Microvascular function relates to insulin sensitivity and blood pressure in normal subjects.
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BACKGROUND: A strong but presently unexplained inverse association between blood pressure and insulin sensitivity has been reported. Microvascular vasodilator capacity may be a common antecedent linking insulin sensitivity to blood pressure. To test this hypothesis, we studied 18 normotensive and glucose-tolerant subjects showing a wide range in insulin sensitivity as assessed with the hyperinsulinemic, euglycemic clamp technique. METHODS AND RESULTS: Blood pressure was measured by 24-hour ambulatory blood pressure monitoring. Videomicroscopy was used to measure skin capillary density and capillary recruitment after arterial occlusion. Skin blood flow responses after iontophoresis of acetylcholine and sodium nitroprusside were evaluated by laser Doppler flowmetry. Insulin sensitivity correlated with 24-hour systolic blood pressure (24-hour SBP; r=-0.50, P<0.05). Capillary recruitment and acetylcholine-mediated vasodilatation were strongly and positively related to insulin sensitivity (r=0.84, P<0.001; r=0.78, P<0.001, respectively), and capillary recruitment was inversely related to 24-hour SBP (r=-0.53, P<0.05). Waist-to-hip ratio showed strong associations with insulin sensitivity, blood pressure, and the measures of microvascular function but did not confound the associations between these variables. Subsequent regression analysis showed that the association between insulin sensitivity and blood pressure was not independent of the estimates of microvascular function, and part of the variation in both blood pressure (R2=38%) and insulin sensitivity (R2=71%) could be explained by microvascular function. CONCLUSIONS: Insulin sensitivity and blood pressure are associated well within the physiological range. Microvascular function strongly relates to both, consistent with a central role in linking these variables. (+info)
The treatment of insulin resistance does not improve adrenal cytochrome P450c17alpha enzyme dysregulation in polycystic ovary syndrome.
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OBJECTIVE: To determine whether metformin. when given to non-diabetic women with polycystic ovary syndrome (PCOS), results in a reduction of insulin resistance and hyperinsulinemia while body weight is maintained. Also we aimed to see whether the reduction in insulin levels attenuates the activity of adrenal P450c17alpha enzyme in patients with PCOS. DESIGN: We investigated the 17-hydroxyprogesterone (17-OHP) and androstenedione responses to ACTH, insulin responses to an oral glucose tolerance test (OGTT) and glucose disposal rate in an insulin tolerance test before and after metformin therapy (500 mg, orally, twice daily, for 12 weeks). METHODS: The presence of hyperinsulinemia in 15 women with PCOS was demonstrated by an OGTT and results were compared with those of 10 healthy women. Insulin sensitivity was measured by the rate of endogenous glucose disposal after i.v. bolus injection of insulin. 17-OHP and androstenedione responses to ACTH were measured in all the women with PCOS and the normal women. RESULTS: Women with PCOS were hyperinsulinemic (102.0+/-13.0 (S.E.M.) VS 46.2+/-4.4 pmol/l) and hyperandrogenemic (free testosterone 15.3+/-1.7 vs 7.9+/-0.6 nmol/l; androstenedione 11.8+/-0.8 vs 8.2+/-0.6 nmol/l) and more hirsute (modified Ferriman-Gallwey score, 17.7+/-1.6 vs 3.0+/-0.3) than healthy women. In addition, women with PCOS had higher 17-OHP and androstenedione responses to ACTH when compared with healthy women. Metformin therapy resulted in some improvement in insulin sensitivity and reduced the basal and post-glucose load insulin levels. But 17-OHP and androstenedione responses to ACTH were unaltered in response to metformin. CONCLUSIONS: PCOS is characterized by hyperactivity of the adrenal P450c17alpha enzyme and insulin resistance. It seems that there is no direct relationship between insulin resistance and adrenal P450c17alpha enzyme dysregulation. (+info)
No association between the -308 polymorphism in the tumour necrosis factor alpha (TNFalpha) promoter region and polycystic ovaries.
