Proinsulin in pregnant women with normal glucose tolerance or mild gestational diabetes mellitus.

Pregnancy is characterized by peripheral insulin resistance, which is physiologically compensated by an increase in insulin secretion. Type 2 diabetes and impaired glucose tolerance (IGT) have been associated with an inappropriate increase in insulin precursors, namely proinsulin. The aim of this study was to determine levels of proinsulin (PI), specific insulin (SI) and the proinsulin-to-specific insulin (PI/SI) ratio in consecutive pregnant women (n = 209) with normal glucose tolerance (NGT), as assessed by a 2h oral glucose tolerance test, and with mild gestational diabetes (GDM), in comparison to 32 healthy, non-pregnant women. Furthermore, we related these variables to surrogate markers of insulin resistance and insulin secretion. We found no significant differences in the levels of PI and the PI/ SI ratio between pregnant and non-pregnant women (PI: 5.0 +/- 3.6 vs. 4.8 +/- 3.5 pmol/L, p = NS), and between pregnant women with mild GDM and NGT (PI: 5.4 +/- 2.4 vs. 4.9 +/- 3.9 pmol/L, p = NS). SI was elevated in women with mild GDM (112.2 +/- 47.3 vs. 94.8 +/- 43.0 pmol/L in NGT, p=0.02). PI was related to fasting glucose (r = 0.17, p < 0.02), but not post-load glucose levels, and to fasting insulin [specific insulin: r = 0.67, p = 0.0001; total immunoreactive insulin (IRI): r = 0.69, p = 0.0001], as well as post-load insulin levels (IRI at 120 min: r = 0.18, p < 0.03). The PI/SI ratio showed no association with fasting or post-load glucose or insulin levels. Pregnant women presented with a metabolic pattern suggestive of enhanced insulin resistance, namely increased fasting and post-load insulin levels. In women with mild GDM, fasting and post-load hyperglycemia, as well as an additional increase in insulin resistance was found. Group differences weakened when accounting for differences in body weight. The data of the present study suggest that in normal pregnancy as well as mild GDM metabolic alterations including enhanced insulin resistance and hyperglycemia do not result in an increase in circulating levels of proinsulin, both in absolute terms and relative to levels of specific insulin, as indicated by the proinsulin-to-specific insulin ratio.     

瘦素与妊娠糖尿病患者胰岛素抵抗及胎儿发育的相关性

目的 探讨瘦素及可溶性瘦素受体(sLR)在妊娠糖尿病发病及胎儿发育中的作用.方法 选取2014年1月至12月在厦门大学附属成功医院连续产检并分娩的673名孕妇为研究对象,跟踪随访至孕晚期.根据糖耐量试验结果,采用随机抽样法选取50例血糖控制良好的妊娠糖尿病患者纳入妊娠糖尿病组,根据一般资料进行匹配选取50名糖耐量试验结果阴性者纳入正常妊娠组.根据妊娠周数分为孕早期和孕晚期亚组,比较两组不同孕期血清及脐血瘦素、sLR、脂联素、抵抗素及生化指标水平,计算稳态模型评估-胰岛素抵抗指数(HOMA-IR),精确测量新生儿生长发育指标,使用多元Logistic回归分析孕早期胰岛素抵抗的危险因素,同时采用Spearman相关性分析血清瘦素与sLR、脂联素、抵抗素及生化指标水平的相关性.结果 与正常妊娠组相比,妊娠糖尿病组孕早期血清瘦素、甘油三酯、总胆固醇、低密度脂蛋白-胆固醇(LDL-C)、空腹胰岛素(FINS)、HOMA-IR明显升高(t=0.938～6.864,P均＜0.05),sLR、脂联素显著降低(t=9.237、2.216,P均＜0.05),抵抗素、高密度脂蛋白-胆固醇(HDL-C)、空腹血糖差异无统计学意义(P均＞0.05).与正常妊娠组相比,妊娠糖尿病组孕晚期血清瘦素、抵抗素、空腹血糖、FINS、甘油三酯、总胆固醇、LDL-C、HOMA-IR明显升高(t=0.429 ～ 13.787,P均＜0.05),sLR、脂联素显著降低(t=2.216、5.623,P均＜0.05),HDL-C差异无统计学意义(P＞0.05).与正常妊娠组相比,妊娠糖尿病组脐血瘦素、抵抗素明显升高(t=1.007、11.857,P均＜0.05),sLR、脂联素显著降低(t=0.201、4.558,P均＜0.05).多元Logistic回归分析显示,瘦素(OR =1.288,95％ CI:1.137 ～4.370)、抵抗素(OR=1.223,95％CI:1.035～ 1.570)、总胆固醇(OR=1.216,95％CI:1.026 ～1.823)、甘油三酯(OR=1.357,95％CI:1.008～ 3.572)、LDL-C (OR=1.634,95％ CI:1.251～3.764)是妊娠糖尿病组孕早期发生胰岛素抵抗的独立危险因素,sLR (OR =0.714,95％ CI:0.161～0.893)、脂联素(OR =0.352,95％CI:0.112 ～0.510)是妊娠糖尿病组孕早期发生胰岛素抵抗的保护性因素.妊娠糖尿病组孕晚期母体血瘦素含量与sLR、脂联素均呈负相关(r=-0.16、-1.13,P均=0.000),与抵抗素呈正相关(r=0.269,P=0.019).妊娠糖尿病组脐血瘦素含量与sLR、脂联素均呈负相关(r=-0.147、-1.250,P均=0.000),与抵抗素、体重、Ponderal 指数均呈正相关(r =0.410、0.673、0.301,P均＜0.05),与头围、身长无关(P均＞0.05).结论 瘦素及sLR与妊娠糖尿病患者胰岛素抵抗存在相关性,但与胎儿宫内生长和发育无关.     

