Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolic Syndrome X defined by Reaven is caused by peripheral insuline receptor resistance, leads to hyperinsulinemia regarded as a cause of secondary dyslipidemia, hypertension, hemostatic disturbances, atherosclerosis and insulin as a growth factor takes part in carcinogenesis. Depending on a contribution of the primary risk factors of type 2 Diabetes Mellitus (2-DM) mainly genetic factors and obesity--an independent cause of insulin receptor resistance--glucose intolerance and 2-DM may overlap the Syndrome X. The aims of these studies were to determine in cross-sectional investigation a plasma insulin concentration in subjects aged over 35 years and to assess the clinical usefulness of insulinemia in early diagnosis of diabetes type 2. Investigations were carried out in Krakow town's district with 200,000 inhabitants, out of those 3060 randomly selected subjects (1720 females and 1340 males aged over 35 years) took part in the Polish Multicenter Study on Diabetes Epidemiology (PMSDE) with protocol and methods previously presented. Glucose concentration was determine by enzymatic method, insuline in plasma by IRMA method using ready kits produced by the Swierk-Poland. Logistic multiple regression model was used to estimate the effect of risk factors on the development of glucose intolerance, Chi square test, Fisher test and Mann-Whitney test were used for statistical analysis by means of statistical package BMPD. Fasting insulinemia in persons with normal glucose tolerance and body weight (BMI < 25 and glycemia < 6.1 mmol/l) in subpopulation aged over 35 years was 5.73 (SD = 3.99) in men and 7.05 (SD = 4.67) microU/ml in women. These values were positively correlated with BMI and at the range 25-30 and > 30 increased by 50 and 100% responsively and in 2-nd h in OGTT by five-times. In the persons with glucose intolerance and new-diagnosed 2-DM insulinemia increased 2-3 fold depending on BMI, and gender. In the subgroup with 2-DM and BMI > 30, insulinemia in 2 h-OGTT treated values 152 (SD = 90) in women and 112 (SD = 83.4) microU/ml in men. Obesity and insulinemia in 2 h-OGTT in multiple analysis have been identified as a strong predictors and risk factors of impaired glucose intolerance (IGT) 2-DM fasting insulinemia may be useful as an indicator of the peripheric insulin receptor resistance. The results lead to the conclusions that determination of the plasma insulin concentration may be useful in early diagnosis of IGT and diabetes type 2, and should be monitored in the course of non-pharmacological and pharmacological treatment 2-DM. One of the main goals in the course of treatment of obesity and early phases of the 2-DM should be normalization or at least reduction of hyperinsulinemia. Insulinemia may be regarded also as an important criterion for selection of the oral antidiabetic drugs.
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PMID:[Insulinemia--a marker of early diagnosis and control of efficacy of treatment of type II diabetes]. 1192 88

New agents are being developed to address the underlying endocrinopathies and metabolic disturbances of type 2 diabetes. Stimulants of the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) are being identified to selectively improve insulin actions, and dual agonists of PPAR gamma and PPAR alpha are being evaluated for enhanced control of hyperglycemia and dyslipidemia. Novel activators of insulin receptor phosphorylation and inhibitors of receptor dephosphorylation are offering encouraging leads for new agents. Analogues of glucagon-like peptide-1 that increase glucose-induced insulin secretion may additionally increase beta-cell neogenesis from progenitor duct cells. The amylin analogue pramlintide, which suppresses glucagon secretion and reduces weight, is advancing in clinical trial. Direct stimulants of glucose utilization and partial inhibitors of gluconeogenesis are providing useful new drug templates. Thus, new pharmacologic approaches are emerging to treat the multiple lesions of type 2 diabetes.
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PMID:New pharmacologic agents for diabetes. 1264 7

