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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipose tissue plays a crucial role in energy homeostasis not only in storing triglyceride, but also responding to nutrient, neural, and hormonal signals, and producing factors which control feeding, thermogenesis, immune and neuroendocrine function, and glucose and lipid metabolism. Adipose tissue secretes leptin, steroid hormones, adiponectin, inflammatory cytokines, resistin, complement factors, and vasoactive peptides. The endocrine function of adipose tissue is typified by leptin. An increase in leptin signals satiety to neuronal targets in the hypothalamus. Leptin activates Janus-activating kinase2 (Jak2) and STAT 3, resulting in stimulation of anorexigenic peptides, e.g., alpha-MSH and CART, and inhibition of orexigenic peptides, e.g., NPY and AGRP. The reduction in leptin levels during fasting stimulates appetite, decreases thermogenesis, thyroid and reproductive hormones, and increases glucocorticoids. Leptin also stimulates fatty acid oxidation, insulin release, and peripheral insulin action. These effects involve regulation of PI-3 kinase, PTP-1B, suppressor of cytokine signaling-3 (SOCS-3), and AMP-activated protein kinase in the brain and peripheral organs. There is emerging evidence that leptin, adiponectin, and resistin act through overlapping pathways. Understanding the signal transduction of adipocyte hormones will provide novel insights on the pathogenesis and treatment of obesity, diabetes, and various metabolic disorders.
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PMID:Adipokines that link obesity and diabetes to the hypothalamus. 1687 74

The pancreatic beta-cell plays a central role in the maintenance of glucose homeostasis and in the pathogenesis of both type 1 and type 2 diabetes mellitus. Elucidation of the insulin secretory defects observed in diabetes first requires a better understanding of the complex mechanisms regulating insulin secretion, which are only partly understood. While there have been reports detailing proteomic analyses of islet cell lines or isolated rodent islets, the information gained is not always applicable to humans. Therefore, definition of the human islet proteome could contribute to a better understanding of islet biology and lead to more effective treatment strategies. We have applied a two-dimensional LC-MS/MS-based analysis to the characterization of the human islet proteome, resulting in the confident identification of 29,021 different tryptic peptides covering 3365 proteins (> or =2 unique peptide identifications per protein). As expected, the three major islet hormones (insulin, glucagon, and somatostatin) were detected, as well as various beta-cell enriched secretory products, ion channels, and transcription factors. In addition, significant proteome coverage of metabolic enzymes and cellular pathways was observed, including the integrin signaling cascade and the MAP kinase, NF-kappa beta, and JAK/STAT pathways. The resulting peptide reference library provides a resource for future higher throughput and quantitative studies of islet biology.
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PMID:Characterization of the human pancreatic islet proteome by two-dimensional LC/MS/MS. 1713 36

Cell-based diabetes therapy may be achieved through xenotransplantation of adult porcine islets, but tissue quality and immunoreactivity barriers need to be overcome. Early identification and exclusion of irreversibly stressed and dying islets may improve transplant outcomes. We used oligonucleotide microarray and quantitative RT-PCR to identify molecular markers of physiological and immunological stress in porcine islets cultured under stress conditions of elevated glucose (16.7 mM), inflammatory cytokine addition (IL-1beta, TNF-alpha, and IFN-gamma), or both, for 48 h. Hyperglycemic conditions were associated with increased thioredoxin interacting protein and metabolic process mRNAs, as observed in rodent and primate species. Cytokine treatment increased expression of JAK-STAT pathway components, oxidative stress (transglutaminase 2), and beta cell dysfunction genes. Transglutaminase 2 induction is unique to porcine islets. Biomarkers involved in hyperglycemia and islet inflammation may serve as novel targets for improving and monitoring isolated porcine islet function and viability.
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PMID:Transcriptional profiling of stress response in cultured porcine islets. 1740 63

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT(1) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), atrasentan (ET(A) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg x kg(-1) x day(-1) intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 +/- 9.0, 130 +/- 3.3, 128 +/- 6.8, and 131 +/- 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 +/- 3.0, 92.6 +/- 7.4, 76.9 +/- 12.1, and 38.3 +/- 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.
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PMID:Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation. 1752 54

