胰岛素增敏剂对多囊卵巢综合征患者卵巢局部胰岛素抵抗的影响

目的探讨多囊卵巢综合征(PCOS)患者卵巢局部胰岛素抵抗状态及胰岛素增敏剂——曲格列酮(troglitazone)对改善卵巢局部胰岛素抵抗的作用。方法收集11例PCOS患者(PCOS组)和排卵功能正常的33例输卵管性不孕患者(对照组)促排卵后卵巢黄素化颗粒细胞(卵巢细胞),进行体外培养,并经不同浓度的胰岛素及胰岛素样生长因子1(IGF-1)作用后,观察卵巢细胞糖原和DNA合成的变化,同时观察卵巢细胞胰岛素受体(IR)、IGT-1受体(IGF-1R)、胰岛素受体底物(IRS)的表达。结果(1)不同浓度IGE-1作用后,PCOS组卵巢细胞的DNA合成增加约为对照组的2倍,曲格列酮可抑制IGF-1的这一作用。(2)胰岛素作用后,PCOS组卵巢细胞的糖原合成量与对照组比较,明显降低;而曲格列酮作用后,两组卵巢细胞中胰岛素促糖原合成作用均增加。(3)与对照组比较,PCOS组卵巢细胞：[RS-1的表达(相对灰度,下同)升高,IRS-2表达降低。曲格列酮可降低IRS-1的表达水平,升高IRS-2的表达水平。结论(1)PCOS患者存在卵巢局部的胰岛素抵抗现象。(2)卵巢局部胰岛素抵抗与PCOS患者卵巢高反应状态相关。(3)曲格列酮可增加卵巢细胞对胰岛素的敏感性。     

Accurate screening for insulin resistance in PCOS women using fasting insulin concentrations

Abstract

The aims of this cross-sectional study were to evaluate the relative agreement of both static and dynamic methods of diagnosing IR in women with polycystic ovary syndrome (PCOS) and to suggest a simple screening method for IR. All participants underwent serial blood draws for hormonal profiling and lipid assessment, a 3?h, 75?g load oral glucose tolerance test (OGTT) with every 15?min measurements of glucose and insulin, and an ACTH stimulation test. The prevalence of IR ranged from 12.2% to 60.5%, depending on the IR index used. Based on largest area under the curve on receiver operating curve (ROC) analyses, the dynamic indices outperformed the static indices with glucose to insulin ratio and fasting insulin (fInsulin) demonstrating the best diagnostic properties. Applying two cut-offs representing fInsulin extremes (<7 and >13?mIU/l, respectively) gave the diagnosis in 70% of the patients with high accuracy. Currently utilized indices for assessing IR give highly variable results in women with PCOS. The most accurate indices based on dynamic testing can be time-consuming and labor-intensive. We suggest the use of fInsulin as a simple screening test, which can reduce the number of OGTTs needed to routinely assess insulin resistance in women with PCOS.     

Fetal growth in women managed with insulin pump therapy compared to conventional insulin

OBJECTIVE: Fetal hyperinsulinaemia secondary to maternal hyperglycaemia is considered to be the driving force behind excessive fetal growth. We hypothesised that insulin pump therapy (continuous subcutaneous insulin infusion, CSII) would improve maternal glycaemic control and normalise fetal growth parameters. To this end, this study compares maternal glycaemic control and fetal growth of women receiving insulin pump therapy with those receiving conventional insulin therapy. STUDY DESIGN: Prospective non-randomised study of 42 women with pre-existing diabetes attending a joint obstetric diabetic clinic. Each woman was offered the choice of commencing insulin pump therapy or remaining on a conventional insulin regime. Estimated fetal weight and fetal growth velocity were calculated from routinely collected third trimester ultrasound biometry and expressed as standard deviation (Z) scores. RESULTS: Eighteen women commenced insulin pump therapy. There was no difference in pre-conception glycosylated haemoglobin A1c concentrations (HbA1c) between pump and conventional therapy groups (mean HbA1c 7.62 versus 8.01; p=0.49) or third trimester glycaemic control (mean HbA1c 6.63 versus 6.44; p=0.51). Women using pump therapy had similar mean growth velocity Z scores (1.5 versus 1.36; p=0.83), similar mean estimated fetal weight Z scores prior to delivery (2.80 versus 2.16; p=0.16) and similar mean birthweight Z scores (2.09 versus 2.00; p=0.86) compared to women using conventional insulin therapy. CONCLUSION: This small, non-randomised study suggests that the use of insulin pump therapy offers no benefit in terms of normalising fetal growth velocity, fetal size, birthweight or improving maternal glycaemic control compared to conventional insulin therapy.     