Do adiponectin,TNFα, leptin and CRP relate to insulin resistance in pregnancy? Studies in women with and without gestational diabetes,during and after pregnancy

BACKGROUND: The role of adiponectin, tumour necrosis factor alpha (TNFalpha), leptin and C-reactive protein in the insulin resistance of pregnancy is not clear. We measured their levels in women with gestational diabetes (GDM) and in controls, during and after pregnancy, and related them to insulin secretion and action. METHODS: Nineteen women with GDM and 19 BMI-matched healthy pregnant women underwent intravenous glucose tolerance tests in the third trimester of pregnancy and 4 months postpartum to determine insulin sensitivity (SI) and insulin secretion. Adiponectin, TNFalpha, leptin and high sensitivity CRP (hsCRP) were measured in fasted blood. RESULTS: Of the circulating factors, only leptin (r = -0.41, p = 0.01) correlated with SI in pregnancy. Leptin and hsCRP levels were elevated in pregnancy compared to postpartum (leptin (mean +/- SEM): 27.8 +/- 2.4 vs 19.3 +/- 2.1 ng/mL, p < 0.001; hsCRP: 5.2 +/- 0.7 vs 3.2 +/- 0.6 mg/L, p < 0.001). Adiponectin levels did not change from pregnancy to postpartum, despite a marked increase in SI. All four factors correlated with SI postpartum (adiponectin: r = 0.38, p = 0.01; TNFalpha: r = -0.48, p = 0.002; Leptin: r = -0.61, p = 0.001; hsCRP: r = -0.48, p = 0.002). TNFalpha correlated inversely with insulin secretion in pregnancy (r = -0.35, p = 0.03) and was significantly higher in the GDM group (2.62 +/- 0.3 vs 1.88 +/- 0.3 pg/mL, p = 0.01) in pregnancy. CONCLUSION: In our study, the influence of adiponectin, TNFalpha and hsCRP upon SI is overwhelmed by other factors in pregnancy. While leptin and SI correlated in pregnancy, it is unclear whether this represents cause or effect. Finally, TNFalpha may exert an inhibitory effect on insulin secretion in GDM, contributing to the associated hyperglycaemia.     

Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity

Hyperleptinemia may be part of the insulin resistance syndrome. We studied serum leptin in preeclampsia, which is an insulin-resistant state, and sought associations between leptin and insulin or insulin sensitivity during and after pregnancy. Twenty-two proteinuric preeclamptic women and 16 normotensive controls were studied during the third trimester. Leptin was higher in preeclampsia (mean +/- SE, 34.6 +/- 3.9 v 20.0 +/- 3.3 microg/L, P = .002) and correlated directly with the level of proteinuria (r = .47, P = .03) and normal pregnancy (r = .52, P = .04), whereas insulin sensitivity as assessed by an intravenous glucose tolerance test showed no relationship to leptin. Leptin was 19.0 +/- 3.6 microg/L in 14 preeclamptic women and 10.1 +/- 2.0 microg/L (P = .11) in 11 controls 3 months after delivery. Leptin correlated directly with insulin both in preeclamptic puerperal women (r = .63, P = .02) and in controls (r = .81, P = .003). Leptin and insulin sensitivity correlated only in preeclamptic puerperal women (r = -.59, P = .02). In conclusion, (1) serum leptin is elevated in preeclampsia, (2) insulin is an important determinant of serum leptin in preeclamptic and normotensive women both during pregnancy and in the puerperium, and (3) hyperleptinemia may be part of the insulin resistance syndrome also in women with prior preeclampsia.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R² = 56.2 %) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R² = 40.1 %). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the β-cell function both in men and women. © 1998 John Wiley & Sons, Ltd.     

Elevated serum acylated (biologically active) ghrelin and resistin levels associate with pregnancy-induced weight gain and insulin resistance

AIM: To study fasting biologically active serum ghrelin (RIA) and resistin (ELISA) levels in different trimesters of pregnancy (HP, n=45, 15 in each) and in gestational diabetes mellitus (GDM, n=30) compared to non-pregnant healthy women (NP, n=40) in correlation with TNF-alpha, soluble (s)TNF-receptor (R)-1, -2, leptin (ELISA), C-peptide (Cp, RIA) and Cp/blood glucose ratio (bg). STUDY DESIGN: Cross-sectional case control study. RESULTS: Acylated ghrelin levels were significantly increased (p<0.0001) in the 2nd (377+/-38pg/ml, X+/-S.D.) and decreased in the 3rd trimester (252+/-36) and in GDM (226+/-21) compared to NP controls (309+/-20) and HP women in the 1st trimester (314+/-41). Serum resistin levels were higher in the 1st (8.5+/-2.6ng/ml), 2nd (10.2+/-2.1) and 3rd (13.1+/-3.6) trimesters of pregnancy and in GDM (15.7+/-3.5) than in NP controls (6.5+/-2.3). Significant (p<0.01) negative linear correlations were found among fasting serum ghrelin and body mass index (BMI), the fasting C-peptide (Cp) level, C-peptide/blood glucose (Cp/bg) ratio, TNF-alpha, soluble (s)TNFR-2, leptin and resistin concentrations in both, HP and GDM groups. Significant positive correlations were observed between serum acylated ghrelin and adiponectin, and between BMI and fasting Cp, Cp/bg, TNF-alpha, sTNFR-1, -2 and leptin levels in both pregnant groups. CONCLUSION: Increased fasting serum acylated ghrelin concentrations in the 2nd trimester may associate with weight gain during pregnancy. Hyperresistinemia may also be associated with the pregnancy-induced insulin resistance. A negative regulatory feed-back mechanism between resistin, TNF-alpha and ghrelin may be hypothesized.     

Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance.

