On preserving the National Institute of Mental Health Career Scientist Award

OBJECTIVES: The pathogenesis of nonalcoholic fatty liver in non-obese persons is poorly understood. We aimed to elucidate whether hyperinsulinemia and glucose intolerance are associated with development of fatty liver in patients with normal body weight. METHODS: Forty-seven patients with fatty liver were divided into non-obese (n = 25) and obese groups (n = 22) according to age adjusted body mass index. Inclusion criteria were as follows: (1) elevated transaminase levels during more than 3 months of follow up period, (2) no detectable HBsAg or anti-HCV in the serum, (3) alcohol consumption less than 40 gm/week, (4) no use of potential hepatotoxic drugs within 3 months and (4) sonographic evidence of fatty liver(moderate to severe degree). Baseline insulin levels and oral glucose tolerance test using 75gm of glucose were performed and the results were compared in each group of patients. RESULTS: Mean baseline insulin levels were elevated in both groups above the reference value, 9.3 +/- 3.5 microU/L in non-obese group and 9.9 +/- 3.5 microU/L in obese group (p = 0.26). Seventeen of non-obese patients (68%) had elevated basal insulin level and 16 of obese patients (73%) had elevated basal insulin level (p = 0.39). In oral glucose tolerance test, there was no difference in glucose level between non-obese and obese groups from O minute to 180 minutes (p > 0.05). Eleven patients from the non-obese group (44%) and 8 patients from the obese group (36%) had either impaired glucose tolerance or diabetes (p = 0.29). CONCLUSION: Our data suggest that hyperinsulinemia and glucose intolerance may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity.     

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

OBJECTIVE: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING: Reproductive endocrinology unit. PATIENT(S): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S): Growth hormone, glucose, and insulin responses to OGTT. RESULT(S): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.     

The effects of chronic ill health and treatment with sulphasalazine on fertility amongst men and women with inflammatory bowel disease in Leicestershire

Our aim was to investigate the effect of GnRH-agonist (GnRH-a) induced suppression of plasma sex steroids on serum GH, insulin like growth factor-I (IGF-I) and insulin levels after an oral glucose load (OGTT) in women with polycystic ovary syndrome (PCOS). Serum insulin, GH and IGF-I levels during a 75-g 4-h OGTT were measured in 3 nonobese and 7 obese hyperandrogenic women with PCOS and normal glucose tolerance before and after 10 weeks of treatment with the GnRH-a triptorelin (3,75 mg im every 28 days). Basal estrogen and androgen levels were also measured at time 0 of the first and the second OGTT. After the therapy serum estrogens and androgens were significantly suppressed. Body weight remained unchanged. Basal GH significantly increased after the treatment while fasting IGF-I and insulin levels decreased from (mean +/- SE) 349.3 +/- 31.8 to 278.7 +/- 33.2 ng/mL and from 22.4 +/- 4.1 to 18.8 +/- 4.4 microU/mL, respectively. The insulin response to OGTT (area under curve) was also reduced (from 16,017 +/- 2598 to 11,736 +/- 2317 microU/mL/240 min). Our results suggest that the GnRH-a induced suppression of ovary secretion may modify the serum GH and IGF-I levels and the insulin response to an OGTT in women with PCOS.     

Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia

Triglyceride levels and free fatty acid metabolism are influenced by body fat distribution. To test whether the pattern of fat distribution in obese subjects results in distinct insulin mediated suppression of non-esterified fatty acids which could account for differences in plasma triglycerides, we studied 59 obese subjects who were classified according to waist-to-hip ratio. Non-esterified fatty acids and insulin response to a 75 g oral glucose tolerance test were higher in abdominal obesity. Total non-esterified fatty acids response, after adjustment for sex, showed a positive association with waist-to hip ratio (r = 0.292; p < 0.05). The abdominal obese group had higher fasting triglycerides (1.74+/-0.83 versus 1.11+/-0.71 mmol/L; p = 0.003) and lower glucose/insulin ratio (5.2+/-2.3 versus 7.1+/-2.4; p = 0.003). Stepwise multiple regression analysis showed that triglyceride levels are explained by fasting and 120 min non-esterified fatty acids and by glucose/insulin ratio. We conclude that abdominal obesity is associated with a higher resistance to insulin mediated suppression of non-esterified fatty acids in obese subjects. Variation of triglyceride concentrations in obesity is dependent on both fasting and 120 min non-esterified fatty acids as well as on insulin sensitivity to glucose utilization.     

