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Biomedical subjects

A Mitrakou

Publications and source records attributed to A Mitrakou.

At least 19 recordsLinked to original sources
PubMed2005

Leptin and adiponectin responses in overweight inactive elderly following resistance training and detraining are intensity related.

CONTEXT: Adiponectin and leptin are closely related to weight control and energy balance, whereas exercise affects elderly metabolic regulation and functional capacity. OBJECTIVE: The objective of this study was to investigate leptin and adiponectin responses in elderly males after exercise training and detraining. DESIGN: The study design was a 1-yr randomized controlled trial. SETTING: The study was performed at the Laboratory of Physical Education and Sport Science Department. PARTICIPANTS: Fifty inactive men [age, 65-78 yr; body mass index (BMI), 28.7-30.2 kg/m2] were recruited from a volunteer database by word of mouth and fliers sent to medical practitioners, physiotherapists, and nursing homes in the local community. INTERVENTION(S): Participants were randomly assigned to a control (n = 10), low-intensity (n = 14), moderate-intensity (n = 12), or high-intensity training (HI; n = 14) group. Resistance training (6 months, 3 d/wk, 10 exercises/three sets) was followed by 6 months of detraining. MAIN OUTCOME MEASURE(S): Strength, exercise energy cost, skinfold sum, body weight, maximal oxygen consumption, resting metabolic rate (RMR), and plasma leptin and adiponectin were determined at baseline and after training and detraining. RESULTS: Strength, maximal oxygen consumption, RMR, and exercise energy cost increased (P < 0.05) after training in an intensity-dependent manner. Skinfold sum and BMI were reduced by resistance training (P < 0.05), with HI being more effective (P < 0.05) than moderate-intensity/low-intensity training. Leptin was diminished (P < 0.05) by all treatments, whereas adiponectin increased (P < 0.05) only in HI. Detraining maintained training-induced changes only in HI. The percent leptin decrease was associated (P < 0.05) with the percent BMI decrease and the percent RMR increase, whereas the percent adiponectin increase was associated (P < 0.05) with the percent BMI decrease. CONCLUSIONS: Resistance training and detraining may alter leptin and adiponectin responses in an intensity-dependent manner. Leptin and adiponectin changes were strongly associated with RMR and anthropometric changes.

Adiponectin↗
PubMed2005

Increased renal glucose metabolism in Type 1 diabetes mellitus.

AIMS: In poorly controlled diabetes, increased renal glucose uptake has been implicated in the pathogenesis of diabetic nephropathy by promoting nonenzymatic glycosylation of proteins, activation of protein kinase C, and increased polyol pathway flux. However, whether glucose uptake by the diabetic kidney is actually increased, especially in patients with Type 1 diabetes, is unclear. METHODS: To examine this question, we used a combination of net balance and isotopic techniques to compare renal glucose uptake in 12 subjects with Type 1 diabetes before and after restoration of near normoglycaemia by infusion of insulin with that in 15 postabsorptive nondiabetic volunteers. RESULTS: Prior to insulin infusion, the diabetic subjects were markedly hyperglycaemic (arterial glucose 15.8 +/- 0.9 vs. 4.4 +/- 0.1 mm) and their renal tissue glucose uptake (i.e. total glucose disappearance across the kidney minus glycosuria) was increased more than 2 1/2-fold (388 +/- 43 vs. 148 +/- 12 micromol/min, P < 0.001). This was wholly explained by the mass action effects of hyperglycaemia since the diabetic subjects had normal renal blood flow (1575 +/- 82 vs. 1492 +/- 68 mL/min, P = 0.46) and reduced renal tissue glucose fractional extraction (1.7 +/- 0.2 vs. 2.3 +/- 0.1%, P = 0.027). Insulin infusion for three hours, which restored near normoglycaemia (arterial glucose 7.6 +/- 0.7 mm), reduced renal tissue glucose uptake toward normal (258 +/- 41 micromol/min, P = 0.006) without altering renal blood flow (1557 +/- 110, P = 0.63) or renal tissue glucose fractional extraction (2.1 +/- 0.3%, P = 0.35). Renal and hepatic glucose release, which had been increased (419 +/- 49 and 960 +/- 54 vs. 204 +/- 9 and 734 +/- 32 micromol/min, both P < 0.001), were suppressed by insulin to 138 +/- 22 and 520 +/- 53 micromol/min, respectively (both P < 0.001). CONCLUSIONS: In poorly controlled Type 1 diabetes, renal glucose uptake is markedly increased, which provides a link between hyperglycaemia and biochemical processes implicated in the pathogenesis of diabetic nephropathy. Its reversal by restoration of near normoglycaemia with insulin may explain the benefit of intensive insulin therapy in preventing diabetic nephropathy.

Adult↗
PubMed2000

Relative conributions of beta-cell function and tissue insulin sensitivity to fasting and postglucose-load glycemia.