OBJECTIVE: To determine the predictive value of serum triglyceride levels (TG) for neonatal weight in pregnant women with positive diabetic screening but normal glucose tolerance. RESEARCH DESIGN AND METHODS: We enrolled 180 pregnant Caucasian women with positive diabetic screening. All women underwent a 3-h 100-g oral glucose tolerance test (OGTT) at 27th +/- 4 week of gestation. At the time of OGTT, we measured: fasting plasma glucose, fasting lipids profile and determined ApoE polymorphisms to evaluate the effects on lipid levels. In 83 women with normal glucose tolerance and at term delivery we evaluated the association between maternal serum TG, specific maternal parameters known to affect fetal growth and newborn weight. RESULTS: Based on OGTT, gestational diabetes mellitus (GDM) was diagnosed in 36 women (20%), impaired glucose tolerance (IGT) in 23 (13%), and normal glucose tolerance (NGT) in 121 (67%). Serum TG concentration was significantly higher in women with GDM (2.47 +/- 0.77 mmol/l) as compared with NGT (1.99 +/- 0.64 mmol/l) or IGT (1.98 +/- 0.81 mmol/l) (P < 0.01). ApoE3 allelic frequency was 86%, ApoE2 and ApoE4 were 5 and 9%, respectively. We found no clear-cut association between apoE genotype and serum TG concentration. Macrosomia and LGA newborns were more frequent in IGT than in GDM or NGT (P < 0.01). In the 83 women with positive diabetic screening but normal glucose tolerance who delivered at term, the incidence of LGA infants was significantly higher in those with TG levels higher than the 75th percentile (> 2.30 mmol/l) (21%) than in mothers who had normal TG levels (4.5%) (P < 0.05). Pre-pregnancy BMI (r(2) = 0.067), weight gain during pregnancy (r(2) = 0.062), fasting serum TG (r(2) = 0.09), and 2-h post-OGTT glucose levels (r(2) = 0.044) were all associated with neonatal body weight (all P < 0.05 or less). However, on a multiple regression analysis, only pre-pregnancy BMI (F-test = 7.26, P < 0.01), and fasting serum TG (F-test = 4.07, P < 0.01) were independently associated with birth weight. CONCLUSIONS: Pre-pregnancy BMI and fasting maternal serum TG determined in the last trimester of gestation were independently associated with neonatal birth weight in women with normal glucose tolerance, but positive screening test. TG levels measured in the third trimester of pregnancy are independent of the genetic polymorphism of ApoE.     

Gender differences in relation to leptin concentration and insulin sensitivity in nondiabetic Chinese subjects.

OBJECTIVE: To investigate the relationship between fasting plasma leptin concentrations and insulin resistance in Chinese men and women. DESIGN: Cross-sectional study design. SUBJECTS: Ninety-six nondiabetic Chinese (51 men and 45 women) with body mass index (BMI) between 18.4-35.8 kg/m2 were studied. MEASUREMENTS: Plasma glucose and insulin concentrations were measured every 30 min for 2 h after a 75 g oral glucose load. The degree of insulin resistance was assessed using a modified insulin suppression test. Plasma leptin values were determined by radioimmunoassay. RESULTS: Fasting plasma glucose, glucose areas, fasting insulin, insulin areas, most of the lipoprotein concentrations and steady state plasma glucose (SSPG) concentrations were relatively similar between men and women. Despite the fact that men had higher BMI values (26.1 +/- 0.5 vs 24.7 +/- 0.5 kg/m2, P < 0.05), fasting plasma leptin concentrations were significantly lower in men than in women (4.9 +/- 0.5 vs 9.0 +/- 0.8 ng/ml, P < 0.001). Fasting leptin values were positively related to SSPG concentrations by simple correlation analysis in both sexes. However, this relationship persisted in men (r = 0.513, P < 0.01) but not in women (r = 0.119, P = NS) after adjustment for BMI. Multiple regression analysis showed that SSPG concentrations, BMI, glucose and insulin responses together accounted for 62.5% and 52.2% of the variation in plasma leptin concentrations in Chinese men and women respectively. CONCLUSION: Fasting plasma leptin concentrations were lower in Chinese men than in Chinese women despite the higher BMI observed in men. After adjustment for BMI, plasma leptin values correlated with the degree of insulin resistance in men but not in women.     

C-reactive protein and gestational diabetes: the central role of maternal obesity