17 alpha-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic ovary syndrome offer dietary weight loss

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity (i.e. increased 17 alpha-hydroxylase and, to a lesser extent, increased 17,20-lyase) are both features of the polycystic ovary syndrome (PCOS). Evidence suggests that hyperinsulinemia may stimulate ovarian P450c17 alpha activity in obese women with PCOS. We hypothesized that weight loss would decrease serum insulin and P450c17 alpha activity in PCOS. Therefore, we measured serum steroid concentrations and 17 alpha-hydroxyprogesterone responses to leuprolide administration and performed oral glucose tolerance tests before and after 8 weeks of a hypocaloric diet in 12 obese women with PCOS (PCOS group) and 11 obese women with normal menses (control group). Serum insulin decreased in both groups. In the PCOS group, basal serum 17 alpha-hydroxyprogesterone decreased from 4.2 +/- 0.6 to 3.0 +/- 0.5 nmol/L (P < 0.05), and leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 14.9 +/- 2.6 to 8.9 +/- 0.8 nmol/L (P < 0.025). Serum testosterone decreased from 2.47 +/- 0.52 to 1.56 +/- 0.33 nmol/L (P < 0.05), and free testosterone decreased from 9.03 +/- 1.39 to 5.95 +/- 0.50 pmol/L (P < 0.02). None of these values changed in the control group. Serum sex hormone-binding globulin increased by 4.5- and 3-fold in the PCOS (P < 0.003) and control (P < 0.007) groups, respectively. We conclude that dietary weight loss decreases ovarian P450c17 alpha activity and reduces serum free testosterone concentrations in obese women with PCOS, but not in obese ovulatory women. The changes in women with PCOS may be related to a reduction in serum insulin.     

Cryptococcosis in tree shrews (Tupaia tana and Tupaia minor) and elephant shrews (Macroscelides proboscides)

OBJECTIVE: To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS: Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17-36 years, body mass index (BMI) 29.9 +/- 0.9 kg/m2, mean +/- SD) and 18 control women (25-47 years, BMI 25 +/- 1.7 kg/m2). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS: Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS: Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/ hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 +/- 1.3 vs 12.1 +/- 2.3 micrograms/l, mean +/- SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS: Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.     

Multiple metachronous metastasis of adenocarcinoma of the kidneys in crossed ectopy with fusion

OBJECTIVE: Hyperandrogenism in patients with polycystic ovary syndrome has been shown to correlate with hyperinsulinaemia of insulin resistance. We have investigated if basal levels of insulin and the response to the intravenous administration of glucagon can reveal insulin resistance in patients with polycystic ovary syndrome. PATIENTS: Nine obese (BMI > 25 kg/m2) and nine non-obese (BMI 19-25 kg/m2) women with PCOS, chosen from a population of 91 women attending the infertility clinic, and 19 normally cycling women (seven obese, 12 non-obese) were studied. Oligo or amenorrhoea, hirsutism, and 12 or more follicles in a given ovary were selection criteria. MEASUREMENTS: Glucagon, 1 mg, was given intravenously to 18 of the 91 women and to the control subjects. Blood was taken at -5, 0, 5, 10 and 15 minutes for measurements of integrated areas under the response curve for insulin, C-peptide and glucose, respectively. Basal blood samples were drawn for fasting insulin, C-peptide, glucose, testosterone, sex hormone-binding globulin (SHBG), free fatty acids and IGF-I measurements. The free androgen index was calculated according to the formula FAI = testosterone x 100/SHBG. RESULTS: There were no significant differences in maximal increment and area under the response curve for glucose, C-peptide and insulin. FAI was significantly higher in all patients with features of polycystic ovary syndrome. However, fasting insulin levels were significantly higher only in obese patients when compared with obese control subjects and lean patients. CONCLUSIONS: The administration of 1 mg glucagon i.v. did not distinguish patients with polycystic ovary syndrome from control subjects. The mild insulin resistance of polycystic ovary syndrome is related only to obesity and is therefore unlikely to play an important role in the hyperandrogenism associated with the syndrome.     

