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)

Resistin is an adipokine with putative prodiabetogenic properties. Like other hormones secreted by adipose tissue, resistin is being investigated as a possible etiologic link between excessive adiposity and insulin resistance. Although there is growing evidence that circulating levels of this adipokine are proportional to the degree of adiposity, an effect on insulin resistance in humans remains unproven. To evaluate the relations among resistin, obesity, and insulin resistance, we measured fasting serum resistin levels in 113 nondiabetic (75-g oral glucose tolerance test) Pima Indians (ages 29 +/- 7 years, body fat 31 +/- 8%, resistin 3.7 +/- 1.1 ng/ml [means +/- SD]), who were characterized for body composition (assessed by hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M; assessed by hyperinsulinemic clamp), basal hepatic glucose output (BHGO) and hepatic glucose output during low-dosage insulin infusion of a hyperinsulinemic clamp (HGO; a measure of hepatic insulin resistance), and acute insulin secretory response (AIR; assessed by 25-g intravenous glucose tolerance test). Follow-up measurements of M, BHGO, HGO, and AIR were available for 34 subjects who had normal glucose tolerance at baseline and remained nondiabetic at follow-up. The average time to follow-up was 4.5 +/- 2.7 years. In cross-sectional analyses, serum resistin levels were positively associated with percent body fat (r = 0.37, P = 0.0001) and 2-h glucose (r = 0.19, P = 0.04), respectively. Serum resistin levels were not associated with fasting glucose and insulin levels, M, BHGO, HGO, or AIR (r = 0.17, 0.12, -0.13, -0.06, -0.03, and -0.04, respectively; all P > 0.05). After adjusting for percent body fat, there was no association between serum resistin levels and 2-h glucose (r = 0.06, P = 0.6). In prospective analyses, high serum resistin levels at baseline were not associated with a decline in M (r = -0.1, P > 0.5). Resistin levels were, however, associated with increases in percent body fat, fasting plasma insulin, and HGO (r = 0.34, 0.36, and 0.37; all P < 0.05) after adjusting for sex, age, and time to follow-up. After additional adjustment for the change in percent body fat, there was no association between baseline serum resistin levels and changes in plasma insulin or HGO (r = 0.26 and 0.23; both P > 0.1). We conclude that in Pima Indians, like other human populations, circulating resistin levels are proportional to the degree of adiposity, but not the degree of insulin resistance. We unexpectedly found that high serum resistin levels do predict future increases in percent body fat. Our data suggest that resistin promotes obesity but not obesity-associated insulin resistance in humans.
Diabetes 2004 May
PMID:High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. 1511 97

Both impaired glucose tolerance (IGT) (as defined by the 1985 World Health Organization criteria) and impaired fasting glucose (IFG) (as defined by the 1997 American Diabetes Association criteria) represent intermediate metabolic states between normal and diabetic glucose homeostasis. Cardiovascular disease may be related to postglucose load rather than fasting glycemia, i.e., IGT rather than IFG. We hypothesized that subjects with IGT may be more insulin resistant and have higher levels of common cardiovascular risk factors than those with isolated IFG. In the Insulin Resistance Atherosclerosis Study (IRAS), we studied S(i) and first-phase insulin secretion (acute insulin response [AIR]), as derived from a frequently sampled intravenous glucose tolerance test, as well as common cardiovascular risk factors in four different glucose tolerance categories (NFG/NGT [n = 654], NFG/IGT [n = 255], IFG/NGT [n = 59], and IFG/IGT [n = 102]) among nondiabetic subjects. Subjects with isolated postchallenge hyperglycemia (NFG/IGT) had lower S(i) (means +/- SE: 2.10 +/- 0.04 vs. 2.59 +/- 0.13 x 10(-4) min(-1). microU(-1). ml(-1); P = 0.005), lower proinsulin levels (34.4 +/- 1.8 vs. 42.0 +/- 4.5 pmol/l; P = 0.03), higher AIR (273.1 +/- 18.1 vs. 215.9 +/- 30.0 pmol/l; P = 0.04), higher C-reactive protein (2.49 +/- 0.3 vs. 1.49 +/- 0.5 mg/l; P = 0.0015), and higher triglyceride levels (137.7 +/- 5.5 vs. 108.4 +/- 8.9 mg/dl; P = 0.0025) than subjects with isolated fasting hyperglycemia (IFG/NGT). The relation of insulin resistance to glucose tolerance category was consistently seen in women and men and across the three ethnic groups of the IRAS (non-Hispanic whites, African Americans, and Hispanics). Nondiabetic individuals with isolated postchallenge hyperglycemia (IGT) are more insulin resistant than individuals with isolated fasting hyperglycemia (IFG). The risk factor pattern (including increased insulin resistance) seen in isolated IGT identifies a subgroup of nondiabetic individuals who are likely to benefit from early intervention.
Diabetes 2004 Jun
PMID:Differences in insulin resistance in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose. 1516 60