Acute-phase biomarkers such as C-reactive protein (CRP) and IL-6 have emerged as predictors of incident type 2 diabetes mellitus, implicating chronic subclinical inflammation as a factor in the pathophysiology of diabetes. Gestational diabetes (GDM) identifies a population of women at high risk of subsequent type 2 diabetes mellitus, representing an early stage in the natural history of the disease. In this context, we performed a cross-sectional study to determine whether markers of subclinical inflammation are elevated in patients with GDM. We studied 180 healthy pregnant women undergoing oral glucose tolerance testing in the late second or early third trimester. Based on oral glucose tolerance testing and prepregnancy body mass index (BMI), participants were stratified into four groups: 1) normal glucose tolerance (NGT) lean (BMI, <25 kg/m(2)) (n = 65); 2) NGT overweight (n = 28); 3) impaired glucose tolerance (n = 39); and 4) GDM (n = 48). Median CRP level was highest in overweight NGT subjects (8.8 mg/liter), followed by GDM (5.5 mg/liter), impaired glucose tolerance (4.4 mg/liter), and lean NGT (4.4 mg/liter) (overall P = 0.0297). CRP was significantly correlated with prepregnancy BMI (r = 0.38, P < 0.0001), followed by fasting insulin (r = 0.27, P = 0.0002) and fasting blood glucose (r = 0.18, P = 0.016). In multivariate linear regression analysis, prepregnancy BMI emerged as the most important determinant of CRP concentration, whereas glycemic tolerance status was not a significant factor. Furthermore, the observed stepwise increase in CRP per tertile of prepregnancy BMI was not significantly attenuated by glycemic tolerance status or factors known to be associated with GDM. In summary, we demonstrate that maternal serum levels of CRP are not related to GDM but rather correlate significantly with prepregnancy obesity. An independent contribution of CRP to risk of GDM could not be confirmed. These data suggest a model in which obesity mediates a systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and glucose dysregulation.     

Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease

OBJECTIVE: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children. DESIGN AND METHODS: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients. RESULTS: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001). CONCLUSIONS: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.     

Size at birth and plasma leptin concentrations in adult life

OBJECTIVE: To determine whether low birthweight is associated with higher plasma leptin concentrations in adult life and whether leptin contributes to the metabolic alterations in adults that are associated with reduced foetal growth. DESIGN: Measurement of plasma leptin concentrations in a group of 502 men and women, aged 61-73, who were born in Hertfordshire and for whom records of birth and infant weight are available. Glucose tolerance was measured with a standard 75 g oral glucose tolerance test. MEASUREMENTS: Leptin concentrations were assayed in fasting plasma samples using a radioimmunoassay. RESULTS: Leptin concentrations ranged from 1.4 to 128.9 (mean 13.4) ng/ml and were higher in the 193 women than the 309 men (23.4 vs. 7.1 ng/ml). In both sexes leptin concentrations correlated positively with body mass index (r=0.65 in both men and women). Leptin concentration also correlated with fasting insulin (r=0.41) and with glucose and insulin concentrations 2 h after a glucose load (r=0.19 and 0.49). Adults with lower birth or infant weight had higher leptin concentrations than those of higher birthweight with similar degrees of obesity (P=0.02 and 0.06, respectively). Although both 2 h glucose and insulin concentrations negatively correlated with birthweight (r=-0.17, P<0.001 and r=-0.18, P<0.001, respectively), regression analysis suggested that the higher levels of leptin in adults who had low birthweight did not explain the association between low birthweight and glucose or insulin concentrations. CONCLUSION: These results suggest that adults who had had low birthweight had higher plasma concentrations of leptin than would be expected from their degree of obesity. The higher leptin concentrations, however, do not account for the association between birthsize and glucose tolerance. They may be a consequence of the altered body composition, hyperinsulinaemia, and other long-term endocrine changes associated with reduced foetal growth.     

Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance.

Proinsulin release is increased relative to insulin secretion in subjects with type 2 diabetes, indicative of islet dysfunction. However, it has not been conclusively shown whether there is an increased relative proinsulin release in subjects with impaired glucose tolerance (IGT), i.e. whether it precedes the development of diabetes. We therefore determined the proinsulin to insulin ratios in the fasting state and after acute stimulation of insulin secretion in 23 postmenopausal women, aged 61-62 yr (mean +/- SD, 61.7 +/- 0.5 yr). Ten women had normal glucose tolerance (NGT), and 13 had IGT. The groups were matched for insulin sensitivity and did not differ in body mass index. Proinsulin and insulin secretion were measured after arginine stimulation (5 g, i.v.) at three glucose levels (fasting, 14 mmol/L, and >25 mmol/L), and the acute insulin (AIR(arg)) and proinsulin responses (APIR(arg)) were calculated as the mean 2-5 min postload increase. At fasting glucose, levels of insulin, proinsulin, or the proinsulin/insulin ratio (13.6 +/- 5.0% vs. 11.1 +/- 2.7%; P = NS) did not differ between NGT and IGT. Although the AIR(arg) values were decreased in the IGT group at all glucose levels (P < 0.05), the absolute proinsulin levels and the APIRs(arg) were similar between IGT and NGT women. Therefore, the IGT women had higher proinsulin/insulin ratios at 14 mmol/L (10.7 +/- 4.4% vs. 6.4 +/- 1.8%; P = 0.006) and more than 25 mmol/L glucose (11.4 +/- 5.2% vs. 6.7 +/- 2.1%; P = 0.007). The IGT group had increased APIR(arg)/AIR(arg) at fasting (2.2 +/- 1.4% vs. 1.3 +/- 0.6%; P = 0.047) and more than 25 mmol/L glucose (3.5 +/- 1.6% vs. 2.3 +/- 0.7%; P = 0.037). We conclude that women with IGT exhibit increased relative proinsulin secretion, suggesting a defect in the intracellular proinsulin processing before diabetes develops.     