Insulin resistance, defined as the decreased ability of insulin to perform its biological functions, is likely to represent the primary physiologic defect underlying the insulin resistance syndrome (IRS), which includes insulin resistance/hyperinsulinemia, glucose intolerance and/or type 2 diabetes mellitus, visceral obesity, hypertension, and dyslipidemia. This constellation of traits is a leading cause of cardiovascular mortality and morbidity. Insulin sensitivity varies widely among individuals. Although environmental provocations including physical inactivity and caloric excess play an important role in the development of obesity and thus insulin resistance, epidemiologic and family studies show that there are also moderate genetic influences on the development of insulin resistance. Extreme forms of insulin resistance may be caused rarely by mutations in the genes for the insulin receptor and peroxisome proliferator-activated receptor gamma. However, the genetic basis for common more moderate forms of insulin resistance is likely to be polygenic and heterogeneous. Evidence further suggests that gene variants may have phenotypic influences on more than one IRS trait (so-called pleiotrophy), which may explain, in part, the clustering of these traits. This article reviews the evidence that insulin resistance has a genetic basis. Progress to date toward identifying specific gene variants are reviewed. Ultimately, the identification of specific gene variants that influence insulin resistance and other IRS traits will have profound influences on our understanding of the molecular and pathophysiologic basis of these disorders, from which new and more effective preventive and therapeutic interventions will be possible.
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PMID:Genetics of insulin resistance. 1264 27

White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.
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PMID:Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice. 1468 12

The metabolic or insulin resistance syndrome, characterized by hypertension, dyslipidemia, glucose intolerance and hyperinsulinemia, may have genetic determinants. The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. We examined eight polymorphisms in these genes in 163 individuals from Yucatan, Mexico; this population has a high prevalence of obesity, type 2 diabetes mellitus and dyslipidemia. Subjects were evaluated for body mass index (BMI) and blood pressure. Blood samples were collected to determine glucose, insulin, triglycerides and cholesterol levels, as well as for DNA isolation. Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. Among the eight polymorphisms analyzed, the PstI polymorphism in INS was significantly associated with hypertriglyceridemia and with the presence of at least one abnormality related to the metabolic syndrome (P=0.007 and 0.004, respectively). The MaeIII polymorphism in INS was associated with fasting hyperinsulinemia (P=0.045). In multilocus analyses including both INS polymorphisms, significant associations were seen with hypertriglyceridemia (P=0.006), hypercholesterolemia (P=0.031) and with presence of at least one metabolic abnormality (P=0.009). None of the polymorphisms in INSR or IRS1 was associated with any of these traits. These findings suggest that the insulin gene may be an important determinant of metabolic syndrome, and particularly of dyslipidemia, in this population.
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PMID:Polymorphisms in candidate genes for type 2 diabetes mellitus in a Mexican population with metabolic syndrome findings. 1469 12

Acid phosphatase locus 1 (ACP1) is a highly polymorphic enzyme that has an important role in flavoenzyme activity and in the control of insulin receptor activity and band 3 protein phosphorylation status. Adenosine deaminase (ADA) is a polymorphic enzyme that catalyses the irreversible deamination of adenosine to inosine and has an important role in regulating adenosine concentration. Based on the hypothesis that ACP1 counteracts insulin signaling by dephosphorylating the insulin receptor and that adenosine has an anti-insulin action, we reasoned that low ACP1 activity (low dephosphorylating action on insulin receptor) when associated with high ADA activity (low adenosine concentration) would result in a cumulative effect towards an increased glucose tolerance. On the contrary, high ACP1 activity when associated with low ADA activity would result in a cumulative effect towards a decreased glucose tolerance. A total of 280 adult subjects with type 2 diabetes from the population of Penne (Italy) were studied. There was a nonsignificant trend toward an increase in the proportion of subjects with the complex type with high ACP1 activity and low ADA activity (ie, *B/*B; *A/*C; *B/*C; *C/*C//ADA*1/*2 and *2/*2) in type 2 diabetes relative to that observed in newborn infants from the same population. High ACP1 activity/low ADA activity joint genotype was positively associated with high glycemic levels and with high body mass index (BMI) values. Low ACP1 activity/high ADA activity joint genotype was also positively associated with dyslipidemia. These findings suggest that both ACP1 and ADA contribute to the clinical manifestations of type 2 diabetes and probably also have a marginal influence on susceptibility to the disease. Both additive and epistatic interactions between the 2 systems seem to be operative.
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PMID:Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms. 1528 Oct 7