Genetic and environmental determinants play critical roles in insulin resistance and beta-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity (S(I)), glucose disposition (S(G)), acute insulin response to glucose (AIR(G)), and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. A genome scan for glucose homeostasis phenotypes in nondiabetic subjects has been carried out in African-American (n = 21) and Hispanic (n = 45) extended families as part of the IRAS Family Study. In African-American families, there was significant evidence for linkage of DI between D11S2371 and D11S2002 (logarithm of odds [LOD] = 3.21) at 81 cM, and in the combined sample of African-American and Hispanic families, there was evidence at GATA117D01 (140 cM) on chromosome 11 (LOD = 2.21). Evidence of linkage was also observed for S(I) in Hispanic (LOD = 2.28, between D15S822 and GTTTT001) and AIR(G) in African-American families (LOD = 2.73, between D4S1625 and D4S1629; and LOD = 2.56 at PAH (phenylalanine hydroxylase) on chromosome 12). These results provide impetus for future positional cloning of quantitative trait loci (QTLs). Identifying genes in these regions should provide insight into the nature of the metabolic syndrome and diabetes, and facilitate the development of more effective therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.
Diabetes 2004 Jul
PMID:Identification of quantitative trait loci for glucose homeostasis: the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. 1522 Feb 12

Endothelial cells, platelets, and oxidized LDL could play very important roles in the development of atherosclerosis in diabetes patients. The levels of plasma endothelial cell-derived microparticles (EDMP), platelet-derived microparticles (PDMP), platelet-P-selectin (plt-PS), soluble CD40 ligand (sCD40L), and anti-oxidized LDL antibody were measured and compared to develop a better understanding of their potential contribution to diabetic vascular complications. The concentrations of EDMP, PDMP, plt-PS, and sCD40L in diabetic patients were significantly higher than those in normal subjects. The number of EDMPs in patients with diabetes complicated by nephropathy was significantly higher than that in those without complications. Levels of anti-oxidized LDL antibody were also higher in type 2 diabetic patients than in control subjects. In addition, anti-oxidized LDL antibody levels correlated with EDMP, PDMP, plt-PS, and sCD40L levels in nephropathy patients. In the nephropathy group treated with sarpogrelate hydrochrolide, a 5-HT(2A) receptor antagonist, EDMP, PDMP, plt-PS, and sCD40L levels were decreased significantly. Oxidized LDL increased expression of plt-PS, and also promoted shedding of PDMP. Furthermore, oxidized LDL promoted a dose-dependent release of 5-hydroxytriptamine. On the other hand, activated platelets and PDMP promoted endothelial cells and THP-1 (monocytic cell line) interaction, and membrane vesiculation occurred in the presence of oxidized LDL. These findings suggest that activated platelets and oxidized LDL induce EDMP generation, and that elevated EDMPs may be a sign of vascular complications in type 2 diabetic patients, particularly those who suffer from diabetes-associated nephropathy.
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PMID:Activated platelet and oxidized LDL induce endothelial membrane vesiculation: clinical significance of endothelial cell-derived microparticles in patients with type 2 diabetes. 1524 77

Low-density lipoprotein (LDL) in patients with diabetes is subject to modification by both oxidation and glycation. In contrast to oxidized LDL, the biological effects of glycoxidized LDL have not been well characterised. In this study, the effects of oxidized, glycated, glycoxidized and oxidized LDL on scavenger receptor gene expressions, and the induction of oxidized LDL uptake and cholesteryl ester accumulation in THP-1 macrophages were compared. Modified LDL was incubated with THP-1 macrophages. Gene expression of scavenger receptor class A (SR-A), CD36 and scavenger receptor class B type I (SR-BI) was determined by quantitative reverse transcriptase PCR (RT-PCR). Glycoxidized LDL was able to significantly induce SR-A and CD36 expression by 3- and 4.5-fold, respectively, in macrophages whereas SR-BI expression was suppressed by glycoxidized LDL, glycated LDL and oxidized LDL. Incubation with glycoxidized LDL enhanced the uptake of DiI-labeled oxidized LDL by macrophages to a greater extent than that of glycated LDL or oxidized LDL. Glycoxidized LDL also induced a significant degree of intracellular cholesteryl ester accumulation. Taken together, our results would suggest that glycoxidized LDL might be an important candidate in the initiation of foam cell formation and might play a significant role in the pathogenesis of atherosclerosis in diabetes mellitus.
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PMID:Glycoxidized low-density lipoprotein regulates the expression of scavenger receptors in THP-1 macrophages. 1553 Sep 5

