It has recently been proposed that the peripheral taste organ is one of the targets for leptin. In lean mice, leptin selectively suppresses gustatory neural and behavioral responses to sweet compounds without affecting responses to other taste stimuli, whereas obese diabetic db/db mice with defects in leptin receptor lack this leptin suppression on sweet taste. Here, we further examined potential links between leptin and sweet taste in humans.

Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic beta-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation.

Cerebral edema (CE) is a potentially life-threatening complication of diabetic ketoacidosis (DKA) in children. Osmotic fluctuations during DKA treatment have been considered responsible, but recent data instead suggest that cerebral hypoperfusion may be involved and that activation of cerebral ion transporters may occur. Diminished cerebral blood flow (CBF) during DKA, however, has not been previously demonstrated. We investigated CBF and edema formation in a rat model of DKA and determined the effects of bumetanide, an inhibitor of Na-K-Cl cotransport.

Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.

Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.

Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo.

The aim of this study was to evaluate the efficiency and safety of simultaneous islet and kidney transplantation in patients with type 1 diabetes and end-stage renal disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction.

The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which generates active cortisol from cortisone, and 5alpha-reductase (5alphaR), which inactivates cortisol, has been implicated.

To define the mechanisms underlying the accumulation of monocytes/macrophages in the islets of Langerhans.

OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IkappaB/NFkappaB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS- TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IkappaB/NFkappaB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS- Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.

To ascertain the importance and mechanisms underlying the role of brain glucagon-like peptide (GLP)-1 in the control of metabolic and cardiovascular function. GLP-1 is a gut hormone secreted in response to oral glucose absorption that regulates glucose metabolism and cardiovascular function. GLP-1 is also produced in the brain, where its contribution to central regulation of metabolic and cardiovascular homeostasis remains incompletely understood.

Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue.

To document the transcriptome of the pancreatic islet during the early and late development of the mouse pancreas and highlight the qualitative and quantitative features of gene expression that contribute to the specification, growth, and differentiation of the major endocrine cell types. A further objective was to identify endocrine cell biomarkers, targets of diabetic autoimmunity, and regulatory pathways underlying islet responses to physiological and pathological stimuli.

In vitro expansion of beta-cells from adult human islets could solve the tissue shortage for cell replacement therapy of diabetes. Culture of human islet cells typically results in <16 cell doublings and loss of insulin expression. Using cell lineage tracing, we demonstrated that the expanded cell population included cells derived from beta-cells. Understanding the molecular mechanisms involved in beta-cell fate in vitro is crucial for optimizing expansion and redifferentiation of these cells. In the developing pancreas, important cell-fate decisions are regulated by NOTCH receptors, which signal through the hairy and enhancer of split (HES)-1 transcriptional regulator. Here, we investigated the role of the NOTCH signaling pathway in beta-cell dedifferentiation and proliferation in vitro.

To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells.

Diabetes results from a deficiency of functional beta-cells due to both an increase in beta-cell death and an inhibition of beta-cell replication. The molecular mechanisms responsible for these effects in susceptible individuals are mostly unknown. The objective of this study was to determine whether a gene critical for cell division and cell survival in cancer cells, survivin, might also be important for beta-cells.

Association between genetic variants at the FTO locus and obesity has been consistently observed in populations of European ancestry and inconsistently in non-Europeans. The aim of this study was to examine the effects of FTO variants on obesity and type 2 diabetes in Southeast Asian populations.

Despite tremendous progress in vitreoretinal surgery, certain postsurgical complications limit the success in the treatment of proliferative vitreoretinal diseases (PVDs), such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). One of the most significant complications is the cicatricial contraction of proliferative membranes, resulting in tractional retinal detachment and severe vision loss. Novel pharmaceutical approaches are thus urgently needed for the management of these vision-threatening diseases. In the current study, we investigated the inhibitory effects of statins on the progression of PVDs.

Pharmacogenomics is a key component of personalized medicine. The Israel Cardiovascular Events Reduction with Vitamin E Study, a prospective placebo-controlled study, recently demonstrated that vitamin E could dramatically reduce CVD in individuals with diabetes and the haptoglobin (Hp) 2-2 genotype (40% of diabetic individuals). However, because of the large number of clinical trials that failed to demonstrate benefit from vitamin E coupled with the lack of a mechanistic explanation for why vitamin E should be beneficial only in diabetic individuals with the Hp 2-2 genotype, enthusiasm for this pharmacogenomic paradigm has been limited. In this study, we sought to provide such a mechanistic explanation based on the hypothesis that the Hp 2-2 genotype and diabetes interact to promote HDL oxidative modification and dysfunction.

There is evidence that monocytes of patients with type 1 diabetes show proinflammatory activation and disturbed migration/adhesion, but the evidence is inconsistent. Our hypothesis is that monocytes are distinctly activated/disturbed in different subforms of autoimmune diabetes.