Heritability of factors of the insulin resistance syndrome in women twins

The insulin resistance syndrome (IRS) is characterized by a combination of interrelated coronary heart disease (CHD) risk factors, including low high-density lipoprotein cholesterol (HDL-C) levels, obesity and increases in triglyceride (TG), blood pressure, small low-density lipoprotein particles (LDL), and both fasting and postload plasma insulin and glucose. Using factor analysis, we previously identified 3 uncorrelated factors that explained 66% of the variance among these variables, based on data from women participating in examination 2 of the Kaiser Permanente Women Twins Study in Oakland, CA during 1989-1990. The factors were interpreted as: 1) body mass/fat distribution, 2) insulin/glucose, and 3) lipids: TG, HDL-C, LDL peak particle diameter. In this analysis, heritability of each of the factors was estimated based on data from 140 monozygotic and 96 dizygotic pairs of non-diabetic women twins. Heritability estimates were calculated using the classical approach, the analysis of variance (ANOVA) approach, and the maximum likelihood approach. For the body mass/fat distribution factor heritability estimates suggest moderate genetic influences; 0.61 (P < 0.001), 0.14 (P > 0.05), and 0.71 (P < 0.001), respectively. The insulin/glucose factor appeared to be highly heritable, with estimates of 0.87, 0.92, and 0.57 (all P < 0.001), respectively. The heritability estimates for the lipid factor were moderate and consistent across methods: 0.25 (P < 0.10), 0.32 (P < 0.05), and 0.30 (P < 0.05), respectively. These results are consistent with genetic influences on each of the 3 "factors," and suggest that both genetic and environmental effects are involved in the clustering of IRS risk factors.     

Obesity and insulin resistance syndrome

Obesity is commonly associated with insulin resistance. The etiology of insulin resistance syndrome such as syndrome X or deadly quartet is not clear. We have proposed visceral fat syndrome, in which fat accumulation is predominant in the intra-abdominal cavity, frequently accompanied by disorders of glucose and lipid metabolism, and also hypertension. Excess free fatty acid of the portal circulation may cause the enhancement of lipid synthesis and gluconeogenesis as well as insulin resistance, resulting in hyperlipidemia, glucose intolerance and hypertension and finally atherosclerosis. Enhanced production of PAI-1 by increased visceral fat may be partly responsible for the development of cardiovascular disease in patient with visceral fat assmulation.     

Fasting hyperinsulinism, insulin resistance syndrome, and coronary artery disease in men and women

A large segment of the population gradually develops insulin resistance, and the related metabolic syndrome is one of the most frequent causes of atherosclerosis. Searching for a practical indicator of insulin resistance, we studied the correlations between fasting serum insulin level, the general manifestations of insulin resistance syndrome, and various aspects of coronary artery disease in 797 men and 322 women. After we classified patients according to the quartiles of serum insulin level, we noted in the top quartile the presence of practically all manifestations of insulin resistance syndrome in persons of both sexes (e.g., increased waist/hip ratio, body mass index, glucose, uric acid, triglycerides, apolipoprotein B and decreased high-density lipoprotein cholesterol levels as well as apolipoprotein A-I/B ratios, and so forth). We also noted a higher prevalence of hypertension, diabetes mellitus, and type IV hyperlipidemia. Significantly more women in the fourth than in the first quartile had angiographically documented significant stenosis of the coronary arteries (p = 0.0016, odds ratio 2.9, 95% confidence interval 1.5 to 5.6) and previous myocardial infarction (p = 0.0297, odds ratio 2.1, 95% confidence interval 1.1 to 4.1). Men in both the first and the fourth quartile had a more disturbed lipid profile and a higher prevalence of significant stenoses of coronary arteries and/or previous myocardial infarction than women; there was a tendency toward a lower prevalence of alcohol consumption (p = 0.0503), a higher prevalence of gout (p = 0.0634), and previous myocardial infarction (p = 0.0791) in men in the fourth than in the first quartile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperinsulinemia, hyperproinsulinemia and insulin resistance in the metabolic syndrome