The growing worldwide obesity epidemic is frequently linked to an increased risk of developing diseases such as diabetes, cardiovascular disease, and cancer. These diseases are associated with the infiltration of macrophages in white adipose tissue (WAT), the artery wall, and tumors, respectively; and these macrophages likely contribute to disease progression and pathogenesis. Abdominal WAT, adipose tissue surrounding the heart and artery wall, as well as carcinoma cells, secrete many factors that could induce macrophage infiltration. Leptin is an adipocyte-secreted hormone, and deficiency of either leptin or its receptor has been shown to cause morbid obesity in animals and in humans. However, what is more commonly noted in human obesity is the presence of central leptin resistance leading to hyperleptinemia. As leptin receptors are present on macrophages, we hypothesized that leptin could act as a monocyte/macrophage chemoattractant. Our current study demonstrates: 1) leptin is a potent chemoattractant for monocytes and macrophages, inducing maximal chemotactic responses at 1 ng/ml; 2) leptin-mediated chemotaxis requires the presence of full-length leptin receptors on migrating cells; 3) leptin causes increased influx of intracellular calcium in macrophages; and 4) activation of janus kinase/signal transducers and activators of transduction (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) pathways are all necessary for leptin-induced macrophage migration. Taken together, these data demonstrate that leptin is a potent monocyte/macrophage chemoattractant in vitro and that canonical cell motility machinery is activated upon macrophage exposure to leptin. These data have implications for the impact of hyperleptinemia on obesity-related pathophysiological conditions such as diabetes, cardiovascular disease, and cancer.
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PMID:Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. 1772 93

Hepatocyte nuclear factor-1beta (HNF-1beta) is a Pit-1, Oct-1/2, Unc-86 (POU) homeodomain-containing transcription factor expressed in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1beta cause maturity-onset diabetes of the young, type 5 (MODY5), which is characterized by early-onset diabetes mellitus and congenital malformations of the kidney, pancreas, and genital tract. Knockout of HNF-1beta in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1beta are poorly understood. Using genome-wide chromatin immunoprecipitation and DNA microarray (ChIP-chip) and microarray analysis of mRNA expression, we identified SOCS3 (suppressor of cytokine signaling-3) as a previously unrecognized target gene of HNF-1beta in the kidney. HNF-1beta binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1beta knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1beta. Increased levels of SOCS-3 inhibit HGF-induced tubulogenesis by decreasing phosphorylation of Erk and STAT-3. Conversely, knockdown of SOCS-3 in renal epithelial cells expressing dominant-negative mutant HNF-1beta rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1beta regulates tubulogenesis by controlling the levels of SOCS-3 expression. Manipulating the levels of SOCS-3 may be a useful therapeutic approach for human diseases induced by HNF-1beta mutations.
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PMID:Mutations of HNF-1beta inhibit epithelial morphogenesis through dysregulation of SOCS-3. 1807 49

Excessive cellular proliferation is a major contributor to the pathological changes associated with the secondary complications of diabetes. In particular, hyperglycemia (HG)-induced growth of vascular smooth muscle cells (VSMC) and glomerular mesangial cells (GMC) are characteristic features of the cardiovascular and renal complications of diabetes. VSMC and GMC respond to traditional growth factors, however in diabetes this occurs in the context of an environment, enriched in circulating vasoactive mediators and HG. For example, signaling via the angiotensin II (Ang II) pathway has been implicated in the pathogenesis of diabetic vascular disease. Recent findings indicate that HG and Ang II activate intracellular processes, including the polyol pathway and the generation of reactive oxygen species. These pathways activate the JAK (janus kinase)/STAT (signal transducers and activators of transcription) signaling cascades in both VSMC and GMC. Activation of the latter signaling cascade can stimulate excessive proliferation and growth of these cells, contributing to the accelerated atherosclerosis and nephropathy seen in the diabetic state. This review focuses on key factors in the diabetic microenvironment, in particular the interplay between HG, accumulation of advanced glycation end products and Ang II mediated signaling events both in vitro and in vivo.
Curr Diabetes Rev 2005 May
PMID:Angiotensin II-induced signaling pathways in diabetes. 1822 May 95