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The tumour necrosis factor (TNF)2 allele appears to be linked with increased insulin resistance and obesity, conditions often found in overweight patients with polycystic ovary syndrome (PCOS). The significance of TNFalpha polymorphism in relation to the clinical and biochemical parameters associated with PCOS was investigated in 122 well-characterized patients with polycystic ovaries (PCO). Of these, 84 had an abnormal menstrual cycle and were classified as having PCOS, while the remaining 38 had a normal menstrual cycle and were classified as having PCO. There were a further 28 individuals without PCO (non-PCO) and 108 individuals whose PCO status was undetermined (reference population). The promoter region of the TNFalpha gene was amplified by polymerase chain reaction (PCR), and the presence or absence of the polymorphism at -308 was determined by single-strand conformational polymorphism (SSCP) analysis. The less common TNF allele (TNF2) was found as TNF1/2 or TNF2/2 in 11/38 (29%) of PCO subjects, 25/84 (30%) of PCOS subjects, 7/28 (25%) of non-PCO subjects, and 45/108 (42%) of the reference population. There was no significant difference in the incidence of the TNF2 allele between the groups. The relationship of TNF genotype to clinical and biochemical parameters was examined. In both the PCO group and the PCOS group, the presence of the TNF2 allele was significantly associated with lower glucose values obtained from the glucose tolerance testing (P<0.05). The TNF genotype was not significantly associated with any clinical or biochemical parameter measured in the PCO, PCOS or non-PCOS groups. Thus, the TNFalpha -308 polymorphism does not appear to strongly influence genetic susceptibility to polycystic ovaries. (+info)
Training in swimming reduces blood pressure and increases muscle glucose transport activity as well as GLUT4 contents in stroke-prone spontaneously hypertensive rats.
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Exercise improves muscle insulin sensitivity and GLUT4 contents. We investigated the beneficial effects of swimming training on insulin sensitivity and genetic hypertension using stroke-prone hypertensive rats (SHRSP). We studied the relationship between genetic hypertension and insulin resistance in SHRSP and Wistar Kyoto rats (WKY) as a control. The systolic blood pressure of SHRSP was significantly reduced by 4-week swimming training (208.4 +/- 6.8 mmHg vs. 187.2 +/- 4.1 mmHg, p < 0.05). The swimming training also resulted in an approximately 20% increase in the insulin-stimulated glucose transport activity (p < 0.05) of soleus muscle strips and an approximately 3-fold increase in the plasma membrane GLUT4 protein expression (p < 0.01) in SHRSP. However, basal and insulin-stimulated glucose transport activity and GLUT4 contents were not significantly different between WKY and SHRSP. There was no difference in insulin resistance in skeletal muscle of SHRSP as compared with WKY. Our results indicated swimming training exercise improved not only hypertension but also muscle insulin sensitivity and GLUT4 protein expression in SHRSP. (+info)
Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.
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Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity. (+info)
Insulin resistance of muscle glucose transport in male and female rats fed a high-sucrose diet.
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It has been reported that, unlike high-fat diets, high-sucrose diets cause insulin resistance in the absence of an increase in visceral fat and that the insulin resistance develops only in male rats. This study was done to 1) determine if isolated muscles of rats fed a high-sucrose diet are resistant to stimulation of glucose transport when studied in vitro and 2) obtain information regarding how the effects of high-sucrose and high-fat diets on muscle insulin resistance differ. We found that, compared with rat chow, semipurified high-sucrose and high-starch diets both caused increased visceral fat accumulation and insulin resistance of skeletal muscle glucose transport. Insulin responsiveness of 2-deoxyglucose (2-DG) transport measured in epitrochlearis and soleus muscles in vitro was decreased approximately 40% (P < 0.01) in both male and female rats fed a high-sucrose compared with a chow diet. The high-sucrose diet also caused resistance of muscle glucose transport to stimulation by contractions. There was a highly significant negative correlation between stimulated muscle 2-DG transport and visceral fat mass. In view of these results, the differences in insulin action in vivo observed by others in rats fed isocaloric high-sucrose and high-starch diets must be due to additional, specific effects of sucrose that do not carry over in muscles studied in vitro. We conclude that, compared with rat chow, semipurified high-sucrose and high-cornstarch diets, like high-fat diets, cause increased visceral fat accumulation and severe resistance of skeletal muscle glucose transport to stimulation by insulin and contractions. (+info)
Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.
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Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, +info)
Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS).
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Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic. (+info)