Protein tyrosine phosphatase-1B (PTP-1B) plays an important role in regulation of insulin signal transduction, and modulation of PTP-1B expression seems to have a profound effect on insulin sensitivity and diet-induced weight gain. The molecular link between PTP-1B expression and metabolic dyslipidemia, a major complication of insulin resistance, was investigated in the present study using PTP-1B knockout mice as well as overexpression and suppression of PTP-1B. Chronic fructose feeding resulted in a significant increase in plasma VLDL in wild-type mice but not in PTP-1B knockout mice. Lipoprotein profile analysis of plasma from PTP-1B knockout mice revealed a significant reduction in apolipoprotein B (apoB100) lipoproteins, associated with reduced hepatic apoB100 secretion from isolated primary hepatocytes. In addition, treatment of cultured hepatoma cells with PTP-1B siRNA reduced PTP-1B mass by an average of 41% and was associated with a 53% decrease in secretion of metabolically labeled apoB100. Conversely, adenoviral-mediated overexpression of PTP-1B in HepG2 cells downregulated the phosphorylation of insulin receptor and insulin receptor substrate-1 and caused increases in cellular and secreted apoB100 as a result of increased intracellular apoB100 stability. Collectively, these findings suggest that PTP-1B expression level is a key determinant of hepatic lipoprotein secretion, and its overexpression in the liver can be sufficient to induce VLDL overproduction and the transition to a metabolic dyslipidemic state.
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PMID:Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies. 1556 34

Low-molecular-weight organic chromium complexes such as chromium picolinate are often used as dietary supplements to improve insulin sensitivity and to correct dyslipidemia. However, toxicity associated with such chromium compounds has compromised their therapeutic value. The aim of this study was to evaluate the impact of a newly synthesized complex of chromium with phenylalanine, Cr(pa)3 on insulin-signaling and glucose tolerance. Cr(pa)3 was synthesized by chelating chromium(III) with D-phenylalanine ligand in aqueous solution. In mouse 3T3-adipocytes, Cr(pa)3 augmented insulin-stimulated glucose-uptake as assessed by a radioactive-glucose uptake assay. At the molecular level, Cr(pa)3 enhanced insulin-stimulated phosphorylation of Akt in a time- and concentration-dependent manner without altering the phosphorylation of insulin receptor. Oral treatment with Cr(pa)3 (150 microg/kg/d, for six weeks) in ob/ob+/+ obese mice significantly alleviated glucose tolerance compared with untreated obese mice. Unlike chromium picolinate, Cr(pa)3 does not cleave DNA under physiological reducing conditions. Collectively, these data suggest that Cr(pa)3 may represent a novel, less-toxic chromium supplement with potential therapeutic value to improve insulin sensitivity and glycemic control in type II diabetes.
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PMID:A newly synthetic chromium complex--chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance. 1573 57

The insulin resistance syndrome refers to a constellation of findings, including glucose intolerance, obesity, dyslipidemia, and hypertension, that promote the development of type 2 diabetes, cardiovascular disease, cancer, and other disorders. Defining the pathophysiological links between insulin resistance, the insulin resistance syndrome, and its sequelae is critical to understanding and treating these disorders. Over the past decade, two approaches have provided important insights into how changes in insulin signaling produce the spectrum of phenotypes associated with insulin resistance. First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. Second, in vivo and in vitro studies of the complex network of insulin signaling have provided insight into how insulin resistance can develop in some pathways whereas insulin sensitivity is maintained in others. These data, taken together, give us a framework for understanding the relationship between insulin resistance and the insulin resistance syndromes.
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PMID:From mice to men: insights into the insulin resistance syndromes. 1646 Feb 69

The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature.
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PMID:Insulin resistance and atherosclerosis. 1649 3


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