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.

. Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice. Am J Physiol Endocrinol Metab 288: E510 -E518, 2005. First published November 2, 2004; doi:10.1152/ajpendo.00128.2004.-To evaluate preventive effects of pioglitazone on pancreatic ␤-cell damage in C57BL/KsJ db/db mice, an obese diabetic animal model, the pancreatic islets were compared morphologically between pioglitazonetreated (100 mg/kg daily po) and untreated db/db mice (n ϭ 7 for each) after a 12-wk intervention (6 -18 wk of age). The fasting blood glucose level was significantly improved by the treatment with pioglitazone (260 Ϯ 12 vs. 554 Ϯ 62 mg/dl, P Ͻ 0.05). The islet mass in the pancreas was significantly greater in pioglitazone-treated mice than in untreated mice (10.2 Ϯ 1.1 vs. 4.6 Ϯ 0.2 mg, P Ͻ 0.01). Subsequently, biochemical and physiological analyses of the ␤-cell function were employed using pioglitazone-treated and untreated db/db mice (n ϭ 6 for each) and pioglitazone-treated and untreated db/ϩ mice (n ϭ 6 for each). After 2 wk of treatment (10 -12 wk of age), the plasma levels of triglyceride and free fatty acid were significantly decreased, whereas the plasma adiponectin level increased significantly compared with the untreated group (65.2 Ϯ 18.0 vs. 18.3 Ϯ 1.3 g/ml, P Ͻ 0.05). Pioglitazone significantly reduced the triglyceride content in the islets (43.3 Ϯ 3.6 vs. 65.6 Ϯ 7.6 ng/islet, P Ͻ 0.05) with improved glucose-stimulated insulin secretion. Pioglitazone showed no significant effects on the biochemical and physiological parameters in db/ϩ mice. The present study first demonstrated that pioglitazone prevents ␤-cell damage in an early stage of the disease progression in db/db mice morphologically and physiologically. Our results suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the pancreatic islets.pancreatic ␤-cells; adiponectin; type 2 diabetes mellitus DIABETES MELLITUS induces a variety of metabolic abnormalities because of insufficient insulin action. Of these, abnormalities in glucose metabolism are the most specific and are manifested clinically as hyperglycemia after glucose ingestion. In type 2 diabetes mellitus, which affects the majority of patients with diabetes mellitus, the factors involved in the pathogenesis and the progression of the disease are insufficient insulin secretion and decreased insulin sensitivity (insulin resistance) (7, 33). The relationship between insufficient insulin secretion and diabetes mellitus was underscored by the discovery of the causative gene for maturity onset diabetes of the young (9), and abnormalities in insulin secretion are considered to be particularly important (3). Prevention of the progression of pancreatic ␤-cell dysfunction in subjects with diabetes mellitus should be a key in the long-term management of this disease.Hyperglycemia and hyperlipidemia have attracted attention recently as factors that affect the mechanism of insulin secretion. Impaired glucose-mediate...

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.

The present observations suggest that visceral and subcutaneous fat has an impact on microangiopathy as well as macroangiopathy, possibly through different adipocytokines.

Pioglitazone preserves pancreatic β-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects β-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved β-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves β-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).