Insulin sensitivity in women with polycystic ovary syndrome

The aim of our study was to compare insulin sensitivity in lean and obese European polycystic ovary syndrome (PCOS) women with lean healthy women. We performed the euglycemic hyperinsulinemic clamp in 83 women with PCOS [53 lean with body mass index (BMI) of 21.5 +/- 1.8 kg/m2 and 30 obese with BMI of 29.6 +/- 3.7 kg/m2] and in 15 healthy women with BMI of 21.6 +/- 1.8 kg/m2 to determine glucose disposal (M) and the insulin sensitivity index (ISI). Statistical evaluation was done using Kruskal-Wallis ANOVA followed by Kruskal-Wallis multiple-comparison z-value test. The basal blood glucose was significantly higher in lean and obese PCOS women than in controls (P < 0.02). Fasting insulin was significantly higher in both lean and obese PCOS women than in controls (P < 0.000001). Obese PCOS women were more insulin resistant than controls (P < 0.02 for M and P < 0.0008 for ISI); lean PCOS women did not differ from controls in M or ISI. Posthepatic insulin delivery was significantly higher in both lean and obese PCOS women compared with controls (P < 0.000008). We conclude that lean PCOS women are not more insulin resistant than healthy controls. Insulin hypersecretion, on the other hand, is present even in lean PCOS women.     

Phenotypic characteristics according to insulin sensitivity in non-obese Korean women with polycystic ovary syndrome

Over 50% of women with polycystic ovary syndrome (PCOS) have been reported to have varying degree of insulin resistance and it may contribute to hyperandrogenism. The aim of the study is to identify whether the insulin resistance is present in non-obese Korean women with PCOS and whether the phenotype is different according to insulin sensitivity. Seventy-three non-obese (BMI<23 kg/m(2)) women with PCOS and 34 age and BMI comparable control women with regular menstrual cycles were examined. Standard 75 g OGTT was performed to determine the status of glucose tolerance. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp technique. The fasting plasma glucose (p<0.01) and post-glucose load plasma insulin (p<0.01) of women with PCOS were higher than those of controls. Glucose disposal rate (M-value) was lower in women with PCOS compared to controls (p<0.05). Insulin resistant (IR) and insulin sensitive (IS) PCOS were divided by the M-value of 25-percentile (5.5mg/kg min) in controls. Between IR and IS groups, DHEAS (p<0.01), post-glucose load plasma insulin (p<0.05) showed differences after the adjustment for BMI. Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects and their insulin resistance may contribute to hyperandrogenism especially via adrenal androgen overproduction.     

Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome

Overproduction of proinflammatory factors is associated with obesity and diabetes. Interleukin (IL)-18 as a member of IL-1 cytokine family is increased in obese, in diabetic, and even in polycystic ovary syndrome (PCOS) patients. In the present study we evaluated the association of serum IL-18 levels with insulin resistance in PCOS women. Forty-two PCOS women and 38 control subjects were enrolled in this study and matched with respect to age and body mass index (BMI). Serum IL-18 levels and hormones were measured for all subjects. Furthermore, euglycemic hyperinsulinemic clamp test was performed in selected 30 PCOS women and 11 control subjects. Serum IL-18 levels were elevated in PCOS women compared with the control (p=0.003). IL-18 levels were positively correlated with homeostasis model assessment index (HOMA) β index, which assesses β cell function (p=0.035), but were inversely correlated with clamp indices, which best-represent insulin resistance status: M, Clamp ISIS100, and MCRg values (p=0.006, 0.010, and 0.009 respectively). No correlation was found between IL-18 and age, BMI, waist-to-hip ratio (WHR), lipid profile, dehydroepiandrosterone-sulfate (DHEAS), sex hormone-binding globulin (SHBG), or fasting insulin levels. In conclusion, in the present study, serum IL-18 levels were significantly increased in PCOS women and firmly associated with insulin resistance displayed by euglycemic hyperinsulinemic clamp test. It indicates that IL-18 may be a contributing factor linking inflammation and insulin resistance in PCOS women.     