Raloxifene modifies the insulin sensitivity and lipid profile of postmenopausal insulin resistant women

Abstract

Objective: To investigate the effects of raloxifene on the insulin sensitivity and lipid profile in insulin-sensitive and insulin-resistant postmenopausal women.

Study design: This placebo-controlled, double-blind, randomized study involved 64 postmenopausal women aged between 45 and 55 years. All subjects were screened with the insulin resistance homeostasis model assessment (IR-HOMA) and those patients in the lowest quartile (n?=?16) were assigned as insulin sensitive and those in the highest quartile as insulin resistant (n?=?16). Patients in both groups received either raloxifene hydrochloride (60?mg/day) or a placebo for a period of 12 weeks. Insulin sensitivity, the serum lipid profile and anthropometric measurements were established before and after therapy.

Results: Women with the highest IR-HOMA scores were associated with a significantly higher weight, body mass index, waist and waist-to-hip ratio (p?<?0.05). Raloxifene significantly reduced the IR-HOMA scores from 5.76?±?2.91 to 1.93?±?0.96 (p?=?0.02) and modified the lipid profile in insulin-resistant patients when compared with the placebo group and those patients receiving raloxifene in the insulin-sensitive group.

Conclusion: Raloxifene reduced insulin resistance and modified the lipid profile in insulin-resistant postmenopausal women.     

Reproducibility of the measurement of insulin sensitivity by the modified insulin suppression test.

A significant increase in insulin resistance has been implicated in many human diseases and the absence of a simple, accurate, reproducible measurement of in vivo insulin sensitivity has become a major concern. In order to evaluate the reproducibility of insulin sensitivity measured by the modified insulin suppression test, 12 healthy young Chinese men were subjected to the same test two weeks apart. After three days on a standard diet and an overnight fast, somatostatin (350 micrograms/h), insulin (25 mU/m2/min) and glucose (240 mg/m2/min) were infused concomitantly for three hours. A steady state plasma glucose (SSPG) concentration achieved during the last 30 minutes of infusion represented the measurement of insulin sensitivity. Comparisons between the metabolic clearance rate of insulin (MCRi), plasma total triglyceride and lipoprotein cholesterol fractions on two different days were carried out. The results indicated that mean SSPG concentrations on Day 1 (5.73 +/- 0.43 mmol/L) correlated with mean SSPG concentrations on Day 14 (5.51 +/- 0.38 mmol/L; r = 0.82, p < 0.002). The relationship slope did not differ from 1 (0.74, p > 0.05), the intercept was close to the origin (1.24 mmol/L, p > 0.05) and the mean coefficient of intra-individual variation was 10.3%. There was no difference between the MCRi for Day 1 and Day 14 (529 +/- 26 vs 526 +/- 24 mL/m2/min, p = NS), with a mean coefficient of intra-individual variation of 6.9%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic insulin in gestational diabetes

Patients with gestational diabetes were divided into two groups according to the results of three-hour oral glucose tolerance tests. Those with fasting euglycemia (serum glucose 95 mg/dL or lower) on oral glucose tolerance test (class A) were treated with diet alone, whereas those with fasting hyperglycemia on oral glucose tolerance test (class A/B) were treated with both diet and insulin (15 U neutral protamine Hagedorn insulin before breakfast). The frequency of macrosomia (birth weight more than 4000 g) among class A/B gestational diabetics was 16.2%, which was significantly greater than the 5.6% incidence in class A diabetics and the 6.4% incidence in controls. After controlling for potential confounding risk factors, it was determined that class A diabetics had a frequency of macrosomia no different from that of nondiabetics. Nonobese gestational diabetics with fasting hyperglycemia (class A/Bs), who were treated with diet and prophylactic insulin, also had a frequency of macrosomia no different from that of nondiabetics or class A diabetics. However, the diet and insulin regimen did not prevent excess macrosomia in class A/B diabetics who were obese.     

Impaired insulin action on granulosa-lutein cells in women with polycystic ovary syndrome and insulin resistance

We studied the in vitro response to insulin of granulosalutein cells derived from patients with polycystic ovary syndrome (PCOS) and clinically defined insulin resistance. Insulin sensitivity was assessed by continuous infusion of glucose with model assessment test (CIGMA). Insulin resistant (PCOS-IR; n = 8), non-insulin resistant (PCOS-NIR; n = 9) patients with PCOS, and women with tubal factor infertility (TF; n = 8) underwent controlled ovarian stimulation with long-term gonadotropin-releasing hormone (GnRH) agonist, recombinant follicle stimulating hormone (FSH), and in vitro fertilization. Primary cultures of granulosa-lutein cells were incubated with insulin (10, 100, 500 ng/ml) and/or luteinzing hormone (LH) (10, 100 ng/ml) in the presence of low density lipoprotein (100 μg/ml). The progesterone and lactate accumulation were measured in the culture medium. LH potently stimulated the progesterone secretion in all groups. Insulin alone had no effect on progesterone release in any of the groups, but stimulated lactate formation in the PCOS-NIR and TF groups. Insulin augmented the effect of LH on progesterone secretion selectively in the PCOS-NIR group. The expression of the insulin receptor was determined by Western blotting in separate cultures of granulosa-lutein cells, and showed receptor down-regulation in the PCOS-IR patients. We infer that the in vitro effect of insulin on progesterone and lactate release by granulosa-lutein cells is impaired in insulin resistant PCOS patients.     