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.     

Zinc and flunitrazepam modulation of GABA-mediated currents in rat suprachiasmatic neurons

We know that upper body obesity is associated with metabolic complications, but we don't know how regional body fat distribution influences postprandial lipemia in obese adults. Thus, this study explored the respective effects of android or gynoid types of obesity and fasting triglyceridemia on postprandial lipid metabolism and especially triglyceride-rich lipoproteins. Twenty-four obese and 6 lean normotriglyceridemic women (control), age 24-57 yr, were enrolled. Among obese women with an android phenotype, 9 exhibited normal plasma triglyceride levels (mean: 1.38 mmol/L) (NTAO), and 7 displayed a frank hypertriglyceridemia (mean: 2.40 mmol/L) (HTAO). The 8 patients with a gynoid phenotype had normal triglyceride levels (mean: 1.00 mmol/L) (GO). All were given a mixed test meal providing 40 g triglycerides. Serum and incremental chylomicron triglycerides 0-7 h areas under the curve (AUCs) as well as triglyceride levels in apoB-48-containing triglyceride-rich lipoprotein (TRLs) or chylomicrons were significantly higher in HTAOs and NTAOs than in GOs and controls postprandially. The size of chylomicron particles was bigger in controls and GOs than in HTAOs and NTAOs postprandially. Android obese subjects showed abnormally elevated fasting apoB-48 and apoB-100 triglyceride-rich lipoprotein (TRL) levels. Most abnormalities that were found correlated to plasma levels of insulin and apoC-III. In conclusion, an abnormal postprandial lipid pattern is a trait of abdominal obesity even without fasting hypertriglyceridemia.     

Medical and health impact of complex emergencies: implications for the International Society of Nephrology Disaster Relief Task Force

The aim of the present study was to measure whole body glucose uptake (M) and oxidation rate by euglycaemic hyperinsulinaemic clamp and indirect calorimetry in 7 morbidly obese subjects (BMI > 40 kg/m2) at three time points: before bilio-pancreatic diversion (BPD) surgery (Ob); 3 months after surgery POI; and after reaching stable body weight, at least 2 years after surgery POII. A group of 7 control subjects (C), matched groupwise for sex, age and BMI with POII patients, was also studied. The M value at POI was significantly higher than at Ob (49.12 +/- 8.57 vs 18.14 +/- 8.57 mumol.kg-1.min-1). No statistical difference was observed between the POII and C groups. Similarly, glucose oxidation rate was significantly increased at POI with respect to Ob (24.2 +/- 7.23 vs 9.42 +/- 3.91 mumol.kg-1.min-1) and was not significantly different between POII and C. Basal levels of non-esterified fatty acids (NEFA) decreased significantly both from Ob to POI and from POI to POII (1517.1 +/- 223.9 vs 1039.6 +/- 283.4 vs 616.0 +/- 77.6 mumol.1(-1). The same applied to basal plasma triglycerides (2.07 +/- 0.77 vs 1.36 +/- 0.49 vs 0.80 +/- 0.19 g.1(-1). Weight decreased mainly in the late postoperative period (POI to POII 124.28 +/- 11.22 to 69.71 +/- 11.78, 83% of total decrement), rather than in the early postoperative period (Ob to POI 135.25 +/- 14.99 to 124.28 +/- 11.22 kg, 17% of total decrement). We also report the clinical case of a young woman of normal weight, who underwent BPD for chylomicronaemia (secondary to familial lipoprotein lipase deficiency), whose M value, plasma insulin and blood glucose levels were normalized upon normalization of serum NEFA and triglyceride levels as determined by the therapeutic lipid malabsorption. In conclusion, in obese diabetic patients lipid malabsorption induced by BPD causes a definite enhancement of insulin sensitivity and glucose tolerance. This improvement in metabolism is noticeable before the surgery has major effects on body weight. These observations suggest that lowered plasma lipids, rather than weight loss per se, are the cause of the reversibility of insulin resistance.     

Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome

Recent data in the mouse demonstrate that leptin, a protein hormone produced by fat cells, is required for fertility. In the absence of leptin the mice become obese, diabetic and infertile. Polycystic ovary syndrome (PCOS), a common cause of infertility in women, is associated with obesity and insulin resistance. Because of the increased frequency of PCOS in obese women we tested the hypothesis that alterations in serum leptin concentrations might be associated with PCOS. Immunoreactive leptin concentrations were measured in 58 women with PCOS and 70 regularly menstruating (control) women. As has previously been shown there was a positive correlation between leptin levels and body mass index (BMI). Although the leptin levels in the majority of women with PCOS fell within the control range, 29% of PCOS women had leptin levels above the 99% prediction interval for their BMI and none had low leptin levels. There were also positive correlations of leptin levels with free testosterone and insulin sensitivity in control women. In women with PCOS, 13% and 9.5% exhibited higher than expected leptin concentrations with respect to free testosterone and insulin sensitivity, respectively. Insulin resistant PCOS women had higher leptin levels than controls. The data demonstrate that a substantial proportion of women with PCOS have leptin levels that are higher than expected for their BMI, free testosterone and insulin sensitivity. These results suggest that abnormalities in leptin signaling to the reproductive system may be involved in certain cases of PCOS.     

Fasting hyperinsulinemia and cardiovascular disease risk factors in nondiabetic adults: stronger associations in lean versus obese subjects. Atherosclerosis Risk in Communities Study Investigators

The association between hyperinsulinemia and atherogenic risk factors has not been well studied in blacks and may be different for obese versus lean individuals. To investigate this possibility and to confirm the associations of hyperinsulinemia with cardiovascular disease risk factors in blacks and whites, we analyzed the joint associations of fasting serum insulin and obesity with risk factors in the Atherosclerosis Risk in Communities (ARIC) Study (1,293 black men, 4,797 white men, 2,033 black women, and 5,445 white women). Insulin values > or = 90th percentile (> or = 21 microU/mL) constituted hyperinsulinemia; body mass index (BMI) values > or = 27.3 kg/m2 for women and > or = 27.8 for men constituted obesity. Participants with hyperinsulinemia in all four race-sex groups had more atherogenic levels of most risk factors studied than those with normoinsulinemia. Among black men and women, mean levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo) B, glucose, and fibrinogen (men only) were higher in hyperinsulinemic lean participants as compared with the normoinsulinemic obese group. Furthermore, most associations between insulin level and risk factors were stronger among lean versus obese subjects. For example, among lean black men, the difference in mean triglyceride concentration between those with hyperinsulinemia and those with normoinsulinemia was 147 - 99 = 48 mg/dL; among obese black men, the difference was 155 - 121 = 34 mg/dL (P < .05 for the interaction). Generally, similar negative interactions between BMI and insulin concentration were also observed among whites.(ABSTRACT TRUNCATED AT 250 WORDS)     

