Comparison between surrogate indexes of insulin sensitivity/resistance and hyperinsulinemic euglycemic glucose clamps in rhesus monkeys

The euglycemic glucose clamp is the reference method for assessing insulin sensitivity in humans and animals. However, clamps are ill-suited for large studies because of extensive requirements for cost, time, labor, and technical expertise. Simple surrogate indexes of insulin sensitivity/resistance including quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) have been developed and validated in humans. However, validation studies of QUICKI and HOMA in both rats and mice suggest that differences in metabolic physiology between rodents and humans limit their value in rodents. Rhesus monkeys are a species more similar to humans than rodents. Therefore, in the present study, we evaluated data from 199 glucose clamp studies obtained from a large cohort of 86 monkeys with a broad range of insulin sensitivity. Data were used to evaluate simple surrogate indexes of insulin sensitivity/resistance (QUICKI, HOMA, Log HOMA, 1/HOMA, and 1/Fasting insulin) with respect to linear regression, predictive accuracy using a calibration model, and diagnostic performance using receiver operating characteristic. Most surrogates had modest linear correlations with SI(Clamp) (r ≈ 0.4-0.64) with comparable correlation coefficients. Predictive accuracy determined by calibration model analysis demonstrated better predictive accuracy of QUICKI than HOMA and Log HOMA. Receiver operating characteristic analysis showed equivalent sensitivity and specificity of most surrogate indexes to detect insulin resistance. Thus, unlike in rodents but similar to humans, surrogate indexes of insulin sensitivity/resistance including QUICKI and log HOMA may be reasonable to use in large studies of rhesus monkeys where it may be impractical to conduct glucose clamp studies.     

Comparison of the insulin action parameters from hyperinsulinemic clamps with homeostasis model assessment and QUICKI indexes in subjects with different endocrine disorders

The aim of this study was to compare insulin sensitivity expressed by the hyperinsulinemic clamp and by the homeostasis model assessment (HOMA) and QUICKI indexes in subjects with various disorders influencing insulin action. We examined 41 type 2 diabetic patients, 20 insulinoma patients, 32 women with polycystic ovary syndrome, 16 patients with primary hyperaldosteronism, 12 patients with essential high renin hypertension, and 47 healthy subjects. The metabolic clearance rate of glucose and the insulin sensitivity index calculated from the clamps were compared with both the HOMA and QUICKI indexes. The relationship of insulin action to body mass index, serum cholesterol, and triglycerides as well as to systolic and diastolic blood pressures was also evaluated. Body mass index was very strongly associated with the insulin sensitivity index (r = -0.70; P < 0.0001) in the entire cohort of 168 subjects. Cholesterol, triglycerides, and blood pressure influenced insulin action in the healthy subjects and type 2 diabetic patients. A significant relationship was observed between the insulin sensitivity index and the HOMA or QUICKI indexes in healthy subjects (r = -0.66; P < 0.0001), type 2 diabetic patients (r = -0.68; P < 0.0001), and women with polycystic ovary syndrome (r = -0.65; P < 0.0001). We did not find any relationship between the above variables in the patients with insulinoma or primary hyperaldosteronism. The HOMA and QUICKI indexes do not offer the same information as glucose clamps in the rare cases with differently impaired peripheral or hepatic insulin action.     

Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in United States, affecting 6-10% of females in the reproductive age group. Recent studies have shown that insulin resistance plays an important role in the pathogenesis of PCOS. Traditionally, management of PCOS consisted mainly of ovulation induction, treatment of acne and hirsutism, and prevention of endometrial cancer. However, with mounting evidence showing that PCOS is associated with dysmetabolic syndrome and an increased risk for developing diabetes and heart disease, this can no longer be our sole focus. Current data support a strong recommendation that women with PCOS should undergo comprehensive evaluation for diabetes and recognized cardiovascular risk factors and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many obese women with PCOS find weight loss difficult to achieve and maintain, and this is not an option for lean women with PCOS. For these reasons, insulin-sensitizing drugs are proving to be a promising and unique therapeutic option for chronic treatment of PCOS.     

Association of insulin resistance with anti-Mullerian hormone levels in women without polycystic ovary syndrome (PCOS)

Objective  To explore the relationship of insulin resistance (IR) and adipokines (leptin, adiponectin, RBP4) to anti-Mullerian hormone (AMH) levels in women without polycystic ovary syndrome (PCOS).
Design/patients/measurements  We recruited 120 healthy, reproductive age women without PCOS. An overnight fasting blood draw, anthropometric measurements, analyses of serum levels of AMH, adipokines (leptin, adiponectin and RBP4) and total testosterone, a homeostasis model assessment for insulin resistance (HOMA-IR) and a transvaginal ultrasound scan were performed between the third and fifth day of their spontaneous menstrual cycles.
Results  Higher HOMA-IR levels were associated with lower levels of AMH. After adjustment for age, serum AMH levels negatively correlated with insulin, fasting glucose, HOMA-IR and RBP4. However, a positive correlation was identified between serum AMH and adiponectin. A final multiple stepwise linear regression demonstrated that HOMA-IR was independently associated with AMH.
Conclusion  An independent relationship exists between HOMA-IR and AMH in women without PCOS, possibly due to the effect of abnormal insulin action on AMH secretion by granulosa cells.     

