Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In patients with type 2 non-insulin-dependent diabetes mellitus (NIDDM), the biguanide, metformin, exerts its antihyperglycemic effect by improving insulin sensitivity, which is associated with decreased level of circulating free fatty acids (FFA). The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-alpha (TNF-alpha), a cytokine largely expressed in adipose tissue, stimulates chronic lipolysis, which may be associated with increased systemic FFA and insulin resistance in obesity and NIDDM. In this study, we examined the role of metformin in inhibiting lipolytic action upon various lipolytic stimulations in primary rat adipocytes. Treatment with metformin attenuated TNF-alpha-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 and reversing the downregulation of perilipin protein in TNF-alpha-stimulated adipocytes. The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by metformin. A high concentration of glucose in the adipocyte culture promoted the basal rate of glycerol release and significantly enhanced the lipolytic action stimulated by either TNF-alpha or isoproterenol. Metformin not only inhibits the basal lipolysis simulated by high glucose, but also suppresses the high glucose-enhanced lipolysis response to TNF-alpha or isoproterenol. The antilipolytic action in adipocytes could be the mechanism by which cellular action by metformin reduces systemic FFA concentration and thus improves insulin sensitivity in obese patients and the hyperglycemic conditions of NIDDM.
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PMID:Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-alpha or isoproterenol. 1690 33

Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic beta-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets. Islet beta-cells responded to CD40L interaction by secreting interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and macrophage inflammatory protein (MIP)-1beta, the latter a chemokine first reported to be produced by islets. Induction of IL-8 and MIP-1beta was confirmed at the transcriptional level by quantitative RT-PCR. MIP-1beta expression in beta-cells was verified by double-immunofluorescence staining. CD40-CD40L interaction activates extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways in insulinoma NIT-1 cells, and inhibitors of either pathway suppress cytokine/chemokine production in islets. Moreover, ligation of CD40 receptor upregulates intercellular adhesion molecule-1, associated with inflammation, at both transcriptional and translational levels. Our results in vitro indicate that the CD40 receptor expressed by beta-cells could be activated in vivo, inducing proinflammatory responses contributing to early islet graft loss after transplantation.
Diabetes 2006 Sep
PMID:CD40-CD40 ligand interaction activates proinflammatory pathways in pancreatic islets. 1693 91

Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic beta-cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal-regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokine-induced apoptosis. In islets isolated from diabetic rodents, FGF-21 treatment increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21-treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of beta-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals.
Diabetes 2006 Sep
PMID:Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. 1693 95

Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 +/- 8 years, BMI 25 +/- 4 kg/m(2) [mean +/- SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R(2) = 0.88 +/- 0.09). After 3 h, 2DG uptake increased 2.1 +/- 0.8- and 4.7 +/- 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 +/- 0.6 to 10 +/- 0.6 mg x kg(-1) x min(-1) (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.
Diabetes 2007 Aug
PMID:5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. 1751 6

5'-AMP-activated protein kinase (AMPK) serves as an energy sensor and is at the center of control for a large number of metabolic reactions, thereby playing a crucial role in Type 2 diabetes and other human diseases. AMPK is present in the nucleus and cytoplasm; however, the mechanisms that regulate the intracellular localization of AMPK are poorly understood. We have now identified several factors that control the distribution of AMPK. Environmental stress regulates the intracellular localization of AMPK, and upon recovery from heat shock or oxidant exposure AMPK accumulates in the nuclei. We show that under normal growth conditions AMPK shuttles between the nucleus and the cytoplasm, a process that depends on the nuclear exporter Crm1. However, nucleocytoplasmic shuttling does not take place in high-density cell cultures, for which AMPK is confined to the cytoplasm. Furthermore, we demonstrate that signaling through the mitogen-activated protein kinase kinase (MEK)-->extracellular signal-regulated kinase 1/2 (ERK1/2) cascade plays a crucial role in controlling the proper localization of AMPK. As such, pharmacological inhibitors that interfere with this pathway alter AMPK distribution under nonstress conditions. Taken together, our studies identify novel links between the physiological state of the cell, the activation of MEK-->ERK1/2 signaling, and the nucleocytoplasmic distribution of AMPK. This sets the stage to develop new strategies to regulate the intracellular localization of AMPK and thereby the modification of targets that are relevant to human disease.
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PMID:Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK-->ERK1/2 pathway. 1772 96

