Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of hydrogen peroxide (H2O2) by neutrophilic polymorphonuclear leukocytes (PMN) after stimulation with PMA, FMLP, aggregated IgG and phagocytosis were determined in 36 patients with non-insulin dependent diabetes mellitus (NIDDM). The H2O2 production of PMN after the stimulation was measured using by flow cytometry. The patients were divided into four stages as follows: (1) non-microalbuminuric stage, (2) microalbuminuric stage, (3) proteinuric stage without impairment of renal function (less than 1.2 mg/dl of serum creatinine) and (4) proteinuric stage with impairment of renal function (more than 1.3mg/dl of serum creatinine). The H2O2 production after stimulation with PMA or phagocytosis was significantly higher in patients with NIDDM than normal controls. And also, there is the tendency of an increase in the H2O2 production after stimulation with FMLP or aggregated IgG. This increase of the H2O2 production was observed in all four stages of NIDDM patients after the stimulation, especially in patients with renal failure associated with diabetic nephropathy. These results suggest that reactive oxygen species produced by PMN after stimulation under various conditions may play an important role in the progression and exacerbation of diabetic nephropathy.
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PMID:[The production of hydrogen peroxide by neutrophilic polymorphonuclear leukocytes in patients with non-insulin dependent diabetes mellitus]. 129 76

The PPAR gamma agonists, thiazolidinediones (TZDs), have anti-inflammatory properties as well as increasing insulin sensitivity. This has widened their therapeutic scope to treat inflammatory diseases such as atherosclerosis in addition to Type 2 Diabetes. TZDs are known to reduce monocyte/macrophage expression of Matrix metalloproteinase (MMP)-9, which is implicated in atherosclerotic plaque destabilization. This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis. The synthetic PPAR gamma agonist, GW7845, and the natural agonist 15d-PGJ2, suppressed PMA stimulated MMP-9 in human monocyte-like cells (THP-1) only in the presence of 9-cis-retinoic acid. Quantitative Real-Time PCR showed that this reduction was regulated at the mRNA level. Expression of ADAMs 8, 9, and 17 were increased, and ADAM15 was decreased by stimulation of THP-1 with PMA, although these ADAMs were not regulated by PPAR gamma or RXR agonists. PMA-induced ADAM28 expression was further enhanced by the addition of 9-cis-retinoic acid. ADAMTS4, implicated in rheumatoid arthritis, was expressed in THP-1 cells, and significantly increased after 24 h of PMA stimulation. ADAMTS4 expression was suppressed by both PPAR gamma and RXR agonists and was undetectable when the agonists were combined. Pretreatment of THP-1 cells with the PPAR gamma antagonist, GW9662, suggests that PPAR gamma plays subtly different roles in the regulation of MMP-9, ADAMTS4 and ADAM28 gene expression. These results indicate that PPAR gamma and RXR agonists have complex effects on monocyte metalloproteinase expression, which may have implications for therapeutic strategies.
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PMID:Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. 1453 4

Pancreatic amyloid is found in patients with insulinomas and type 2 diabetes. To study mechanisms of islet amyloidogenesis, we produced transgenic mice expressing the unique component of human islet amyloid, human islet amyloid polypeptide (hIAPP). These mice develop islet amyloid after 12 mo of high-fat feeding. To determine whether we could accelerate the rate of islet amyloid formation, we crossbred our hIAPP transgenic animals with RIP-Tag mice that develop islet tumors and die at 12 wk of age from hypoglycemia. At 12 wk of age, this new line of hIAPPxRIP-Tag mice was heavier (29.7 +/- 1.0 vs. 25.0 +/- 1.3 g, P < 0.05) and had increased plasma glucose levels (4.6 +/- 0.4 vs. 2.9 +/- 0.6 mmol/l, P < 0.05) compared with littermate RIP-Tag mice. However, the hIAPPxRIP-Tag mice did not display islet amyloid or amyloid fibrils despite high circulating hIAPP levels (24.6 +/- 7.0 pmol/l). Interestingly, hIAPPxRIP-Tag mice had a longer life span than RIP-Tag mice (121 +/- 8 vs. 102 +/- 5 days, P < 0.05). This increase in life span in hIAPPxRIP-Tag was positively correlated with body weight (r = 0.48, P < 0.05) and was associated with decreased insulin sensitivity compared with RIP-Tag mice. hIAPPxRIP-Tag mice did not develop amyloid during their 4-mo life span, suggesting that increased hIAPP secretion is insufficient for islet amyloid formation within such a short time. However, hIAPPxRIP-Tag mice did have an increase in life span that was associated with insulin resistance, suggesting that hIAPP has extrapancreatic effects, possibly on peripheral glucose metabolism.
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PMID:Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide. 1461 23