We performed hyperglycemic clamps in 283 nondiabetic Caucasians and, with multiple linear regression, determined the contribution of beta-cell function and tissue insulin sensitivity to variations in glycemia and insulinemia during oral glucose tolerance tests (OGTTs). Impaired glucose tolerance (IGT) subjects had reduced insulin sensitivity (P < .02) and beta-cell function (P < .0001). Normal glucose tolerance (NGT) subjects with first-degree type 2 diabetic relatives had reduced first and second phase insulin secretion (both, P < .05), but normal insulin sensitivity (P = .37). Beta-Cell function and insulin sensitivity accounted for one fourth of the variability in glucose tolerance. Fasting plasma glucose in subjects with NGT (n = 185) was a function of both phases of insulin secretion and of insulin sensitivity (all, P < .05), whereas, in IGT subjects (n = 98), it was a function of first phase insulin secretion and insulin sensitivity (P < .01). Two-hour glycemia was a function of second phase secretion and insulin sensitivity (P < .01). Fasting and 2-hour plasma insulin levels were determined by insulin sensitivity (and glycemia) in NGT subjects (P < .001), but by second phase secretion in IGT (P < .001). We conclude that beta-cell function is reduced in subjects with IGT; glycemia and insulinemia are not regulated by the same mechanisms in IGT and NGT; insulin sensitivity does not contribute to insulinemia in IGT; family history of diabetes influences beta-cell function, but not insulin sensitivity in Caucasians.

Adult↗
PubMed2000

Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.

OBJECTIVE: The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. RESEARCH DESIGN AND METHODS: We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. RESULTS: The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. CONCLUSIONS: We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.

Blood Glucose↗
PubMed1999

Important role of the kidney in human carbohydrate metabolism.

Recent studies using a combination of isotope and balance techniques have shown that, in the postabsorptive state, the human kidney contributes substantially to overall glucose production and consumption. The kidney may contribute as much as the liver to gluconeogenesis and play an important role in the counterregulation of hypoglycemia. Furthermore, increased renal glucose production may contribute to fasting hyperglycemia found in type I and type II diabetes mellitus. Finally, loss of renal tissue as a consumer of glucose could explain the insulin resistance of uremia. We hypothesize that the human kidney may play a more important role in human carbohydrate metabolism than previously appreciated.

Carbohydrate Metabolism↗
PubMed1998

Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.

Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.

3-Hydroxybutyric Acid↗
PubMed1998

Long-term effectiveness of a new alpha-glucosidase inhibitor (BAY m1099-miglitol) in insulin-treated type 2 diabetes mellitus.

In a double-blind, randomized study, miglitol (BAY m 1099), an alpha-glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C-peptide were measured at the beginning and at the end of each 4-week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 +/- 1.5 vs miglitol: 8.2 +/- 1.5 mmol l-1, mean +/- SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16% (p = < 0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

1-Deoxynojirimycin↗
PubMed1998

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Adult↗
PubMed1998

Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness.

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.

Adrenergic beta-Agonists↗
PubMed1998

Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.

OBJECTIVE: The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). RESEARCH DESIGN AND METHODS: We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. RESULTS: Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. CONCLUSIONS: We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

Adult↗
PubMed1997

Coronary microcirculation evaluation with transesophageal echocardiography Doppler in type II diabetics.

Evaluation of coronary microvascular function can be obtained through coronary flow reserve measurements. The aim of this study was to evaluate the coronary microvascular function by using transesophageal-Doppler echocardiographic assessment of coronary flow reserve. The study included 32 normotensive patients with type II diabetes mellitus (group A) of short duration (6.1+/-3.8 years) aged 55.4+/-9.4 years and 14 healthy volunteers matched for age, gender and BMI (group B). No patients had clinical evidence of coronary artery disease and all of them produced a negative recent stress ECG test. Excluded from the study were patients with anemia, left ventricular hypertrophy, arrhythmia, congenital, or acquired structural heart disease. All subjects underwent transesophageal-Doppler echocardiography. Satisfactory coronary blood flow velocity recordings could be obtained from the initial segment of the left anterior descending coronary artery in healthy volunteers and in 27 patients at baseline and 2 min after dipyridamole infusion (0.56 mg/kg, for 4 min). In the remaining 5 patients no satisfactory recordings were available. The indexes of coronary flow reserve, i.e. the ratios of dipyridamole over basal maximum and mean diastolic velocities were calculated. Dipyridamole/rest maximal coronary reserve (Table 3) was 1.946+/-0.743, while this ratio for the mean diastolic velocity was 1.969+/-0.805 in group A. The respective values for group B, were 2.811+/-0.345 (P=0.000 vs. group A) and 2.914+/-0.303 (P=0.000 vs. group A). Thus, the increase in coronary flow reserve although present in both groups, it was more impressive in the normal group. Multiple regression logistic analysis of: age, sex, smoking, glucosylated hemoglobin, duration of diabetes and type of therapy, did not show any correlation of these parameters with the above ratios. This study shows that coronary flow reserve, as measured with transesophageal echocardiography-Doppler, is severely impaired in normotensive patients with type II diabetes, with relatively short duration of the disease.