多囊卵巢综合征患者血清白细胞介素18与胰岛素抵抗相关

目的 运用正葡萄糖高胰岛素钳夹技术评价多囊卵巢综合征(PCOS)患者白细胞介素18(IL-18)血清浓度和胰岛素抵抗的关系.方法 共收集42例PCOS患者和38例年龄和体重指数(BMI)相匹配的对照组女性的相关临床资料,并检测其血清IL-18浓度.对其中41例受试者进行正葡萄糖高胰岛素钳夹试验.计算胰岛素抵抗各相关指标[稳态期平均葡萄糖输注率(M),单位血清胰岛素浓度下葡萄糖输注率(M/I)及葡萄糖代谢清除率(MCRg)值].结果 PCOS患者血清IL-18水平显著高于对照组(P=0.033).而肥胖组与正常体重组相比,IL-18血清浓度并无显著差异(P=0.902).血清IL-18浓度与钳夹试验所得各参数呈显著负相关(与M、M/I和MCRg分别为r=-0.419、-0.396和-0.405,分别P=0.006、0.010和0.009),而与稳态模型评估β细胞功能指数(HOMA-β)指数间呈显著的正相关(r=0.334,P=0.035).结论 血清IL-18浓度在PCOS患者中显著升高,同时其值与钳夹试验所得反映胰岛素抵抗的各参数间显著负相关,提示IL-18血清浓度可能是介导体内炎症过程与胰岛素抵抗发生间的重要细胞因子.     

Failure of mathematical indices to accurately assess insulin resistance in lean, overweight, or obese women with polycystic ovary syndrome

Insulin resistance is a common metabolic feature of polycystic ovary syndrome (PCOS). In this study, we examined the validity of the mathematical indices [the quantitative insulin sensitivity check index (QUICKI) and the homeostasis model of assessment (HOMA)] that calculate insulin sensitivity and their correlation to glucose utilization with the insulin infusion rate in 40 mU/m(2).min by the euglycemic clamp (M) in women with PCOS. We studied 59 women with PCOS (20 lean, 16 overweight, and 23 obese subjects). Euglycemic clamp testing was performed, and QUICKI, HOMA, total testosterone, fasting insulin, fasting glucose, and glucose-to-insulin ratio were estimated. No difference was found in testosterone and glucose levels among the three groups. Lean or overweight women compared with obese women differed in insulin levels, glucose-to-insulin ratio, QUICKI, and HOMA (P < 0.01). No statistical difference was found between lean and overweight women in the above parameters. M differed when lean women were compared with overweight (P < 0.002) or obese women (P < 0.0001); however, no statistical difference was observed between overweight and obese women. No significant correlation was found between M and QUICKI or HOMA. We conclude that mathematical indices should be applied with caution in different insulin-resistant populations and should not be considered a priori equivalent to the euglycemic clamp technique.     

Meal suppression of circulating ghrelin is normalized in obese individuals following gastric bypass surgery

OBJECTIVE: It has been proposed that the success of maintained weight loss in morbidly obese subjects following Roux-en-Y gastric bypass (RYGBP) surgery depends on inappropriately low circulating concentrations of the appetite-stimulating peptide ghrelin, being unresponsive to food intake. In this study, this hypothesis was examined. DESIGN: Cross-sectional study with repeated blood samples in 40 subjects after 14 h of prolonged overnight fasting followed by a standardized mixed meal (770 kcal). SUBJECTS: Twenty men and 20 women were included: 10 middle-aged morbidly obese (body mass index (BMI) 43.9+/-3.3 kg/m(2)), 10 middle-aged subjects who had undergone RYGBP at the Uppsala University Hospital (BMI 34.7+/-5.8 kg/m(2)), 10 middle-aged non-obese (BMI 23.5+/-2.2 kg/m(2)) and 10 young non-obese (BMI 22.7+/-1.8 kg/m(2)). MEASUREMENTS: Ghrelin, glucose and insulin levels were analysed pre- and postprandially. RESULTS: In the morbidly obese, ghrelin concentrations were lower in the morning than in the RYGBP group and did not change following the meal. In the RYGBP group, fasting ghrelin levels fell after meal intake and showed similar suppression as both age-matched and young non-obese controls. The RYGBP surgery resulted in an increased meal-induced insulin secretion, which was related to the degree of postprandial ghrelin suppression. CONCLUSION: The present study demonstrates low circulating concentrations of ghrelin and blunted responses to fast and feeding in morbidly obese subjects. Marked weight reduction after RYGBP at our hospital is followed by a normalization of ghrelin secretion, illustrated by increased fasting levels compared to the preoperative obese state and regain of meal-induced ghrelin suppression.     

Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study

Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m(2)) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 microg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 +/- 5.1 (SE) to 29.8 +/- 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 +/- 0.01 to 0.75 +/- 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 +/- 0.3 to 2.0 +/- 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 +/- 0.2 to 1.4 +/- 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.     

The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study

To evaluate the cardiovascular risk of polycystic ovary syndrome (PCOS), we investigated lipid profile, metabolic pattern, and echocardiography in 30 young women with PCOS and 30 healthy age- and body mass index (BMI)-matched women. PCOS women had higher fasting glucose and insulin levels, homeostasis model assessment score of insulin sensitivity, total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels, and TC/high density lipoprotein cholesterol (HDL-C) ratio and lower HDL-C levels than controls. Additionally, PCOS women had higher left atrium size (32.0 +/- 4.9 vs. 27.4 +/- 2.1 mm; P < 0.0001) and left ventricular mass index (80.5 +/- 18.1 vs. 56.1 +/- 5.4 g/m(2); P < 0.0001) and lower left ventricular ejection fraction (64.4 +/- 4.1 vs. 67.1 +/- 2.6%; P = 0.003) and early to late mitral flow velocity ratio (1.6 +/- 0.4 vs. 2.1 +/- 0.2; P < 0.0001) than controls. When patients and controls were grouped according to BMI [normal weight (BMI, >18 and <25 kg/m(2)), overweight (BMI, 25.1-30 kg/m(2)), and obese (BMI, >30 kg/m(2))], the differences between PCOS women and controls were maintained in overweight and obese women. In normal weight PCOS women, a significant increase in left ventricular mass index and a decrease in diastolic filling were observed, notwithstanding no change in TC, LDL-C, HDL-C, TC/HDL-C ratio, and TG compared with controls. In conclusion, our data show the detrimental effect of PCOS on the cardiovascular system even in young women asymptomatic for cardiac disease.     

Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients.

OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.     

The metabolic syndrome in young Korean women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and consequent hyperinsulinemia. Insulin resistance also plays an important role in the metabolic syndrome (MS). We conducted a cross-sectional study to determine the prevalence of the MS in young Korean women with PCOS and whether it is associated insulin resistance. One hundred and seventeen young women with PCOS (age: 26+/-5, 16-39 years) were evaluated for the frequency of MS according to the modified Adult Treatment Panel III. Total testosterone (T), free T, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured, and insulin sensitivity was evaluated by euglycemic hyperinsulinemic clamp technique. The prevalence of MS in women with PCOS was 14.5%, nearly 3.5-fold higher than in age-matched women in Korean urban population (4.3%) [J.-Y. Oh, Y.-A. Sung, Y.S. Hong, E. Barrett-Conner, Prevalence and factor analysis of metabolic syndrome in an urban Korean population, Diabetes Care 27 (2004) 2027-2032]. The most frequently occurring component of MS was low HDL cholesterol (45%), and the least frequent was high fasting serum glucose level (0.9%). PCOS women with MS had significantly higher free T, and lower SHBG compared with those without MS. And women with MS showed significantly lower M-value and higher fasting/post-glucose load insulin levels. M-value was still significantly lower in women with MS even after the adjustment for BMI. MS is frequent in young Korean women with PCOS and it reflects more severe insulin resistance. These results suggest the importance of early and regular screening of metabolic disturbance in even young women with PCOS.     

Normal serum alanine aminotransferase activity in uncomplicated obesity

AIM: To evaluate serum alanine aminotransferase (ALT) activity in a well-characterized group of uncomplicated obese subjects and its correlation with insulin resistance, plasma adiponectin, and leptin concentrations. METHODS: One hundred and five uncomplicated obese subjects (87 women, 18 men, age 34.3±9.6 years, BMI 39.9±8.3 kg/m2)were studied. Serum ALT activity was evaluated. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M index) and fasting insulin. Plasma leptin and adiponectin levels were also measured. RESULTS: Serum ALT concentration in the whole group of uncomplicated obese subjects was 17.73±6.33 U/L with none of the subjects presenting ALT levels greater than 43 U/L and only 9 (11%) women and 3 (19%) men showed ALT levels >19 and >30 U/L for women and men, respectively. No significant difference was detected in serum ALT levels between severe obese subjects (BMI >40 kg/m2) and those with BMI <40 kg/m2 (18.63±6.25 vs 17.26±6.02 U/L). ALT was significantly correlated with fasting insulin (r=0.485, P= 0.02) and triglycerides (r= 0.358, P=0.03). CONCLUSION: Serum ALT activity is practically normal in uncomplicated obese subjects, independently of their obesity degree. These findings suggest the role of obesityrelated comorbidities and not of BMI as main risk factors for elevated ALT levels in obese subjects.     