Endothelial progenitor cells (EPCs) have been shown to be involved in vascular regeneration and angiogenesis in experimental diabetes. Because insulin therapy mobilizes circulating progenitor cells, we studied the effects of insulin on outgrowth of EPCs from peripheral blood mononuclear cells of healthy volunteers and patients with type 2 diabetes. Insulin increased the formation of EPC colony-forming units in a dose-dependent manner, half-maximal at 1.5 nM and peaking at 15 nM. Inhibiting the insulin receptor with neutralizing antibodies or antisense oligonucleotides had no effect on EPC outgrowth.(1) In contrast, targeting the human insulin-like growth factor 1 (IGF-1) receptor with neutralizing antibodies significantly suppressed insulin-induced outgrowth of EPCs from both healthy controls and patients with type 2 diabetes. This IGF-1 receptor-mediated insulin effect on EPC growth was at least in part dependent on MAP kinases(2) and was abrogated when extracellular signal-regulated kinase 1/2 (Erk1/2) and protein kinase 38 (p38) activity was inhibited. To study the functional relevance of the observed insulin effects, we studied EPC-induced tube formation of bovine endothelial cells in vitro. Insulin-stimulated EPCs incorporated into the endothelial tubes and markedly enhanced tube formation. In conclusion, this is the first study showing an insulin-mediated activation of the IGF-1 receptor leading to an increased clonogenic and angiogenic potential of EPCs in vitro.
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PMID:Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling. 1838 19

Pancreatic beta-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of beta-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on beta-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic beta cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2'-deoxyuridine label respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1beta, interferon (IFN)-gamma, and tumour necrosis factor-alpha (TNF-alpha) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in beta-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased beta-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and beta-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic beta cells as well as to delay the development of overt diabetes.
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PMID:Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1. 1848 29

Ferulic acid (FA) is a polyphenol very abundant in vegetables and maize bran. Several lines of evidence have shown that FA acts as a potent antioxidant in vitro, due to its ability to scavenge free radicals and induce a robust cell stress response through the up-regulation of cytoprotective enzymes such as heme oxygenase-1, heat shock protein 70, extracellular signal-regulated kinase 1/2 and Akt. Furthermore, FA inhibited the expression and/or activity of cytotoxic enzymes including inducible nitric oxide synthase, caspases and cyclooxygenase-2. On this basis, FA has been proposed for the treatment of several age-related diseases such as neurodegenerative disorders, cardiovascular diseases, diabetes and cancer. However, although the great abundance of in vitro data, the real efficacy of FA in humans has not been demonstrated so far. New efforts and resources should be transferred to clinical research for the complete evaluation of the therapeutic potential of FA in chronic diseases.
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PMID:Ferulic acid and its therapeutic potential as a hormetin for age-related diseases. 1865 Dec 37

Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ER alpha and ER beta-selective agonists 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ER alpha attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17beta-estradiol to aortic tissues from ER beta- but not ER alpha-knockout mice. These findings suggest a possible role for ER alpha-selective ligands in reducing vascular inflammatory responses under normo- and hyperglycemic conditions.
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PMID:Distinct roles of estrogen receptor-alpha and beta in the modulation of vascular inducible nitric-oxide synthase in diabetes. 1883 49

Diabetic cardiomyopathy is associated with high morbidity and mortality of heart failure. Overactivation of the local chymase-Ang II system plays a dominant role in diabetic cardiomyopathy. Astragalus polysaccharide (APS) is used in traditional Chinese medicine to boost immunity. To study the effect of APS on local system of chymase-Ang II in diabetic cardiomyopathy, we investigated APS/normal saline (NS)-administrated streptozotocin-induced diabetic hamsters. After APS/NS administration at a dose of 1 g/kg per day for 10 weeks, hemodynamic parameters, levels of insulin (INS), C-peptide (C-P), glycosylated serum protein (GSP), lipoproteins, myocardial enzymes, and Ang II (plasma and myocardial) were tested; myocardial collagen (type I and III), myocardial ultrastructure, and activities of matrix metalloproteinase (MMPs) were measured; activities and expression of cardiac chymase and ACE were detected by using quantitative real-time RT-PCR and RIA; protein expression of cardiac phosphoric extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by Western blot. AP-administrated diabetic hamsters had lower levels of GSP, lipoproteins, myocardial enzymes, myocardial Ang II, expression of collagen I and I/ III, activities of pro-MMP-2 and MMP-2, activities and expression of chymase, and expression of p-ERK1/2 than NS-administrated diabetic hamsters and could better protect the myocardial ultrastructure. There was no difference in hemodynamic parameters between two groups. These results indicate that APS could inhibit diabetic cardiomyopathy in hamsters depending on the suppression of the local cardiac chymase-Ang II system.
J Diabetes Complications
PMID:Astragalus polysaccharides inhibited diabetic cardiomyopathy in hamsters depending on suppression of heart chymase activation. 1923 Jul 16


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