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)

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P<.1) or among dose groups (P>.1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P<.002; estradiol increase, P<.0004). The change in response variables on Metformin did not differ (P>.05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P<.05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone (r=.24, P=.13) or androstenedione (r=.27, P=.09), on Metformin, the change in insulin correlated positively with the change in testosterone (r=.35, P=.047) and with the change in androstenedione (r=.48, P=.01). Patients were more likely than normal controls (83% v 64%, P=.016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (> or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.
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PMID:Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. 1020 47

Atherogenesis in the vasculature is accelerated by changes in the dynamic equilibrium between endogenous tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1). Increased expression of PAI-1, decreased expression of tissue plasminogen activator, or both can lead to decreased fibrinolytic activity and predispose to thrombosis. Increased concentrations of insulin (and proinsulin) in the plasma increase plasma PAI-1, although the mechanisms of this effect are not known. In addition, it has been observed that basal fibrinolytic activity is decreased in patients with type 2 diabetes; this may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi. Abnormalities in the vessel wall appear to contribute to the increased risk. There is also evidence that PAI-1 content is increased in atherosclerotic lesions of patients with type 2 diabetes, suggesting that interventions to reduce insulin resistance and improve glycemic control may improve the fibrinolytic response. Clinical studies in patients with polycystic ovary syndrome (characterized by insulin resistance, hyperinsulinemia, ovarian androgen overproduction, and impaired fibrinolytic capacity) demonstrated that treatment with troglitazone, an insulin-sensitizing agent, can markedly reduce blood levels of PAI-1. There is also clinical evidence that these agents may contribute to regression of intimal medial thickness in patients with type 2 diabetes, providing further indication that antidiabetic interventions may help inhibit the progression of early atherosclerotic lesions.
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PMID:Insulin resistance and thrombosis: a cardiologist's view. 1041 58

tPA has been the independent risk factor of the thrombosis associated with atherosclerosis. There are increased tPA levels in type 1 diabetic patients with vascular complications and tPA is endothelial injury marker in this case. In type 2 diabetes mellitus elevated tPA antigen levels in early disease stage are caused by increased production of complexes with inhibitor (PAI-1) and tPA or fibrinolytic activity has been decreased.
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PMID:[Tissue plasminogen activator and diabetes mellitus]. 1042 7

Hypofibrinolysis caused by increased PAI-1 levels in patients with insulin resistance (IR) is one of the most common acquired prothrombotic states with higher risk of arterial thrombosis associated with atherosclerosis. Increased PAI-1 levels are caused by PAI-1 hyperproduction in various compartments owing to various factors (multicompartmental and multifactorial model). Metabolic compartment, including visceral adipocytes and hepatocytes, is sensitive on stimulative action of insulin, proinsulin and some cytokines. This pool is responsible for elevated PAI-1 levels in obesity. Vascular compartment, including mainly endothelium, is sensitive on thrombin, angiotensin IV, cytokines, biological active lipids and oxidative stress effect, while insulin inhibits cytokine induced PAI-1 production on contrary. This compartment is responsible for elevated PAI-1 levels in patients with type 2 diabetes mellitus and hypertension with endothelial dysfunction. PAI-1 levels in patients with IR represent cumulative production in described compartments.
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PMID:[A multicomparmental and multifactorial model of production of plasminogen activator inhibitor (PAI-1). I. Experimental studies]. 1042 16

PAI-1 levels are closely associated with insulin resistance (IR) syndrome, including patients with obesity, hypertension, hypertriglyceridaemia and type 2 diabetes mellitus (DM). Clinical studies demonstrated PAI-1 correlations with insulin (IRI), triglycerides (TG) and body mass index (BMI) values, but these relations have not been confirmed in all studies. In obesity PAI-1 levels correlate with IRI and BMI in the relation to increased adipocyte PAI-1 production, which is dependent on stimulative insulin action. In the case of endothelial hyperproduction in patients with IR elevated PAI-1 levels correlate with TG values. Insulin inhibits induced endothelial PAI-1 production. PAI-1 levels in patients with IR represent cumulative production in described tissues.
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PMID:[A multicompartmental and multifactorial model of production of plasminogen activator inhibitor (PAI-1). II. Clinical study in patients with insulin resistance]. 1042 29