For better comprehension of the metabolic syndrome, it is necessary to differentiate the effect of insulin on glucose metabolism on the one hand, and on other metabolic activities on the other hand. Whereas glucose utilization is affected by insulin resistance, the effect of insulin on lipid metabolism, ion and aminoacid transport does not seem to be diminished. Lipid metabolism, however, seems to play a crucial role in the induction of the vicious cycle. Increased energy and fat ingestion may be due to an increased number of galanin secreting cells in the hypothalamus. The excessive fat intake results in an increased rate of release of insulin and increased influx of triglycerides into the blood. From these triglycerides an excess of free fatty acids is released by the action of lipoprotein lipase. The increased plasma free fatty acid level then results in insulin resistance affecting glucose metabolism. Also, these free fatty acids may impair the secretion of insulin. Induction of insulin resistance results in higher glucose levels, which may cause hyperinsulinemia. Hyperinsulinemia maintains the elevation of triglycerides. When diabetes becomes overt and elevated glucose levels prevail, the hyperinsulinism acts on the metabolic pathways which are still sensitive to insulin, namely lipid metabolism, aminoacid transport and ion transport.     

The deadly quartet--the insulin resistance syndrome

BACKGROUND: Obesity, non-insulin-dependent diabetes mellitus, hypertension, and dyslipidemia (syndrome X, "the deadly quartet") are common metabolic disorders that predispose to early cardiovascular disease. We examine the relationship between insulin resistance and the deadly quartet and address therapeutic implications. METHODS: We review the literature on insulin resistance, using MEDLINE files from 1975 to the present. Fifty references were reviewed. RESULTS: Insulin resistance consists of a cluster of disorders and biochemical abnormalities. We discuss the mechanisms responsible for the defects in insulin-mediated glucose utilization, as well as the relation of insulin resistance to obesity, hypertension, and dyslipidemia. We review the current strategies used in light of this pathophysiologic approach. CONCLUSIONS: This extremely common syndrome contributes excessively to mortality and morbidity of millions of Americans and generates enormous costs to the health care system. Better molecular understanding of insulin resistance is leading to improved treatment of all components of the syndrome.     

Weight gain and the risk of developing insulin resistance syndrome

OBJECTIVE: Obesity and weight gain have been associated independently with hypertension, hyperinsulinemia, and dyslipidemia; however, prior research has not looked at the relation between weight gain from early adulthood to middle age and the development of this cluster of risk factors, known as insulin resistance syndrome. RESEARCH DESIGN AND METHODS: The association between weight gain over 30 years (defined as the difference between measured weight in middle age and participant recall of their weight at age 20) and the odds of developing insulin resistance syndrome at middle age was examined in a population-based sample of 2,272 eastern Finnish men. RESULTS: Each 5% increase in weight over the reported weight at age 20 was associated with nearly a 20% greater risk of insulin resistance syndrome by middle age, after adjustment for age and height. Moreover, there was a strong graded association between categories of weight gain and risk of insulin resistance syndrome. Men with weight increases of 10-19%, 20-29%, or > or =30% since age 20 were 3.0, 4.7, or 10.6 times more likely to have insulin resistance syndrome, respectively, by middle age, compared with men within 10% of their weight at age 20. Adjustments for age, height, physical activity, smoking, education, and parental history of diabetes did not alter these findings. CONCLUSIONS: The odds of having developed the hemodynamic and metabolic abnormalities that characterize insulin resistance syndrome by middle adulthood were increasingly higher the greater the weight gain over the preceding 30 years. This study adds to the literature identifying deleterious effects of weight gain from young to middle adulthood.     

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.     

'True' fasting serum insulin level, insulin resistance syndrome and coronary artery disease