Restored insulin inhibition on insulin secretion in nondiabetic severely obese patients after weight loss induced by bariatric surgery

OBJECTIVE: To examine the impact of important weight loss on insulin inhibition of its own secretion during experimentally induced hyperinsulinemia under euglycemic conditions. DESIGN: Longitudinal, clinical intervention study--bariatric surgery (vertical banded gastroplasty--gastric bypass--Capella technique), re-evaluation after 4 and 14 months. SUBJECTS: Nine obese patients class III (BMI=54.6+/-2.6 kg/m2) and nine lean subjects (BMI=22.7+/-0.7 kg/m2). MEASUREMENTS: Euglycemic hyperinsulinemic clamp (insulin infusion: 40 mU/min m2), C-peptide plasma levels, electrical bioimpedance methodology, and oral glucose tolerance test (OGTT). RESULTS: BMI was reduced in the follow-up: 44.5+/-2.2 and 33.9+/-1.5 kg/m2 at 4 and 14 months. Insulin-induced glucose uptake was markedly reduced in obese patients (19.5+/-1.9 micromol/min kg FFM) and improved with weight loss, but in the third study, it was still lower than that observed in controls (35.9+/-4.0 vs 52.9+/-2.2 micromol/min kg FFM). Insulin-induced inhibition of its own secretion was blunted in obese patients (19.9+/-5.7%, relative to fasting values), and completely reversed to values similar to that of lean ones in the second and third studies (-60.8+/-4.2 and -54.0+/-6.1%, respectively).CONCLUSION: Weight loss in severe obesity improved insulin-induced glucose uptake, and completely normalized the insulin inhibition on its own secretion.     

Early endocrine, metabolic, and sonographic characteristics of polycystic ovary syndrome (PCOS): comparison between nonobese and obese adolescents

Approximately half of all women with polycystic ovary syndrome (PCOS) are overweight or obese, and studies have reported endocrine and metabolic differences between lean and obese women with PCOS. PCOS has not been as extensively investigated in the adolescent population. The objectives of our study were to further characterize early endocrine and metabolic alterations in adolescents with PCOS and to determine whether differences between nonobese and obese women with PCOS are present early in its course. We studied an ethnically heterogeneous group of 48 adolescents: 11 nonobese with PCOS [age, 16.1 +/- 1.9 yr; body mass index (BMI), 22.5 +/- 1.5 kg/m(2)], 22 obese with PCOS (age, 15.5 +/- 1.4 yr; BMI, 35.9 +/- 6.2 kg/m(2)), and 15 obese controls (age, 14.4 +/- 1.5 yr; BMI, 35.8 +/- 7.1 kg/m(2)). Fasting levels of glucose, insulin, proinsulin, hemoglobin A1c, testosterone, SHBG, Delta4-androstenedione (Delta4-A), dehydroepiandrosterone sulfate (DHEAS), LH, FSH, IGF-I, IGF binding protein-1, free IGF-I, and lipids were measured. Six of the 11 nonobese PCOS subjects, 11 of the 22 obese PCOS subjects, and six of the 15 controls underwent standard oral glucose tolerance testing. The insulin response to the oral glucose tolerance test was measured by the insulin area under the curve (I(AUC120)). Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. The nonobese adolescents with PCOS demonstrated higher levels of LH, SHBG, Delta4-A, DHEAS, dihydrotestosterone, free IGF-I, and high-density lipoprotein, and lower low-density lipoprotein, compared with the obese PCOS group. Fasting levels of insulin and proinsulin, I(AUC120), and log I(AUC120) were higher, and the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index were lower in the obese compared with the nonobese PCOS subjects. Greater levels of LH and androgens, including total and free testosterone, Delta4-A, and DHEAS, and lower SHBG levels were found in the obese PCOS group compared with the obese controls. Adolescents with PCOS manifest clinical, metabolic, and endocrine features similar to those of adult women, and differences between nonobese and obese women with PCOS may be detected in adolescence. Our findings indicate a more pronounced alteration in the hypothalamo-pituitary-adrenal axis in nonobese adolescents with PCOS and a more marked dysregulation of insulin levels and impairment of insulin sensitivity in their obese counterparts. Our data also suggest differences in the IGF system between nonobese and obese adolescents with PCOS.     

Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study

OBJECTIVE: Abdominal obesity, insulin resistance and compensatory hyperinsulinaemia play a central role in the pathogenesis of the polycystic ovary syndrome (PCOS). Abdominal adipose tissue is a source of adipokines, such as adiponectin and resistin, both of which may be involved in the development of insulin resistance and chronic inflammation in PCOS. Ghrelin, an important regulatory peptide of food intake, may also play a role in metabolic disturbances related to PCOS. The aim of this study was to examine the effects of 4 months of treatment with the insulin sensitizer rosiglitazone on plasma adiponectin, resistin and ghrelin levels in overweight women with PCOS. DESIGN: A randomised placebo-controlled study. METHODS: Thirty overweight/obese women with PCOS (body mass index>25 kg/m(2), mean age 29.1+/- 1.2 (S.E.M.) years) were randomly allocated to either rosiglitazone (Avandia, 4 mg twice a day) or placebo treatment. Plasma levels of adiponectin, resistin and ghrelin and their correlation to serum levels of insulin, C-peptide and steroid hormones, and insulin sensitivity (euglycaemic hyperinsulinaemic clamp) were assessed. RESULTS: Adiponectin and ghrelin levels correlated significantly with most metabolic markers of insulin resistance and with serum levels of DHEA and 17-hydroxyprogesterone. Plasma levels of adiponectin increased from 9.26+/-0.90 (S.E.M.) to 22.22+/-3.66 microg/ml (P<0.001) and those of resistin decreased from 12.57+/-1.63 to 9.21+/-0.53 ng/ml (P=0.009) at 4 months of treatment, but plasma ghrelin levels did not change. CONCLUSIONS: Rosiglitazone had beneficial effects on serum levels of adiponectin and resistin, suggesting that these adipocytokines may contribute to the improvement in insulin sensitivity observed during the treatment.     

Increased expression of the macrophage markers and of 11beta-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity

OBJECTIVE: To determine whether increased expression of macrophage markers and of inflammatory markers in subcutaneous adipose tissue is associated with liver fat in human obesity. We also determined whether expression of TNF (gene encoding TNF-alpha), HSD11B1 (gene encoding 11beta-HSD-1) and RETN (gene encoding resistin) in cultured monocyte-derived macrophages differs between obese/overweight and non-obese subjects. DESIGN: Cross-sectional comparison of obese/overweight and non-obese subjects with respect to adipose tissue gene expression, gene expression in monocyte-derived macrophages, liver fat content and in vivo insulin sensitivity. SUBJECTS: Adipose tissue gene expression, gene expression in monocyte-derived macrophages, liver fat content and in vivo insulin sensitivity: 10 healthy non-obese (24.2+/-1.0 kg/m(2)) and 10 healthy obese/overweight (33.1+/-1.7 kg/m(2)) women. Gene expression in monocyte-derived macrophages: seven healthy non-obese (22.1+/-0.7 kg/m(2)) and seven healthy obese/overweight (36.9+/-2.2 kg/m(2)) women. MEASUREMENTS: Adipose tissue biopsies and blood samples for isolation of peripheral mononuclear cells were taken after an overnight fast. Liver fat content was measured using magnetic resonance proton spectroscopy. Whole body insulin sensitivity was measured using the hyperinsulinemic euglycemic clamp technique. Expression levels of TNF, HSD11B1, RETN and the macrophage markers CD68 and ITGAM were determined by real-time PCR. RESULTS: In adipose tissue, expression of HSD11B1, ITGAM and CD68 was significantly increased in the obese/overweight as compared to the non-obese group. Expression of all these genes was closely positively correlated with liver fat content and inversely correlated with whole body insulin sensitivity. The associations between expression of CD68, ITGAM and HSD11B1 and liver fat were independent of obesity. There were no differences in TNF, HSD11B1, RETN or CD68 gene expression basally or after stimulation with lipopolysaccharide in monocyte-derived macrophages between obese/overweight and non-obese subjects. CONCLUSION: Accumulation of fat in the liver is associated with increased adipose tissue inflammation independent of obesity.     

