and thereby function in an insulin-independent manner. Sodium-glucose cotransporter 2 inhibitors exert beneficial effects to reduce insulin resistance and preserve pancreatic β-cell function. In addition, SGLT2 inhibitors exhibit a variety of beneficial effects in various insulin target tissues, such as amelioration of fatty liver, reduction of visceral fat mass, and increasing glucose uptake in skeletal muscle. Furthermore, SGLT2 inhibitors protect pancreatic β-cells against glucose toxicity and preserve insulin secretory capacity. Together, these observations indicate that SGLT2 inhibitors are promising newly developed antidiabetic agents that are gaining attention in both clinical medicine and basic research.

Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. Materials and Methods We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin ( n = 32), pioglitazone ( n = 33) or glimepiride ( n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography. Results There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable. Conclusions The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

AimWe investigated the molecular mechanisms by which vildagliptin preserved pancreatic β cell mass and function.MethodsMorphological, biochemical and gene expression profiles of the pancreatic islets were investigated in male KK-Ay-TaJcl(KK-Ay) and C57BL/6JJcl (B6) mice aged 8 weeks which received either vildagliptin or a vehicle for 4 weeks.ResultsBody weight, food intake, fasting blood glucose, plasma insulin and active glucagon-like peptide-1 were unchanged with vildagliptin treatment in both mice. In KK-Ay mice treated with vildagliptin, increased plasma triglyceride (TG) level and islet TG content were decreased, insulin sensitivity significantly improved, and the glucose tolerance ameliorated with increases in plasma insulin levels. Furthermore, vildagliptin increased glucose-stimulated insulin secretion, islet insulin content and pancreatic β cell mass in both strains. By vildagliptin, the expression of genes involved in cell differentiation/proliferation was upregulated in both strains, those related to apoptosis, endoplasmic reticulum stress and lipid synthesis was decreased and those related to anti-apoptosis and anti-oxidative stress was upregulated, in KK-Ay mice. The morphological results were consistent with the gene expression profiles.ConclusionVildagliptin increases β cell mass by not only directly affecting cell kinetics but also by indirectly reducing cell apoptosis, oxidative stress and endoplasmic reticulum stress in diabetic mice.