A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are profoundly insulin resistant, and the resultant hyperinsulinemia exacerbates the reproductive abnormalities of the syndrome. Agents that ameliorate insulin resistance and reduce circulating insulin levels could provide a new therapeutic modality for PCOS. Identifying the subset of PCOS women who are most insulin resistant may therefore be useful for selecting women who will respond to this therapy. We examined the correlation of basal and oral glucose-stimulated glucose and insulin levels and fasting and stimulated glucose/insulin (G:I) ratios with parameters of insulin sensitivity obtained by frequently sampled i.v. glucose tolerance test (FSIGT) to assess whether there is a simple screening test for insulin resistance in PCOS. Forty PCOS women (aged 18-40 yr; body mass index, >26 kg/m2) and 15 control women matched for age, weight, and ethnicity underwent both a 75-g oral glucose tolerance test (OGTT) and a FSIGT. The insulin sensitivity index (S(I)) was calculated by application of the minimal model of glucose kinetics to the dynamics of plasma glucose and insulin levels during the FSIGT. The best correlation in PCOS between S(I) and a fasting level was found with fasting G:I ratios (r = 0.73; P < 0.0001). A less substantial, but significant, correlation was found with fasting insulin levels (r = 0.50; P < 0.001), and no significant correlation was found with fasting glucose levels (r = 0.24; P = NS). The fasting G:I was more strongly correlated with S(I) than with integrated glucose and insulin responses during the OGTT. The only stronger correlation was with the OGTT 2 h G:I ratio (r = 0.74; P < 0.001). Stepwise regression analysis with S(I) as the dependent variable and fasting glucose and insulin levels, area under the curve for glucose and insulin, and a fasting G:I ratio showed that only the fasting G:I ratio was significantly predictive of S(I) in the model (F to remove value = 38.1; P < 0.001). When viewed as a screening test for insulin resistance in PCOS, setting a value of the fasting G:I ratio of less than 4.5 as abnormal (using an S(I) value below the 10th percentile of our control population as evidence for insulin resistance), the sensitivity of a fasting G:I ratio was 95%, the specificity was 84%, the positive predictive value was 87%, and the negative predictive value was 94%. Receiver operator curve analysis showed that this fasting G:I ratio was the single best screening measure for detecting insulin resistance. We conclude that a fasting G:I ratio may be useful as a screening test for insulin resistance in obese non-Hispanic white PCOS women. This may be a clinically useful parameter for selecting PCOS women most likely to respond to therapeutic interventions that improve insulin sensitivity.     

Studies on the uptake of 14C-neostigmine in the isolated rat diaphragm

Fatty acid incorporation into adipose tissue (FIAT), the metabolic process assimilating plasma triglyceride fatty acids liberated by lipoprotein lipase, was recently found to be lower in hyper- than in normotriglyceridaemia. In the present report, the relation of FIAT to glucose tolerance and adipose tissue morphology and fatty acid composition has been studied in a popoulation of men with normo- and hypertriglyceridaemia, using needle biopsy specimens. In addition, the associations between plasma triglyceride concentration and these factors as well as FIAT were examined by statistical methods. FIAT and GLIAT (glucose incorporation into adipose tissue) activities per cell were positively correlated with fat cell diameter but not with fat cell number. FIAT activities per cell and per unit surface area were lower in hyper- than in normo-triglyceridaemic subjects. The k-value of the i.v.glucose tolerance test and glycerol release from adipose tissue did not correlate with FIAT or GLIAT activities. The proportion of stearic acid in adipose tissue was negatively correlated with the serum triglyceride level and with fat cell diameter, but positively correlated with FIAT. Linolenic acid in adipose tissue correlated positively with the k-value. The negative correlation between serum triglycerides and FIAT remained when the other variables which were significantly correlated with FIAT or the serum triglycerides were entered in partial correlat-on analysis. These results suggest that although low FIAT activity is related in part to other characteristics, it occurs in hypertriglyceridaemia independent of glucose tolerance or various characteristics in fat. With serum triglyceride concentration as dependent variable, stepwise regression analysis was performed, entering all other variables as independent ones. The highest multiple --value was 0.76 (p less than 0.001) and it was obtained with three adipose tissue parameters: FIAT (or GLIAT), content of linolenic acid and of stearic acid. The other parameters did not give rise to any further improvement in the prediction of the serum triglyceride concentration which is better than 50% (R2 = 0.57).     