Chronic hyperinsulinemia decreases insulin action but not insulin sensitivity

Hyperinsulinemia and insulin resistance are commonly seen in obese and non-insulin-dependent diabetes mellitus (NIDDM) patients, suggesting a causal link exists between hyperinsulinemia and insulin resistance. In a previous study, we demonstrated that chronic (28 days) intraportal hyperinsulinemia (50% increase in basal insulin levels) resulted in a decrease in insulin action as assessed by a one-step euglycemic hyperinsulinemic clamp. Since only one dose of insulin was used during the clamp, it was not possible to determine if the decrease in insulin action was due to a change in insulin sensitivity and/or maximal insulin responsiveness. In the present study, insulin resistance was induced as before, but insulin action was assessed in overnight fasted conscious dogs using a four-step euglycemic hyperinsulinemic clamp (1, 2, 10, and 15 mU/kg/min). Insulin responsiveness was assessed before the induction of chronic hyperinsulinemia (day 0), and after 28 days of hyperinsulinemia (day 28). Transhepatic glucose balance and whole-body glucose utilization were measured to allow assessment of both the hepatic and peripheral effects of insulin. Chronic hyperinsulinemia increased basal insulin levels from 13 +/- 2 to 21 +/- 4 microU/mL. After 4 weeks of chronic hyperinsulinemia, maximal insulin-stimulated glucose utilization was decreased 23% +/- 4% (P less than .05) and insulin sensitivity (ED50) was not significantly altered. During the four-step clamp, the liver was a major site of glucose utilization. The liver was responsible for 13% of the total glucose disposal rate on day 0 (2.9 mg/kg/min) at the highest insulin infusion rate (15 mU/kg/min; 2,000 microU/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Intraportal hyperinsulinemia decreases insulin-stimulated glucose uptake in the dog

Hyperinsulinemia and insulin resistance are commonly seen in obese and non-insulin-dependent diabetes mellitis (NIDDM) patients. While it is known that chronic exposure to severe hyperinsulinemia can lead to an insulin-resistant state and mild hyperinsulinemia for rather short durations (20 to 40 hours) and can also lead to insulin resistance, it is less clear whether mild hyperinsulinemia for a more prolonged duration can lead to insulin resistance. In the present study we determined the effects of chronic (28 days) exposure to mild hyperinsulinemia on insulin-stimulated glucose use. Chronic hyperinsulinemia was produced by an intraportal infusion of porcine insulin (425 microU/kg/min), which raised the basal peripheral insulin levels by approximately 50%. Insulin responsiveness was assessed using the euglycemic hyperinsulinemic clamp (2 mU/kg/min) in dogs before the induction of chronic hyperinsulinemia (day 0), after 28 days of hyperinsulinemia (day 28), and 28 days after discontinuation of the chronic insulin infusion (day 56). The amount of glucose (M) required to maintain euglycemia during the euglycemic hyperinsulinemic clamp was decreased (relative to day 0) 39% +/- 3% on day 28 and 18% +/- 3% on day 56 (P less than .05). In control animals that received a chronic infusion of saline for the 28-day period the glucose infusion rate (M) was not changed significantly (decreasing 2% +/- 5% and 5% +/- 10% on days 28 and 56, respectively). In conclusion insulin resistance can be produced by a mild hypersecretion of insulin and discontinuation of the chronic insulin infusion tends to reverse the resistance.     

Ghrelin enhances glucose-induced insulin secretion in scheduled meal-fed sheep

The purpose of this study was to investigate the effects of physiologic levels of ghrelin on insulin secretion and insulin sensitivity (glucose disposal) in scheduled fed-sheep, using the hyperglycemic clamp and hyperinsulinemic euglycemic clamp respectively. Twelve castrated Suffolk rams (69.8 +/- 0.6 kg) were conditioned to be fed alfalfa hay cubes (2% of body weight) once a day. Three hours after the feeding, synthetic ovine ghrelin was intravenously administered to the animals at a rate of 0.025 and 0.05 mug/kg body weight (BW) per min for 3 h. Concomitantly, the hyperglycemic clamp or the hyperinsulinemic euglycemic clamp was carried out. In the hyperglycemic clamp, a target glucose concentration was clamped at 100 mg/100 ml above the initial level. In the hyperinsulinemic euglycemic clamp, insulin was intravenously administered to the animals for 3 h at a rate of 2 mU/kg BW per min. Basal glucose concentrations (44+/- 1 mg/dl) were maintained by variably infusing 100 mg/dl glucose solution. In both clamps, plasma ghrelin concentrations were dose-dependently elevated and maintained at a constant level within the physiologic range. Ghrelin infusions induced a significant (ANOVA; P < 0.01) increase in plasma GH concentrations. In the hyperglycemic clamp, plasma insulin levels were increased by glucose infusion and were significantly (P < 0.05) greater in ghrelin-infused animals. In the hyperinsulinemic euglycemic clamp, glucose infusion rate, an index of insulin sensitivity, was not affected by ghrelin infusion. In conclusion, the present study has demonstrated for the first time that ghrelin enhances glucose-induced insulin secretion in the ruminant animal.     