Diabetes confers an increased propensity to atherosclerosis. Inflammation is pivotal in atherogenesis, and diabetes is a proinflammatory state. Interleukin (IL)-6, in addition to inducing the acute-phase response, contributes to insulin resistance. Monocytes from type 2 diabetic patients secrete increased IL-6. The aim of this study was to examine molecular mechanisms for increased IL-6 release from monocytes under hyperglycemia. Monocytic cells (THP-1) were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were significantly increased with hyperglycemia (P < 0.001). Incubation of cells with inhibitors of reactive oxygen species failed to affect high-glucose-induced IL-6 release. Pan-protein kinase C (PKC) inhibitors significantly decreased high-glucose-induced IL-6 release. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK; SB 202190), but not the extracellular signal-regulated kinase inhibitor PD98059, significantly decreased high-glucose-induced IL-6 release. Furthermore, the PKC-alpha/beta2 inhibitor decreased p38MAPK and the resulting high-glucose-induced IL-6 release. Both antisense oligos to PKC-beta and -alpha as well as small interfering RNA (siRNA) to PKC-alpha and -beta resulted in significantly decreased high-glucose-induced IL-6 release. Nuclear factor-kappaB (NF-kappaB) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-beta and -alpha also significantly decreased NF-kappaB activity and IL-6 release. The combination was not additive to either siRNA alone, suggesting that they work through a common pathway. Thus, IL-6 release from monocytes under hyperglycemia appears to be mediated via upregulation of PKC, through p38MAPK and NF-kappaB, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-alpha and -beta can ameliorate the proinflammatory state of diabetes.
Diabetes 2005 Jan
PMID:Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}. 1561 14

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.
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PMID:Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha. 1597 14

Type 2 diabetes, a major risk factor for atherosclerosis, is associated with a cluster of lipid risk factors, many of which can be mechanistically linked with underlying dysregulated fatty acid metabolism and elevated plasma non-esterified fatty acids (NEFA). Thus, we tested the hypothesis that elevated NEFA dysregulates lipid metabolism at the levels of lipid synthesis and gene expression in THP-1 monocyte derived macrophages (MDM). THP-1 MDM incubated with oleic acid (OA) and a BODIPY-conjugated NEFA, accumulate, respectively, intracellular inclusions that are positive for oil red O and BODIPY-labeling. Parallel studies with [(14)C]OA show dose-dependent accumulation of intracellular (14)C-labeled neutral lipid, almost exclusively as triglyceride; the rate of [(3)H]OA uptake increases as THP-1 MDM convert to foam cells. Preincubation of THP-1 MDM with higher concentrations of OA (1.8mM versus 0.2mM) was associated with enhanced uptake of Ac-LDL, and increased expression of adipocyte fatty acid binding protein, FAT/CD36, and cyclooxygenase-2 (COX-2); COX-2 mass and activity also increased. These observations suggest a mechanistic link between sustained elevations in albumin-bound NEFA and foam cell formation that may be mediated by enhanced adipogenesis, increased uptake of modified LDL, and upregulated formation of eicosanoids, which may be proinflammatory.
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PMID:Sustained elevations in NEFA induce cyclooxygenase-2 activity and potentiate THP-1 macrophage foam cell formation. 1687 Jan 93

Chemokines mediate the recruitment and activation of blood monocyte/macrophages and lymphocytes to sites of inflammation. Expression of the chemokine IP-10 (interferon-gamma-inducible protein) has been documented in several inflammatory and autoimmune disorders including type 1 diabetes. However, the mechanism of its expression in monocytes or its functional role in diabetes is not known. Advanced glycation end products acting via their receptor, RAGE, play major roles in diabetic complications. In this study, we observed for the first time that S100b, an inflammatory protein as well as a specific RAGE ligand, significantly increased IP-10 mRNA and protein levels in THP-1 monocytes as well as peripheral blood monocytes. Promoter luciferase assays showed that IP-10 mRNA accumulation by S100b was not via increased transcription. On the other hand, S100b significantly increased IP-10 mRNA half-life and stability. This appeared to be mediated by S100b-induced binding of specific RNA-binding protein(s) to a 3'-untranslated region-responsive region of the IP-10 mRNA. Our results demonstrate for the first time that diabetic stimuli such as RAGE ligands can induce inflammatory gene expression in monocytes via increased message stability.
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PMID:Interferon-gamma-inducible protein (IP)-10 mRNA stabilized by RNA-binding proteins in monocytes treated with S100b. 1693 19

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved beta-cell function is not clear. In vitro studies showed improved beta-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on beta-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect beta-cell function. We evaluated beta-cell function and insulin sensitivity (S(I)) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved S(I), glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (S(G))]. Neither pioglitazone nor metformin significantly improved beta-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline S(I). Insulin secretion in response to arginine at maximally potentiating glucose levels (AIR(max)) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for S(I), the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving S(I) and S(G). We did not find any evidence that either pioglitazone or metformin improved beta-cell function. Improved beta-cell compensation was observed primarily in the subgroup of subjects that had the lowest S(I) at baseline.
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PMID:Effects of pioglitazone and metformin on beta-cell function in nondiabetic subjects at high risk for type 2 diabetes. 1696 13


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