Fine needle aspiration biopsy of salivary gland, 1985-1995

Cellular insulin resistance in polycystic ovary syndrome (PCOS) has been shown to involve a novel postbinding defect in insulin signal transduction. To find possible mechanisms for this defect, adipocytes were isolated from age- and weight-matched obese normal cycling (NC) and PCOS subjects. Insulin sensitivity for glucose transport stimulation was impaired in PCOS adipocytes (EC50 = 290 +/- 42 pmol/L) compared to that in NC cells (93 +/- 14; P < 0.005). The lipolytic responses to isoproterenol as well as maximal suppression by insulin were similar in NC and PCOS adipocytes. However, PCOS cells were less sensitive to the antilipolytic effect of insulin (EC50 = 115 +/- 33 pmol/L) compared to NC cells (42 +/- 8; P < 0.01). Treatment of adipocytes from NC subjects with the adenosine receptor agonist N6-phenylisopropyl adenosine had no effect on either insulin responsiveness or sensitivity for glucose transport stimulation. However, N6-phenylisopropyl adenosine treatment was able to normalize insulin sensitivity in PCOS cells (EC50 = 285 +/- 47 vs. 70 +/- 15 pmol/L, before and after treatment; P < 0.05). In conclusion, our results suggest that insulin resistance in PCOS, as accessed in the adipocyte, occurs at an early step in insulin signaling that is common for glucose transport and lipolysis. In addition, this insulin resistance involves an impairment of the system by which adenosine acts to modulate insulin signal transduction.     

Impaired left ventricular relaxation and hyperinsulinemia in patients with primary hypercholesterolemia

Fifteen non-obese patients with familial hypercholesterolemia and fifteen normocholesterolemic subjects matched for age, body mass index, waist/hip ratio, arterial blood pressure and sedentary life style underwent blood sampling for determination of fasting plasma glucose, insulin, total-, LDL-, HDL-cholesterol, triglycerides, free fatty acids, apolipoprotein A1 and B. In both groups of subjects we determined erythrocyte membrane microviscosity and performed an echocardiographic study. We demonstrated that hypercholesterolemic patients had a significant increase in fasting plasma total cholesterol (8.9 +/- 0.5 vs. 5.5 +/- 0.3 mmol/l, P less than 0.001), insulin (79 +/- 4 vs. 58 +/- 4 pmol/l, P less than 0.05) and apolipoprotein B (2.2 +/- 0.5 vs. 1.3 +/- 0.5 g/l P less than 0.01). In the echocardiographic study we found a significant impairment in left ventricular relaxation (isovolumic relaxation time (IRT) 106 +/- 6 vs. 73 +/- 7 ms, P less than 0.01). Erythrocyte membrane microviscosity (0.253 +/- 0.004 vs. 0.225 +/- 0.003, P less than 0.05) was also increased in hypercholesterolemic patients. Finally we found that erythrocyte membrane microviscosity correlated with fasting plasma insulin levels (r = -0.46, P less than 0.03) and IRT (r = -0.52, P less than 0.01).     

Magnetic resonance imaging assessment of disc degeneration 10 years after anterior lumbar interbody fusion