Effect of hormone replacement therapy on insulin secretion and insulin sensitivity in postmenopausal diabetic women

The aim of the present study was to evaluate the effect of three different combinations of hormone replacement therapy (HRT) on insulin secretion, peripheral insulin sensitivity, serum lipid levels and parameters of oxidative stress. Seven type II diabetic women of mean age 55.4 ± 4.7 years, who had been menopausal for an average of 5 years, were enrolled in the study. Phases of insulin secretion - first (FPIS) and second (SPIS) - and the area under the curve (AUC) for insulin secretion were studied during an intravenous glucose tolerance test (IVGTT). Insulin sensitivity was determined using the manual euglycemic-hyperinsulinemic clamp technique. Three different HRT combinations were applied consecutively for 3-month periods: estradiol valerate plus cyproterone acetate (Climen^®); transdermal 17β-estradiol (Systen TTS 50^®) plus dydrogesterone (Duphaston^®) 10 mg daily for 10 days a month; oral 17β-estradiol plus dydrogesterone (Femoston^®) for 14 days a month. A group of nine women with normal glucose tolerance (according to World Health Organization criteria during a 75-g oral glucose tolerance test (OGTT)), of mean age 50.1 ± 8.2 years and mean body mass index 24.60 ± 2.01 kg/m², were also studied, and served as a control group. Insulin secretion improved significantly after Climen: FPIS increased by 16% and SPIS by 44%. Insulin sensitivity increased by 50% after Systen TTS 50 + Duphaston; fasting hyper-insulinemia was normalized and total antioxidant capacity of the serum (TAOCS) was significantly raised (p < 0.01). Femoston led to an increase in insulin sensitivity (by 23%) and in TAOCS (p < 0.05), while fasting hyperinsulinemia remained unchanged. HRT should be prescribed in type II diabetic postmenopausal women because of its favorable effect on existing pathophysiological defects. Cyproterone acetate should be preferred in cases with a predominant β-cell insulin secretion defect, while dydrogesterone in combination with a transdermal estrogen should be recommended in cases with leading insulin resistance.     

Serum inhibin levels in polycystic ovary syndrome: effect of insulin resistance and insulin secretion

Insulin resistance is common in women with the polycystic ovary syndrome. We investigated the relationship between insulin resistance and the serum inhibin concentration in a group of 19 women with polycystic ovary syndrome and eight control subjects at different phases of the menstrual cycle. Insulin resistance was measured by the frequently sampled intravenous glucose tolerance test, and inhibin was measured by a specific radioimmunoassay. Insulin sensitivity (mean +/- SE) was significantly reduced in the polycystic ovary syndrome group compared with controls: reduced insulin sensitivity 46.7 +/- 5.0 min-1/(nmol/mL), normally insulin-sensitive 106.6 +/- 11.7 min-1/(nmol/mL) (P less than .01). The women with polycystic ovary syndrome had inhibin levels (126 +/- 15.2 microLEq/mL) comparable to those found during the early follicular phase of the control group (117 +/- 22.1 microLEq/mL), but significantly lower than late follicular phase (259 +/- 25.6 microLEq/mL) or luteal phase (448 +/- 91.8 microLEq/mL) levels in the control group. No association was found between the degree of insulin resistance and the inhibin concentration, which remained unaltered over a 3-hour period despite maximal stimulation of endogenous insulin secretion. The inhibin concentrations in polycystic ovary syndrome may reflect impaired follicular maturation. Inhibin secretion is not acutely affected by insulin secretion in normal or in hyperandrogenic women.     

Impaired insulin action on granulosa-lutein cells in women with polycystic ovary syndrome and insulin resistance.