Non-insulin dependent diabetes mellitus (NIDDM) is connected with a higher incidence of macrovascular atherosclerotic disorders. The aim of the study was to detect any difference in levels of "cardiovascular risk factors"--fibrinogen, PAI-1 and inflammation response (documented by an increase of protein of acute phase orosomucoid) and of soluble cytoadhesive molecule sE-selectin and sICAM-1 (as markers of endothelial dysfunction) in blood plasma of 118 patients with NIDDM in comparison to the levels in blood plasma of 59 healthy persons as a control group. We observed higher levels of fibrinogen (fibrinogen level was 3.44 +/- 1.02 g/l in NIDDM pts versus 2.44 +/- 0.55 g/l in control group, p < 0.01) and PAI-1 Ag concentration was 159.7 +/- 110.3 ng/ml in NIDDM pts versus 51.43 +/- 24.64 ng/ml in control group, p < 0.01) together with an increase of acute phase protein orosomucoid as a "inflammatory response marker" (orosomucoid concentration was 0.85 +/- 0.23 g/l in NIDDM pts versus 0.54 +/- 0.18 g/l in control group, p < 0.01) in patients with NIDDM. The increase of these "cardiovascular risk factors" levels will be probably induced by higher activity of inflammatory cytokines IL-1 beta and/or TNF alpha in NIDDM patients, because both are inducers of orosomucoid fibrinogen and PAI-1 synthesis. This hypothesis is also supported by observation of higher levels of soluble cytoadhesive molecules sE-selectin (sE-selectin level was 64.25 +/- 26.8 ng/ml in NIDDM pts versus 46.64 +/- 29.57 ng/ml in control group, p < 0.01) and sICAM-1 (sICAM-1 level was 307.71 +/- 86.2 ng/ml in NIDDM pts versus 255.6 +/- 58.0 ng/ml in control group, p < 0.01) in patients with NIDDM. Both cytoadhesive molecules are produced by endothelial cells which are influenced by IL-1 beta and/or TNF alpha. According to these findings we suppose that an "inflammation" plays an important role in the evolution of atherosclerotic process at NIDDM together with the known influence of glucose and lipid metabolism pathology.
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PMID:Haemostasis, cytoadhesive molecules (sE-selectin and sICAM-1) and inflammatory markers in non-insulin dependent diabetes mellitus (NIDDM). 1053 88

This study evaluated abnormal fibrinolysis in diabetic patients in terms of the pathophysiological significance and reversibility by oral hypoglycemic agents. Forty-seven patients with type 2 diabetes mellitus were randomly treated for 4 weeks with glibenclamide (n = 23) or troglitazone (n = 24). Before and after treatment, glycemic control, steady-state plasma glucose and insulin (SSPG and SSPI, respectively), and markers of fibrinolysis (tissue plasminogen activator [tPA] and plasminogen activator inhibitor-1 [PAI-1]) were analyzed in each patient. Pretreatment plasma PAI-1 in diabetic patients, but not tPA, was well correlated with the severity of retinopathy assessed by the fluorescence technique. Four weeks of treatment with troglitazone significantly decreased hemoglobin A1c (HbA1c), SSPG, and PAI-1 without an alteration of tPA. The troglitazone-induced decrease in plasma PAI-1 (50.3 v28.8 micromol/L; P < .05) was correlated with HbA1c (8.80% v7.21%, r = .539, P < .01) and SSPG (16.2 v 8.97 mmol/L, r = .562, P < .01) but not with SSPI. In contrast, treatment with glibenclamide for 4 weeks also reduced the HbA1c titer to almost the same extent as troglitazone (1.38% v 1.59%), but did not change the plasma PAI-1 or SSPG titer. These results suggest that an abnormal fibrinolytic state, especially overproduction of PAI-1, may be a pathogenic factor in the development of diabetic complications such as retinopathy, which may be improved by correction of the insulin resistance with troglitazone.
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PMID:Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. 1083 Nov 80

To elucidate the relationship between the recovery of skin temperature in an extremity after exposure to cold water and various factors associated with diabetes, we measured skin temperature in type2 diabetic patients (N=61) and control subjects (N=16). A thermo-tracer was used in thermographic measurements. The right third toe of each subject was immersed in cold water at 0 degrees C for 10 sec. Rt represents the recovery rate of skin temperature at t min after exposure. Rt was significantly reduced in the diabetic patients every 5 min in the 20 min period following exposure compared with control subjects. The diabetic patients group exhibited a significantly positive correlation between R20 and the ankle-brachial index. R20 in the diabetic patients showed a significantly positive correlation with the reduction in systolic blood pressure at the arm observed in Schellong's test. In addition, R20 showed a significantly negative correlation with plasma levels of fibrinogen and plasminogen activator inhibitor-1. However, the severity of diabetic retinopathy and nephropathy was not significantly related to R20 in the diabetic patients. The present data indicate that the recovery of skin temperature after immersion in cold water was markedly reduced in patients with type 2 diabetes mellitus as compared with healthy control subjects. Peripheral arteriosclerosis, impaired sympathetic nerve function and the activation of the blood coagulation system may all contribute to this reduced recovery of skin temperature.
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PMID:Thermographic measurement of skin temperature recovery time of extremities in patients with type 2 diabetes mellitus. 1108 67

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.
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PMID:Molecular mechanisms of insulin resistance and the role of the adipocyte. 1112 35

Only recently are we beginning to understand the complex interplay of factors involved in vascular disease and diabetes. Insulin resistance provides a starting point to explain the many factors that lead to the more severe vascular disease characteristic of diabetes. Insulin resistance syndrome comprises insulin resistance and compensatory hyperinsulinaemia as well as hypertension, dyslipidaemia, macrovascular disease, and increased plasminogen activator inhibitor-1 activity. The development of type 2 diabetes may be viewed as the inability of the pancreas to continue to overcome insulin resistance, even with excessive insulin production.
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PMID:Pathogenesis of vascular disease. 1121 Feb 41


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