BACKGROUND: Increased fasting serum insulin level not associated with hypoglycemia is considered to be a practical indicator of the insulin resistance syndrome, a frequent risk factor for atherosclerosis in industrialized countries. However, in most studies, insulin was measured by using antibodies which cross-react with proinsulin and 31/32, 32/33 split products of insulin. We re-examined the correlations between the insulin resistance syndrome and 'true' fasting serum insulin level. METHODS: We studied 242 post-menopausal women (age 63 +/- 8 years), a population in whom insulin resistance syndrome is particularly frequent. Serum insulin was measured by a recent specific microparticle immunoassay. RESULTS: There was a significant correlation between elevated 'true' fasting serum insulin level and various constituents of the insulin resistance syndrome, such as obesity, dyslipidemia (hypertriglyceridemia, increased apolipoprotein B and decreased high-density lipoprotein cholesterol and apolipoprotein A1 concentrations), increased serum glucose, uric acid levels, and plasminogen activator inhibitor type I concentration, as well as increased frequency of diabetes. There was also a correlation between insulin level and various manifestations of coronary artery disease: patients in the highest quartile of 'true' insulin level had significantly more entirely occluded coronary arteries than in the lowest one. Similarly, in the highest insulin quartile more patients had occluded arteries with lumen diameter stenoses greater than 50% (P < 0.05) and more of them had history of previous myocardial infarction approaching the level of significance (P = 0.0587) than in the lowest one. Most of these correlations were also noted in nondiabetic people. CONCLUSIONS: An increase of 'true' fasting serum insulin level is a useful practical index to identify patients with the insulin resistance syndrome exposed to increased risk of coronary artery disease.     

Serum ferritin as a component of the insulin resistance syndrome

Six human cancer cell lines exhibiting a large range of sensitivity to 5-fluorouracil (5-FU) were evaluated for thymidylate synthase (TS) and p53 gene expression, TS and dihydropyrimidine dehydrogenase (DPD) activity, as well as cell cycle parameters, S-phase fraction (SPF), bromodeoxyuridine labelling index (LI) and S-phase duration (SPD). All these parameters were investigated for 7 days in asynchronously growing cell populations and compared with the cell sensitivity to 5-FU. No significant correlation was found between S-phase parameters and TS gene expression and/or activity. TS activity was higher in proliferating cells; however, it was not significantly higher in rapidly growing cell lines with short SPD. Neither TS gene expression nor activity was found to correlate with 5-FU sensitivity. On the another hand, a statistically significant correlation (P < 0.0001) was observed between LI and SPD and 5-FU sensitivity. The present results suggest that cell cycle parameters such as SPD and/or LI could be better parameters for 5-FU sensitivity prediction than TS gene expression and/or activity. This could be especially informative in cases of concomitant radio-chemotherapy as S-phase parameters are already proposed for hyperfractionated radiotherapy planning.     

Does insulin resistance unite the separate components of the insulin resistance syndrome? Evidence from the Miami Community Health Study

A number of coronary heart disease risk factors have been identified that often cluster together to increase the risk of macrovascular disease. This cluster is referred to as the insulin resistance syndrome, and the risk factors commonly include dyslipidemia, elevated blood pressure, an android pattern of body fat distribution, and glucose intolerance. Whether hyperinsulinemia or insulin resistance per se provides a common pathway for these metabolic abnormalities is unclear. The authors studied 50 nondiabetic persons who had completed a euglycemic hyperinsulinemic clamp protocol in addition to a 75-g oral glucose tolerance test and other measures of the coronary risk profile. Using principal-component analysis, we reduced nine coronary risk factors to two uncorrelated factors that explained 54.5% of the variance. Factor 1 consisted of positive loadings for uric acid, systolic and diastolic blood pressure, triglyceride concentration, and waist girth and negative loadings for HDL cholesterol and the rate of insulin-mediated glucose disposal (M, in milligrams per kilogram of body weight per minute). M also loaded on factor 2, along with fasting insulin and glucose concentrations, diastolic blood pressure, and waist girth. The observation that M loaded on both factors suggests that a resistance to insulin action may provide the mechanism uniting the features of the insulin resistance syndrome. Hyperinsulinemia with concomitant insulin resistance may be necessary to produce this metabolic derangement, as well as the increased risk of macrovascular complications.     