OBJECTIVE: Insulin-like growth factor (IGF-I) action is influenced by circulating as well as tissue levels of its binding proteins. Because serum IGF binding protein-1 (IGFBP-1) levels have been found to be decreased in patients with polycystic ovary syndrome (PCOS), we tested the hypothesis that regulation of IGFBP-1 secretion may be different in patients with PCOS compared with normal women. METHODS: We studied 15 normal ovulatory women and 15 women with PCOS of similar age (21 +/- 1 and 22 +/- 1 years, respectively). All subjects were studied after an overnight fast between days 5-8 after spontaneous or progestin-induced menses. Perturbations included the administration of insulin intravenously, maintenance of a euglycemic clamp, and, in a subsequent cycle, the administration of a long-acting somatostatin analogue (octreotide, 100 micrograms) given subcutaneously. Blood samples were collected before treatment, every 15 minutes for 6 hours after insulin, and every 30 minutes for 3 hours after octreotide administration. Serum levels of IGF-I, IGFBP-1, IGFBP-3, and insulin were measured by specific immunoassays. RESULTS: Compared with the controls, patients with PCOS had significantly higher insulin levels, similar IGF-I and IGFBP-3 levels, and significantly lower IGFBP-1. Insulin did not change serum IGF-I levels in either group, although a significant decrease in IGFBP-1 levels occurred in normal women but not in patients with PCOS. Octreotide treatment also did not change serum IGF-I levels in either group, but serum insulin levels decreased significantly and IGFBP-1 levels increased significantly in both groups; this response was significantly greater in controls. CONCLUSIONS: Our data are compatible with the notion that regulation of IGFBP-1 is altered in women with PCOS and that several factors may be involved.     

Lack of insulin feedback inhibition in non-obese and obese men

The existence of insulin feedback inhibition is a controversial issue. The present study adopted a novel approach to determine whether insulin feedback inhibition exists in vivo during physiologic hyperinsulinemia and if it could contribute to enhanced insulin secretion in obesity. Serial plasma insulin and C-peptide levels were determined during a basal state and a hyperinsulinemic clamp (287 pmol/min/m2) and following discontinuation of the insulin infusion under euglycemic conditions. Insulin secretion rates were derived from plasma C-peptide levels and individual C-peptide kinetics using a two-compartment model. Eight non-obese and nine obese men were recruited for the studies, which were performed in random order. Men with significant variations in glucose levels during hyperinsulinemia were excluded from the analysis. Plasma glucose levels were similar between the non-obese and obese groups during all phases of the study, and similar plasma insulin levels were achieved in both groups during euglycemic hyperinsulinemia. In obese men, C-peptide levels were significantly greater compared with non-obese men during euglycemic hyperinsulinemia (P < .05). However, neither the non-obese nor the obese group demonstrated significant suppression of insulin secretion rates during euglycemic hyperinsulinemia. Expressing the data in absolute terms or as a percent of basal did not alter the results. Moreover, there was no significant change between the non-obese and the obese group during the rapid onset and cessation of hyperinsulinemia. Under euglycemic conditions, physiologic hyperinsulinemia does not induce suppression of endogenous insulin secretion in non-obese or obese men.     

Impaired endothelium-dependent vasodilatation in women with previous gestational diabetes

OBJECTIVE: To assess whether otherwise healthy women with a history of gestational diabetes mellitus (GDM) may have abnormalities in endothelial function at a very early stage, before glucose intolerance occurs. RESEARCH DESIGN AND METHODS: A total of 33 women with previous GDM (17 nonobese [BMI < 27] and 16 obese [BMI > or = 27]) and 19 healthy nonobese women were examined. A 75-g oral glucose tolerance test was performed, and insulin levels and biochemical parameters were also measured. Using high-resolution ultrasound, we measured vasodilatory responses of the brachial artery during reactive hyperemia (endothelium-dependent vasodilatation), and after nitroglycerin administration, an endothelium-independent vasodilator. RESULTS: Flow-mediated dilatation (FMD) was significantly and equally decreased in both groups of women with previous GDM, compared with control subjects (1.6 +/- 3.7% in the nonobese GDM group and 1.6 +/- 2.5% in the obese GDM group vs. 10.3 +/- 4.4% in control subjects, P < 0.001). FMD correlated inversely with serum uric acid levels, BMI, serum total cholesterol, and basal insulin resistance (homeostasis model assessment). Nitrate-induced dilatation was significantly decreased only in the obese GDM group compared with control subjects, (21.4 +/- 5.1 vs. 27.9 +/- 9.5, P < 0.05). CONCLUSIONS: Endothelial dysfunction, which is considered as a very early index of atherogenesis, is already present in both obese and nonobese women with a history of GDM, even when they have normal glucose tolerance.