多囊卵巢综合征不孕患者血清生长素水平变化及其与胰岛素抵抗的关系

［摘要］　目的　研究多囊卵巢综合征(PCOS)不孕患者血清生长素（Ghrelin）水平的变化及其与胰岛素抵抗(IR)的关系。方法　选择98例PCOS不孕患者（PCOS组）及72例非PCOS不孕患者（非PCOS组）,比较两组患者的体重指数(BMI)、血清Ghrelin、血糖、胰岛素、稳态模型胰岛素抵抗指数(HOMA-IR)间的相互关系。血清Ghrelin采用ELISA法测定,空腹血浆葡萄糖(FPG)采用葡萄糖氧化酶法测定, 空腹胰岛素(FIns)采用化学发光法测定。结果　PCOS组血清Ghrelin水平（pg/ml）明显低于非PCOS组［(442.56±221.71) vs (697.41±157.84),P<0.05］。PCOS组的HOMA-IR高于非PCOS组［(3.84±1.23) vs (2.14±0.77),P<0.05］。Person相关分析表明,PCOS组血清Ghrelin水平与HOMA-IR呈负相关(r=-0.48,P<0.01)。结论　PCOS不孕患者血清Ghrelin水平降低,并且其降低与IR密切相关。提示Ghrelin可能参与PCOS不孕患者胰岛素抵抗的发生与发展。     

Prevalence of Type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome

AIMS/HYPOTHESIS: Insulin resistance with increased risk of Type II (non-insulin-dependent) diabetes is a common feature of polycystic ovary syndrome (PCOS). To investigate antecedents of metabolic disorders in family members of patients with PCOS, we evaluated glucose tolerance and insulin resistance in parents of patients with PCOS compared to parents of healthy women. METHODS: A total of 200 parents of women with clinical and hormonal evidence of PCOS (PCOSp) and 120 parents of healthy normally cycling women (HWp) were studied. A 75-g OGGT was performed and subjects were classified according to the World Health Organization (WHO) criteria (1999). Serum glucose and insulin were measured before the glucose load and 30, 60 and 120 min after. C-peptide and sex hormone-binding globulin were also determined before the glucose load. Insulin resistance was assessed by HOMA model and ISI composite. RESULTS: The prevalence of Type II diabetes was 1.89-(1.06-3.38)-fold higher in PCOSp compared to HWp. Insulin resistance, evaluated by HOMA(IR)and ISI composite was also significantly higher in the PCOSp group compared to the HWp group. After both study groups were distributed by sex, and adjusted by age and BMI, the metabolic parameters were still significantly different between PCOSp and HWp. CONCLUSIONS/INTERPRETATION: The data suggest that parents of PCOS women exhibit insulin resistance and Type II diabetes more frequently than those of healthy women, thus constituting a high-risk group but an ideal cohort to detect and prevent the development of Type II diabetes.     