We studied the in vitro response to insulin of granulosa-lutein cells derived from patients with polycystic ovary syndrome (PCOS) and clinically defined insulin resistance. Insulin sensitivity was assessed by continuous infusion of glucose with model assessment test (CIGMA). Insulin resistant (PCOS-IR; n = 8), noninsulin resistant (PCOS-NIR; n = 9) patients with PCOS, and women with tubal factor infertility (TF; n = 8) underwent controlled ovarian stimulation with long-term gonadotropin-releasing hormone (GnRH) agonist, recombinant follicle stimulating hormone (FSH), and in vitro fertilization. Primary cultures of granulosa-lutein cells were incubated with insulin (10, 100, 500 ng/ml) and/or luteinizing hormone (LH) (10, 100 ng/ml) in the presence of low density lipoprotein (100 micrograms/ml). The progesterone and lactate accumulation were measured in the culture medium. LH potently stimulated the progesterone secretion in all groups. Insulin alone had no effect on progesterone release in any of the groups, but stimulated lactate formation in the PCOS-NIR and TF groups. Insulin augmented the effect of LH on progesterone secretion selectively in the PCOS-NIR group. The expression of the insulin receptor was determined by Western blotting in separate cultures of granulosa-lutein cells, and showed receptor down-regulation in the PCOS-IR patients. We infer that the in vitro effect of insulin on progesterone and lactate release by granulosa-lutein cells is impaired in insulin resistant PCOS patients.     

Changes in insulin therapy during pregnancy

Care of the diabetic pregnant woman requires a proper understanding of anticipated changes in insulin therapy as a guide for establishing and maintaining strict glucose control. Changes in daily insulin doses were reviewed for 58 pregnancies of 50 insulin-dependent women who were followed for 26 +/- 3 weeks (mean +/- 1 SD) before delivery. By late gestation, insulin was administered on two or three occasions each day using a combination of regular--and intermediate--acting preparations in 55 (95%) pregnancies. Regardless of the metabolic control and duration of diabetes, averaged daily insulin requirements increased twofold from earlier in pregnancy. Following initial hospitalization, insulin requirements often decreased before increasing almost linearly between 2 and 9 months gestation. Fluctuations in insulin requirements were greatest during the last trimester. Insulin demand dropped precipitously after delivery and was two-thirds the averaged prepregnancy insulin dose or one-third the dose at 9 months gestation by the third postpartum day. The total average insulin dose was the same as that before pregnancy by the end of the first postpartum week. Explanations for these changes in prescribing insulin are described.     

The ovary and insulin resistance]

Insulin resistance appears to be responsible of approximately half of the cases of polycystic ovaries, the other half being probably provoked by an anomaly of the stimulation of ovaries by an excess of LH. Nevertheless, it is likely that in most cases the two factors conjugate. The excess of androgen production by the ovarian stroma is one of the major symptoms of this disease. Today, however, the diagnosis is carried mainly with the assistance of ultra-sounds which, besides the increased ovarian volume, have permitted to discover an increased ovarian stromal vascularity. Two essential datas derive from the whole works: the increased frequency of ovarian hyperstimulation syndrome and the great number of metabolic complications which requires an endocrinological supervision. But the most recent works focus on the extension to all ages of this form of pathology: from the intra-uterine life to the post menopause; and on the hereditary character of this disease. The mystery remains concerning the mechanism of the favourable effect in clomifene resistant PCOS, of surgical and laparoscopic methods of ovulation induction to which it may be useful to resort after mature consideration. More recently the benefit at the administration of metformine has been confirmed by several works.     

妊娠期胰岛素的应用

无论妊娠合并糖尿病或者妊娠期糖尿病（GDM），在妊娠期均应强调早期治疗、综合治疗、治疗措施个体化的原则。GDM一经确诊，应加强母儿监测，及时干预，控制妊娠期血糖，以降低母儿并发症，改善围生儿结局，减少或延缓产妇在产后发展成为2型糖尿病（T2DM）的可能，并且预防子代T2DM的发生。     

Caffeine and insulin resistance in pregnancy

Outside pregnancy, acute caffeine consumption is associated with insulin resistance. We investigated if during pregnancy plasma concentrations of caffeine and its metabolite, paraxanthine, were associated with insulin resistance. Caffeine, paraxanthine, glucose, and insulin were measured and insulin resistance estimated by homeostasis model assessment (HOMA) in banked samples from 251 fasting subjects at mean gestational age of 20.3?±?2.0 weeks. Analysis of covariance and adjusted logistic regression were performed. Most (96.4%) women had caffeine and/or paraxanthine present. Caffeine concentrations in the upper two quartiles (>266 ng/mL) were associated with threefold higher odds of having higher insulin resistance estimated by log HOMA ≥75th percentile (third quartile odds ratio [OR], 3.02; 95% confidence interval [CI]: 1.21 to 7.54 and fourth quartile OR, 2.95; 95% CI: 1.19 to 7.31). Paraxanthine concentrations in the upper quartile (>392 ng/mL) were also associated with threefold higher odds of having higher insulin resistance (OR, 3.04; 95% CI: 1.28 to 7.25). Adjusted mean HOMA in the first caffeine-to-paraxanthine ratio quartile was 1.5?±?2.2 versus 1.3?±?2.3 in the fourth quartile ( P?相似文献