Feedback inhibition of insulin secretion and insulin resistance in polycystic ovarian syndrome with and without obesity

Hyperinsulinemia/insulin resistance is a well-known feature of polycystic ovarian (PCO) syndrome. In this study, the comparative roles of the peripheral tissues and the pancreatic beta-cells in its pathogenesis were evaluated. We determined basal serum C-peptide values (index of insulin secretion) and in vivo insulin action on peripheral glucose utilization (by the euglycemic hyperinsulinemic clamp technique) in obese (n = 5) and nonobese (n = 5) PCO women compared to obese (n = 5) and nonobese (n = 5) normal ovulatory women. During the clamp, feed-back inhibition of insulin on insulin secretion was studied by C-peptide percentage suppression. Serum C-peptide basal values did not differ significantly between the four groups. Insulin stimulated glucose utilization, expressed as M-value, was significantly decreased in both PCO groups compared to normal ovulatory women (p < 0.005). The metabolic clearance rate of glucose (MCR) and insulin (M/I) had the same behaviour. No differences were found between M, MCR and M/I values and the two groups of PCO subjects (obese/nonobese). The C-peptide percentage suppression was similar in all the groups. We conclude that PCO women have a significant insulin resistance that is independent of obesity, while basal and insulin-inhibited insulin secretion do not differ from normal-cycle subjects.     

Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.     

The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women

To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step (20 and 80 mU/m2.min) hyperinsulinemic euglycemic clamp combined with indirect calorimetry and tracer glucose infusion in 43 women (13 obese and 30 nonobese) with normal glucose tolerance and clinical evidence of increased androgen action (hirsutism and/or polycystic ovary syndrome) as well as 12 age- and body mass index-matched healthy controls. Hyperandrogenic women were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), or the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-mediated glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in both ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on glucose metabolism significantly increased for both the patients as a whole (F = 7.4; P < 0.01) and each treatment group separately. However, insulin action remained lower than in controls and showed no further improvement in patients reevaluated after I yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for the improvement in substrate disposal induced by antiandrogen drugs. The increase in the effectiveness of insulin was greater in the lean subjects, whereas the change was small and not statistically significant in the obese women. Response to treatment was more pronounced in women with nonovarian hyperandrogenism, particularly at the low insulin infusion rate. Endogenous glucose production in hyperandrogenic patients was similar to that in healthy women and was unaffected by therapy. In conclusion, antiandrogen treatment partially reversed the peripheral insulin resistance associated with hyperandrogenism regardless of which antiandrogen was used. These data strongly suggest that in women, androgen excess per se contributes to impairment of insulin action.     

Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women

There is controversy regarding the role of the Trp64Arg variant of the beta3-adrenergic receptor (beta3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 +/- 6 yr old) heterozygous for the beta3AR variant and in 14 women (57 +/- 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in beta3AR heterozygotes (241 +/- 135 mg/min) vs. normal homozygotes (379 +/- 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 +/- 27 mg/min) and normal homozygotes (164 +/- 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 +/- 57 mg/min) and normal homozygotes (56 +/- 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 +/- 111 mg/min) than for normal homozygotes (441 +/- 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the beta3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.     

Biochemical markers and methods to assess insulin resistance in normal, obese and hyperandrogenic women

BACKGROUND: Euglycemic or hyperglycemic clamp and the frequently sampled i.v. glucose tolerance test are the most frequently used methods to assess insulin resistance. However, both are expensive and cumbersome. AIM: To evaluate the relative or discriminatory usefulness of sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and insulin like growth factor binding protein 1 (IGFBP-1) as markers of insulin resistance and to estimate the tissue sensitivity to insulin by means of the insulin tolerance test (ITT) and the frequently sampled i.v. glucose tolerance test (IVGTT) in normal, obese and hyperandrogenic women. SUBJECTS AND METHODS: Six normal, 6 obese and 12 hyperandrogenic women of similar ages, were studied. In two consecutive days, the ITT and the IVGTT were performed and a basal blood sample was obtained to measure SHBG, DHEAS and IGFBP-1. Insulin sensitivity was calculated as the blood glucose slope in the ITT and with the minimal model of Bergman in the IVGTT. RESULTS: Insulin sensitivity, measured with ITT was 0.58 (0.53-0.63) in normal, 0.38 (0.05-0.59) in obese and 0.20 (0.0-0.36) in hyperandrogenic women. The figures for the IVGTT were 7.97 (4.1-15.4), 2.41 (0.81-4.89) and 1.1 (0.46-1.88), respectively. Both methods had a positive correlation coefficient of 0.792 (p < 0.001). SHBG was 87.0 m 37.9 and 18.3 nmol/l in normal, obese and hyperandrogenic women, respectively (p < 0.09). IGFBP-1 values were 3.0, 2.1 and 1.6 ng/ml respectively (p < 0.05). DHEAS values were 132, 190 and 206 ug/dl, respectively (ND). CONCLUSIONS: ITT is a simple and reliable method to assess insulin sensitivity. SHBG discriminates subjects with different levels of insulin sensitivity. Since it is easy to measure, it could be used as a marker on insulin sensitivity.     

Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects

OBJECTIVE: Insulin resistance is associated with a predominance of small, atherogenic LDL particles that are more prone to oxidative modification. Treatment with the insulin-sensitizer troglitazone may improve LDL composition and resistance to oxidation. RESEARCH DESIGN AND METHODS: In a randomized double-blind crossover design, 15 obese subjects were treated with either 400 mg troglitazone daily or placebo for 8 weeks. Insulin sensitivity (clamp), (apo)lipoproteins, LDL subclass pattern, plasma TBARS, and ex vivo LDL oxidation were determined. RESULTS: Troglitazone treatment improved insulin sensitivity. LDL cholesterol increased from 2.58 +/- 0.18 to 2.77 +/- 0.20 mmol/l (P = 0.03) because of an increase in large (buoyant) LDL1 (from 0.45 +/- 0.04 to 0.62 +/- 0.09 mmol/l, P = 0.008). Because small (dense) LDL3 decreased, LDL1:LDL3 ratio increased (P = 0.02). Plasma TBARS concentration declined significantly, and the lag time of ex vivo LDL oxidation showed a small but significant increase. CONCLUSIONS: In obese subjects, treatment with troglitazone improves insulin sensitivity, increases the ratio of large buoyant to small dense LDL, and appears to enhance the resistance of the LDL particle to oxidation. These qualitative changes in lipoproteins may have a beneficial effect on cardiovascular risk profile and compensate for a small increase in LDL cholesterol.     

Variability of plasma HDL subclass concentrations in men and women over time

1. Nitric oxide (NO) has been suggested as a gastrointestinal neurotransmitter, mediating the gastric receptive relaxation and the relaxation in the peristaltic reflex. The aim of the present study was to measure nerve-induced NO formation in vivo in the gastrointestinal tract. 2. Formation of the nitric oxide oxidation products nitrite and nitrate during vagal nerve stimulation were measured in the anaesthetized rabbit. Microdialysis probes were inserted into the wall of the stomach and proximal colon, and nitrite and nitrate in dialysate measured by capillary electrophoresis. 3. During bilateral vagal nerve stimulation there was an increase in nitrite and nitrate formation at the level of the stomach and in nitrite formation at the level of the colon. This increase was inhibited by intravenous administration of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME 30 mg kg-1). Furthermore, L-NAME significantly increased nerve-induced gastric and colonic contractions, as well as spontaneous colonic contractions. 4. In summary, we present a new methodological procedure for quantification of small changes in nitric oxide formation in vivo. This study provides evidence that nitric oxide is released in the stomach and colonic wall during vagal nerve activity, at concentrations able to cause inhibition of smooth muscle contractions in vivo.     

Hypertension and insulin resistance

Non insulin dependent diabetes mellitus (NIDDM) and obesity are defined as classical insulin resistant states. Essential hypertension is now also considered to be an insulin resistant state, even in absence of NIDDM or obesity, as shown in epidemiological, clinical and experimental studies. Neither the underlying mechanism nor a direct causality between the two phenomena has been detected as yet, but different hypotheses have been postulated where, on the one hand, insulin resistance and hypertension are considered to be causally related and, on the other hand, they are considered to be parallel phenomena due to genetic and acquired factors. The clarification of the connection between hypertension and insulin resistance seems to be of great clinical importance, since they are both independent risk factors for cardiovascular disease and mortality from cardiovascular complications. This paper gives an overview of the results of recent research on the possible underlying pathogenetic mechanisms linking hypertension and insulin resistance.     

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.