Glucose intolerance,insulin resistance,and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with hyperinsulinemia, insulin resistance (IR), increased risk of glucose intolerance, and type 2 diabetes. Family studies have indicated a genetic susceptibility to PCOS. The aims of this study were 1) to assess glucose tolerance status, gonadotropins, and androgens in first degree relatives of patients with PCOS; and 2) to assess IR in normal glucose tolerant (NGT) family members. One hundred two family members of 52 patients with PCOS [Mothers(PCOS) (n = 34; mean age, 46.5 yr; mean body mass index (BMI), 28.8 kg/m(2)), Fathers(PCOS) (n = 24; mean age, 50.4 yr; mean BMI, 27.5 kg/m(2)), Sisters(PCOS) (n = 19; mean age, 25.1 yr; mean BMI, 22.9 kg/m(2)), and Brothers(PCOS) (n = 25; mean age, 23.7 yr; mean BMI, 22.5 kg/m(2))] and 82 unrelated healthy control subjects without a family history of diabetes or PCOS (4 age- and weight-matched subgroups, i.e. Control(MothersPCOS), Control(FathersPCOS), Control(SistersPCOS), and Control(BrothersPCOS)) were studied. Glucose and insulin (at baseline and during a 75-g, 2-h oral glucose tolerance test) were measured. IR was assessed by fasting insulin (FI), fasting glucose to insulin ratio (FGI), homeostatic model assessment (HOMA IR), and area under the curve for insulin during the oral glucose tolerance test (AUC(insulin)) in NGT Mothers(PCOS), Fathers(PCOS), Sisters(PCOS), Brothers(PCOS), and matched control subgroups. Including the prestudy-diagnosed 3 mothers and 2 fathers with diabetes, diabetes and impaired glucose tolerance (IGT) were noted in 16% and 30% of Mothers(PCOS) and 27% and 31% of Fathers(PCOS), respectively. There was no diabetes in Sisters(PCOS) and Brothers(PCOS). IGT was found in 5% of Sisters(PCOS). Impaired fasting glucose was found in 3% of Mothers(PCOS) and 4% of Brothers(PCOS). The analysis of NGT family members showed that Mothers(PCOS) had higher FI (P < 0.05), HOMA IR (P < 0.05), and AUC(insulin) (P < 0.01) and lower FGI (P < 0.05) than Control(MothersPCOS), whereas all IR parameters were comparable between Fathers(PCOS) and their matched control subgroup. Sisters(PCOS) had higher FI (P < 0.05), HOMA IR (P < 0.01), and AUC(insulin) (P < 0.05) and lower FGI (P < 0.01), and Brothers(PCOS) had higher AUC(insulin) (P < 0.01) than their matched control subgroups, respectively. Mothers(PCOS) had higher testosterone levels than Control(MothersPCOS) (P < 0.01 and P < 0.05 for pre- and postmenopausal women, respectively). Sisters(PCOS) had higher LH (P < 0.01), testosterone (P < 0.001), androstenedione (P < 0.01), and dehydroepiandrosterone sulfate (P < 0.05) levels than Control(SistersPCOS). There was no difference in gonadotropin and androgen levels in Fathers(PCOS) compared with Control(FathersPCOS) or in Brothers(PCOS) compared with Control(BrothersPCOS). Our results suggest that 1) first degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance; 2) NGT female family members have insulin resistance; and 3) mothers and sisters of PCOS patients have higher androgen levels than control subjects. We propose that the high risks of these impairments warrant screening in first degree relatives of patients with PCOS.     

Neuroendocrine and endocrine dysfunction in the hyperinsulinemic PCOS patient: the role of metformin

Metformin is a widely used and extensively studied insulin sensitising drug for the treatment of women with polycystic ovary syndrome (PCOS), with various actions in tissues responding to insulin that include the liver, skeletal muscle, adipose tissue, the endothelium of blood vessels, and the ovaries. Treatment of PCOS women with metformin has been shown to reduce fasting glucose levels, blood pressure, and serum androgens; further effects of metformin in women with PCOS may include direct effects on the central nervous system; and indirect effects via the modification of gut hormone and adipokine synthesis and/or secretion. A number of "novel" adipokines and metabolic factors have been recently identified which may play a role both in the pathogenesis and the treatment of women with PCOS. We here discuss recent advances in the area, with a focus on neuroendocrine and endocrine dysfunctions in women with PCOS and the potential role of metformin in this context.     

妊娠期糖尿病患者肥胖抑制素水平及其与胰岛素抵抗的关系

肥胖抑制素是与编码胃促生长素的同一基因共同编码的含23个氨基酸的多肽,可通过与G蛋白耦联的孤儿受体39作用减少摄食,减轻体质量,减慢胃排空,抑制肠能动性.在胰腺组织中,胰岛素和肥胖抑制素浓度存在明显的相关性.     

Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus‐infected and hepatitis C virus‐cleared patients

Background/Aims: Our aim was to evaluate the relationship between hepatitis C virus (HCV) infection and development of diabetes mellitus (DM) or insulin resistance (IR) in comparison with hepatitis B virus (HBV) infection and eradication of HCV infection by interferon treatment. Methods: This study consisted of 952 outpatients, including 544 HCV‐infected (HCV+chronic), 286 HBV‐infected (HBV+chronic) and 122 patients whose HCV was cleared by interferon treatment (HCV+cleared) (diabetes study). Among 849 without overt DM, IR was assessed in 423 patients, including 232 HCV‐infected (HCV+chronic), 135 HBV‐infected (HBV+chronic) and 56 HCV‐eradicated patients (HCV+cleared) (IR substudy). Results: The prevalence of DM in the HBV+chronic, HCV+chronic and HCV+cleared groups was 6.3, 13.6 and 9.0%, respectively (HBV+chronic vs HCV+chronic, P<0.005), in the diabetes study, and the prevalence of IR in the HCV+chronic group (54.3%) was also higher than that in the HBV+chronic (36.3%) (P<0.005) and HCV+cleared groups (35.7%) (P<0.05) in the IR substudy. However, HCV infection was not shown to be independently associated with DM development [odds ratio (OR) 1.669; P=0.0936] and with IR (OR 1.531; P=0.2154) by multivariate analysis in comparison with HBV infection as control. Conclusions: HCV‐infected patients showed a higher prevalence of DM and IR than those with HBV infection. However, in Japan, other confounding factors appeared to be more important risk factors for the development of disturbance in glucose metabolism.