Age Factors↗
PubMed1997

Renal glucose production and utilization: new aspects in humans.

According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25% of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed.

Animals↗
PubMed1996

Insulin secretion and insulin sensitivity in people with impaired glucose tolerance.

To assess the roles of pancreatic beta-cell (beta-cell) dysfunction and insulin resistance in the pathogenesis of non-insulin dependent diabetes mellitus, we used euglycaemic hyperinsulinaemic and hyperglycaemic clamps to compare insulin secretion and insulin sensitivity in Caucasian individuals of European ancestry with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Both groups were carefully matched for age, gender, obesity and body fat distribution. During the hyperglycaemic clamps, IGT had significantly lower first phase (650 +/- 60 vs 992 +/- 92 pmol l-1, p = 0.001) and second phase (231 +/- 24 vs 326 +/- 21 pmol l-1, p < 0.001) plasma insulin responses while their insulin sensitivity index (0.126 +/- 0.012 mumol kg-1 pM-1) was not significantly different from that of NGT (0.144 +/- 0.012 mumol kg-1 min-1 pM-1), p = 0.69). Similarly, during the euglycaemic hyperinsulinaemic clamps, the insulin sensitivity index of the IGT (0.076 +/- 0.005 mumol kg-1 min-1 pM-1) was not significantly different from that of the NGT (0.086 +/- 0.007 mumol kg-1 min-1 pM-1), p = 0.28. We conclude that since beta-cell dysfunction is already evident in people with impaired glucose tolerance but insulin resistance is not, impaired insulin secretion is most likely the primary genetic factor predisposing to the development of non-insulin dependent diabetes mellitus in Caucasians of European ancestry.

Blood Glucose↗
PubMed1995

Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative.

OBJECTIVE: To test the hypothesis that insulin resistance precedes impaired insulin secretion in individuals genetically predisposed to non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: Case-control study. SETTING: Outpatient facility of clinical research center. PARTICIPANTS: One hundred volunteers of European ancestry having normal glucose tolerance, 50 with and 50 without a first-degree NIDDM relative, matched for age, sex, and degree of obesity. MAIN OUTCOME MEASURES: Insulin secretion and insulin sensitivity assessed by hyperglycemic (N = 100) and euglycemic-hyperinsulinemic (N = 62) clamp experiments. RESULTS: The individuals with a first-degree NIDDM relative had reduced first- and second-phase insulin responses (mean +/- SEM, 939 +/- 68 vs 1209 +/- 82 pmol/L, and 322 +/- 19 vs 407 +/- 24 pmol/L, respectively, P = .001 and .01), but their insulin sensitivity (148 +/- 6 and 92 +/- 6 nmol.kg-1.min-1/pmol.L-1 in hyperglycemic and euglycemic clamp studies) did not differ from that of the control group (126 +/- 5 and 81 +/- 7 nmol.kg-1.min-1/pmol.L-1, in hyperglycemic and euglycemic clamp studies, P = .07 and .24, respectively). In some individuals only first- or only second-phase insulin responses were reduced. CONCLUSION: In this study population, heterogeneous defects in insulin secretion were demonstrated, while defects in insulin sensitivity were not evident. We therefore conclude that since the earliest defects identified in a group genetically at high risk to develop NIDDM are those related to insulin secretion, defects in insulin secretion rather than insulin sensitivity are likely the major genetic factor predisposing to development of NIDDM.

Adult↗
PubMed1995

Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome.

Polycystic ovary (PCO) syndrome is strongly associated with insulin resistance and the accompanying adverse metabolic profile. To distinguish the mechanisms of this association, we determined the interactions of PCO with obesity and the influence of ameliorating direct androgenic actions via short-term treatment with the antiandrogen flutamide. Insulin sensitivity was determined by the hyperinsulinemic euglycemic clamp in groups of lean and obese PCO women and weight-matched controls. Compared with control values, insulin-mediated glucose utilization in PCO women was significantly lower in lean (1.96 +/- 0.17 v 1.24 +/- 0.10, P < .01) and obese (1.23 +/- 0.18 v 1.03 +/- 0.09 mmol/m2/min, P < .01) subjects. ANOVA indicated that the effects of obesity and androgenicity are independent and additive. In both lean and obese PCO women, treatment with flutamide for 1 or 3 months markedly improved the clinical and biochemical androgenic features, but did not significantly influence the overall insulin sensitivity. A large disparity between individuals in the response to treatment correlated significantly with a simultaneous reduction in plasma levels of dehydroepiandrosterone sulfate (DHEA-S). Thus in women, PCO and obesity exert synergistic effects on insulin resistance. The decreased insulin sensitivity is mediated via indirect androgenic actions or nonandrogenic mechanisms. In some individuals, a direct effect of androgens might have been masked by a decrease in DHEA-S levels.

Adolescent↗