Acute hyperinsulinemia is associated with increased plasma adrenomedullin concentrations in uncomplicated obesity.

OBJECTIVE: Adrenomedullin (AM) is a potent hypotensive peptide which may be implicated in the insulin regulatory system. Acute hyperinsulinemia exerts no influence on plasma AM in normal subjects while no data on obese subjects has been reported. PURPOSE: The aim of the study was to investigate the effect of acute hyperinsulinemia on the plasma AM concentration in patients with uncomplicated obesity. RESEARCH METHODS: We measured the plasma AM levels in 23 obese subjects (BMI 41.9 +/- 9.8 kg/m2), 21 females and 2 males (mean age 31 +/- 7.2 years), before and during a euglycemic hyperinsulinemic clamp. The control group consisted of 43 healthy subjects (HS) (22 males and 21 females; mean age 38 +/- 12 years; BMI 23.3 +/- 3.2 kg/m2). RESULTS: Baseline plasma AM was found to be higher in obese subjects (20.4 +/- 8.4 pg/ml) than in normal subjects (11.3 +/- 0.8 pg/ml) (p < 0.001). A significant increase in the plasma AM levels was observed in obese subjects during acute hyperinsulinemia (from 20.4 +/- 8.4 pg/ml at 0 min to 26 +/- 8.9 pg/ml at 120 min, p < 0.02). Plasma AM concentrations were significantly correlated with insulin levels at 30 min (r = 0.44; p = 0.04) and 120 min (r = 0.40, p = 0.05) during the clamp. DISCUSSION: In conclusion, acute hyperinsulinemia induced a significant increase in the plasma levels of AM in uncomplicated obese subjects. Hyperinsulinemia may, at least in part, regulate levels of AM in obesity, explaining the high levels of the peptide in these subjects.     

Elevated serum RBP4 is associated with insulin resistance in women with polycystic ovary syndrome

Retinol binding protein 4 (RBP4) is a novel adipocyte-secreted protein that contributes to systemic insulin resistance. Experiments in mice suggest that elevated RBP4 causes insulin resistance. In the present study, we determined serum RBP4 concentration and evaluated its association with insulin resistance in women with polycystic ovarian syndrome (PCOS); 39 PCOS women and 45 healthy control subjects were enrolled in this study. Serum RBP4, fasting plasma glucose (FPG) and fasting serum insulin (FINS) were measured in all subjects. Furthermore, oral glucose tolerance test (OGTT), Botnia clamp (an intravenous glucose tolerance test followed by an euglycemic hyperinsulinemic clamp), and measurements of sex hormones were performed in 13 control subjects and all the PCOS women. The levels of serum RBP4 were elevated in PCOS women compared with the control (11.69 +/- 6.72 versus 7.75 +/- 5.96 microg/mL, p = 0.006). RBP4 levels were positively correlated with WHR (r = 0.216, p = 0.048), and intravenous glucose tolerance test beta cell index (IVGTT-beta index) which reflected beta cell function (r = 0.309, p = 0.028), but were inversely correlated with M value during Botnia clamp, which represented insulin sensitivity (r = -0.362, p = 0.008). No correlation was found between RBP4 and age, BMI, blood pressure, FPG, FINS, 2-h postprandial glucose, 2-h postprandial insulin, free testosterone, total testosterone, follicle-stimulating hormone (FSH), or luteinizing hormone (LH). In a linear stepwise regression analysis with a model including age, BMI, WHR, free testosterone, IVGTT-beta index, and M value as independent variables, only M value showed significant correlation with serum RBP4 levels (r2 = 0.105, f = 6.640, p = 0.012). In conclusion, serum RBP4 levels are significantly increased in PCOS women and associated with insulin resistance, which indicates that RBP4 may be a contributing factor linking adipose tissue with insulin resistance in PCOS.