Insulin resistance and type 2 diabetes are associated with elevated circulating levels of nonesterified FA (NEFA) and lipoprotein remnants. The dyslipidemia is an important contributor to the excess arterial disease associated with insulin resistance and type 2 diabetes, but the mechanisms involved are elusive. In the present study we examined the effect of NEFA on macrophages. For this purpose, we utilized human macrophages, prepared by treating THP-1 monocytes with phorbol ester. We found that albumin-bound NEFA at physiological levels increase the secretion of granulocyte macrophage-colony stimulating factor (GM-CSF) by the THP-1 macrophages in a dose-dependent manner. The effect was registered as an increase in mRNA, and the amount of GM-CSF secreted correlated with the accumulation of TAG and DAG in the cell. The NEFA-induced rise in GM-CSF appeared to be mediated by activation of protein kinase C, probably acting on extracellular signal-regulated kinases 1 and 2 and being calcium dependent. We speculate that increased secretion of GM-CSF by resident macrophages in the intima exposed chronically to high levels of NEFA, such as those present in insulin resistance, may contribute to a proatherogenic response of arterial cells.
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PMID:Fatty acids induce increased granulocyte macrophage-colony stimulating factor secretion through protein kinase C-activation in THP-1 macrophages. 1523 3

Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and inhibits food intake, gastric emptying, and glucagon secretion, actions that promote reduction of fasting and postprandial glycemia in subjects with type 2 diabetes. The rapid degradation of native GLP-1 has engendered interest in more stable longer-acting GLP-1 receptor agonists such as exendin-4 (Ex-4); however, the potential consequences of sustained GLP-1 receptor activation leading to receptor desensitization has not been extensively studied. We have now examined a range of GLP-1 receptor-dependent responses following treatment with Ex-4 using INS-1 cells in vitro and both wild-type control and MT-Ex-4 transgenic mice in vivo. Although both GLP-1 and Ex-4 acutely desensitized GLP-1 receptor-dependent cAMP accumulation in INS-1 cells, Ex-4 produced more sustained receptor desensitization, relative to GLP-1, in both acute (5-120 min) and chronic (24-72 h) experiments. PMA (4-phorbol 12-myristate 13-acetate) but not glucagon, glucose-dependent insulinotropic polypeptide (GIP), or epinephrine produced heterologous desensitization in vitro. MT-Ex-4 transgenic mice exhibited a reduced glycemic response to oral but not intraperitoneal glucose challenge following acute Ex-4 administration. In contrast, no differences in glycemic excursion or plasma insulin were observed after 1 week of twice-daily Ex-4 administration to wild-type versus MT-Ex-4 mice. Similarly, the levels of insulin, pdx-1, and GLP-1 receptor mRNA transcripts were comparable in wild-type and MT-Ex-4 transgenic mice after 1 week of Ex-4 administration. However, repeated Ex-4 administration significantly reduced food intake in MT-Ex-4 but not in wild-type mice. These findings illustrate that although Ex-4 is more potent than native GLP-1 in producing GLP-1 receptor desensitization in vitro, chronic exposure to Ex-4 in normal or transgenic mice is not associated with significant downregulation of GLP-1 receptor-dependent responses coupled to glucose homeostasis in vivo.
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PMID:Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. 1556 12

The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1.5-3.0 and approximately 3.0-5.0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.
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PMID:Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD. 1734 75

The PPARgamma Pro12Ala polymorphism has been associated in several studies with a decreased risk of obesity, type 2 diabetes and insulin resistance. Weak hints are available about the influence of PPARgamma Pro12Ala on postprandial metabolism. In 708 men, aged 45 to 65 years the PPARgamma2 Pro12Ala genotypes were determined and postprandial TAG, insulin, glucose and NEFA after a standardized mixed fat meal and insulin and glucose after a glucose load (oral glucose tolerance test; OGTT) were assessed. Using the total sample, we did not find a significant impact of the genotype on the postprandial metabolism. In the subgroup with BMI <30 kg/m2, fasting and postprandial TAG and insulin levels as well as homeostasis model assessment of insulin resistance (HOMA) were significantly lower in the Ala12Ala group than in the Pro12Pro group after the mixed meal. In contrast, the groups did not differ in insulin levels and HOMA after the OGTT. To investigate if differences between a fat-containing meal and OGTT are caused by adiponectin, we examined a BMI- and age-matched subgroup. No differences were found between the genotypic groups. The effects of the PPARgamma2 polymorphism on insulin sensitivity are mediated by affluent dietary fat. We did not find evidence that adiponectin as a fatty-acid-dependent adipocyte factor is a causative factor for this phenomenon.
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PMID:The minor allele of the PPARgamma2 pro12Ala polymorphism is associated with lower postprandial TAG and insulin levels in non-obese healthy men. 1740 25