Obesity is an independent risk factor for cardiovascular diseases. As the first obese gene product identified, leptin participates in many physiological processes. Besides its well known effects on food intake and energy metabolism, leptin has been shown to regulate cardiovascular function, glucose and lipid metabolism. Although the precise role of leptin on cardiac health is still at large, the peptide may initiate both hypertrophic and anti-hypertrophic effects on hearts. Circulating leptin levels are believed to correlate closely with body mass index (BMI) and total amount of body fat, and predict change of heart morphology and function. This is evidenced by that fact that compromised cardiac function is present in both hyperleptinemic (db/db) and hypoleptinemic (ob/ob) mouse models. Leptin replenishment may reconcile depressed cardiac contractile function in ob/ob mice, indicating the permissive effect of leptin on cardiac function. Multiple signal pathways including NO, Jak/STAT, p38 MAP kinase, ET-1 and NADPH oxidase have been implicated to participate in the cardiac regulatory response of leptin. In addition, elevated plasma leptin levels are speculated to be an independent risk factor for cardiovascular diseases such as hypertension and myocardial infarction. The current dogma indicates that physiological range of leptin may be essential for normal cardiomyocyte structure and function whereas disrupted leptin signaling due to too much or too little leptin may trigger functional and morphological alterations leading to cardiac dysfunction.
Curr Diabetes Rev 2007 Aug
PMID:Fitness or fatness--the debate continues for the role of leptin in obesity-associated heart dysfunction. 1822 Jun 67

In both type 1 and type 2 diabetes, increased production of cytokines on autoimmune or metabolic basis is supposed to trigger an inflammatory process leading to dysfunction and death of pancreatic beta-cells. Therefore, anti-inflammatory pharmacological approaches aimed at blocking cytokine signalling pathways and consequent cytotoxicity in beta-cells are highly advisable. Based on previous evidence of cytokine antagonistic effects in other cell types, we explored the protective action of Hypericum perforatum (St-John's-wort) extract and its component hyperforin against cytokine-induced functional impairment and apoptosis in the INS-1E beta-cell line, searching for the underlying mechanisms. The results showed that either St-John's-wort extract or hyperforin (at 1-3 microM) prevented cytokine-induced impairment in glucose-stimulated insulin secretion and protected cells against apoptosis in a dose-dependent fashion. Inducible-NO-synthase expression was also potently hindered by the vegetal compounds. Interestingly, cytokine-induced activations of the signal-transducer-and-activator-of-transcription-1 (STAT-1) and the nuclear-factor-kappaB (NF-kappaB) were both down-regulated by SJW extract or HPF (range 0.5-5 microM) when evaluated by electrophoretic-mobility-shift-assay. Other transcription factors (CBF-1, SP-1) were unaffected. Components of SJW extract other than HPF were much less effective in down-regulating cytokine signalling. Significantly, inhibition of cytokine-elicited STAT-1 and NF-kappaB activation was confirmed in isolated rat and human islets incubated in the presence of these vegetal compounds. In conclusion, St-John's-wort extract and hyperforin are non-peptidyl compounds which, at low concentrations, target key mechanisms of cytokine-induced beta-cell injury, thereby improving beta-cell function and survival. Thus, they are potentially valuable for the prevention or limitation of beta-cell loss in diabetes.
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PMID:Protective effects of St. John's wort extract and its component hyperforin against cytokine-induced cytotoxicity in a pancreatic beta-cell line. 1822 77

Endothelial dysfunction plays a central role in diabetic vascular disease, but its molecular bases are not completely defined. We showed previously that the actin-binding protein proflin-1 was increased in the diabetic endothelium and that attenuated expression of profilin-1 protected against atherosclerosis. Also 7-ketocholesterol up-regulated profilin-1 in endothelial cells via transcriptional mechanisms. The present study addressed the pathways responsible for profilin-1 gene expression in 7-ketocholesterol-stimulated endothelial cells and in the diabetic aorta. In luciferase reporter assays, the response to 7-ketocholesterol within the 5'-flanking region of profilin-1 was dependent on a single STAT response element. In aortic endothelial cells, 7-ketocholesterol enhanced STAT3 activation, which required JAK2 and tyrosine 394 phosphorylation of oxysterol-binding protein-1. These changes were recapitulated in the aorta of diabetic rats. Also 7-ketocholesterol in cultured endothelial cells and diabetes in the aorta elicited the recruitment of STAT3 and relevant coregulatory factors to the oxysterol-responsive region of the profilin-1 promoter. These events were required for profilin-1 up-regulation. These studies identify a previously unrecognized oxysterol-binding protein-mediated mode of activation of STAT3 that controls the expression of the proatherogenic protein profilin-1 in response to 7-ketocholesterol and the diabetic milieu.
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PMID:Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1. 1823 Jun 13


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