This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA), the acute phase reactant high-sensitive C-reactive protein (hsCRP), endothelin-1 (ET-1), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) between healthy controls, subjects with ischemic heart disease (IHD) and type 2 diabetes mellitus (DM) subjects who did not perform coronary artery bypass graft (CABG) surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels, and TAG were positively correlated, as do the association between P-selectin, VCAM-1, and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers, and their downstream effectors adhesion molecules occur in type 2 DM.
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PMID:Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients. 1749 38

Subjects with obesity and elevated fasting blood glucose are at high risk of developing type 2 diabetes which may be reduced by a dietary intervention leading to an improvement of insulin resistance. We investigated the potential of a whole-grain based dietary product (WG) with reduced starch content derived from double-fermented wheat during a hypo-energetic diet to positively influence body weight, fasting blood glucose, insulin resistance and lipids in comparison to a nutrient-dense meal replacement product (MR) in a randomized two-way cross-over study with two 4-week treatment periods separated by a 2-week wash-out. Subjects replaced at least two daily meals with WG and MR, respectively, targeting for a consumption of 200 g of either product per day. Total daily energy intake was limited to 7120 kJ. Thirty-one subjects (BMI 33.9 (SD 2.7) kg/m2, fasting blood glucose 6.3 (SD 0.8) mmol/l) completed the study. In both treatment groups body weight (-2.5 (SD 2.0) v. - 3.2 (SD 1.6) kg for WG v. MR), fasting blood glucose (-0.4 (SD 0.3) v. -0.5 (SD 0.5) mmol/l), total cholesterol (-0.5 (SD 0.5) v. -0.6 (SD 0.5) mmol/l), TAG (-0.3 (SD 0.9) v. -0.3 (SD 1.2) mmol/l) and homeostasis model assessment (HOMA) insulin resistance score (-0.7 (SD 0.8) v. -1.1 (SD 1.7) microU/ml x mmol/l) improved (P < 0.05) with no significant differences between the treatments. After statistical adjustment for the amount of body weight lost, however, the comparison between both groups revealed that fasting serum insulin (P = 0.031) and HOMA insulin resistance score (P = 0.049) improved better with WG than with MR. We conclude that WG favourably influences metabolic risk factors for type 2 diabetes independent from the amount of body weight lost during a hypo-energetic diet.
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PMID:Improvement of insulin resistance after diet with a whole-grain based dietary product: results of a randomized, controlled cross-over study in obese subjects with elevated fasting blood glucose. 1756 26

Naturally-occurring compounds that have been shown to improve insulin sensitivity include Cr and polyphenols found in cinnamon (Cinnamomon cassia). These compounds also have similar effects on insulin signalling and glucose control. The signs of Cr deficiency are similar to those for the metabolic syndrome and supplemental Cr has been shown to improve all these signs in human subjects. In a double-blind placebo-controlled study it has been demonstrated that glucose, insulin, cholesterol and HbA1c are all improved in patients with type 2 diabetes following Cr supplementation. It has also been shown that cinnamon polyphenols improve insulin sensitivity in in vitro, animal and human studies. Cinnamon reduces mean fasting serum glucose (18-29%), TAG (23-30%), total cholesterol (12-26%) and LDL-cholesterol (7-27%) in subjects with type 2 diabetes after 40 d of daily consumption of 1-6 g cinnamon. Subjects with the metabolic syndrome who consume an aqueous extract of cinnamon have been shown to have improved fasting blood glucose, systolic blood pressure, percentage body fat and increased lean body mass compared with the placebo group. Studies utilizing an aqueous extract of cinnamon, high in type A polyphenols, have also demonstrated improvements in fasting glucose, glucose tolerance and insulin sensitivity in women with insulin resistance associated with the polycystic ovary syndrome. For both supplemental Cr and cinnamon not all studies have reported beneficial effects and the responses are related to the duration of the study, form of Cr or cinnamon used and the extent of obesity and glucose intolerance of the subjects.
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PMID:Chromium and polyphenols from cinnamon improve insulin sensitivity. 1823 31


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