Low levels of Sex-Hormone-Binding Globulin predict insulin requirement in patients with gestational diabetes mellitus.

Low Sex-Hormone-Binding Globulin (SHBG) levels--indicating a state of hyperandrogenicity--are associated with a higher risk for the development of non-insulin dependent diabetes (NIDDM) in women and are accepted as a marker of muscular insulin resistance. To analyze whether low SHBG values are also present in patients with gestational diabetes, we investigated levels of SHBG in 42 patients with gestational diabetes mellitus (GDM) in comparison with 48 pregnant women with normal glucose tolerance (NGT). Beside maternal parameters like body-mass index (BMI), HbA1c, fasting, 1- and 2-hour blood glucose and insulin concentrations, parameters of the new-borns (head-circumference, body weight, height and sex) were recorded. Maternal and neonatal variables were then related to SHBG levels. Both groups showed no differences in BMI, height, weight or age of gestation. Patients with GDM revealed significantly lower levels of SHBG than pregnant women with NGT(512 +/- 249 nmol/l vs. 643 +/- 137 nmol/l; p < 0.01). In patients with severe GDM and insulin therapy significantly lower levels of SHBG than in those with dietary treatment only were found (223 +/- 210 nmol/l vs. 592 +/- 102 nmol/l; p < 0.001). SHBG was inversely correlated to BMI (r = - 0.30; p < 0.01), 1-hour (r = - 0.20; p < 0.05) and 2-hour blood glucose levels (r = - 0.30; p <0.01). In summary, we found significantly lower levels of SHBG in patients with GDM, especially in those who developed severe GDM and required insulin therapy during the last months of pregnancy.     

血清瘦素水平与胰岛素原、真胰岛素及胰岛素敏感性的关系

目的　研究中国人群空腹瘦素水平与真胰岛素 (TI)、胰岛素原 (PI)、PI/TI比值及胰岛素敏感性之间的关系。方法　 90 2例非糖尿病者均系 2 0 0 0年接受糖尿病流行病学调查者。测定空腹瘦素、TI和PI浓度以及空腹及餐后 2h血糖。瘦素、TI及PI检测采用本室建立的特异的酶联免疫分析法 (ELISA)。胰岛素敏感性以HOMA胰岛素抵抗指数 (HOMA IR)评价。结果　血清瘦素水平女性高于男性。相关分析显示血清瘦素水平与空腹TI、PI及HOMA IR显著正相关 (男性 792例 ,r分别为0 345、0 2 36和 0 364 ;女性 1 1 0例 ,r分别为 0 574、0 375和 0 576 ,P <0 0 0 1 ) ,但与空腹血糖仅在男性呈弱相关 (r=0 1 5 ,P =0 0 1 5) ,与空腹PI/TI比值不相关。在调整年龄、体重指数 (BMI)和腰臀围比(WHR)后 ,尽管相关性减弱 ,瘦素水平仍然与TI、PI以及HOMA IR显著相关。结论　本组的血清瘦素浓度与TI、PI以及胰岛素抵抗显著正相关 ,且在一定程度上独立于肥胖和脂肪分布。瘦素水平高或瘦素抵抗的个体可能存在高胰岛素血症和胰岛素抵抗 ,提示其瘦素 胰岛素轴的调节异常。本研究未发现瘦素水平与空腹PI/TI比值的相关 ,提示瘦素可能与这一反映胰岛 β细胞的功能异常的标志无关。本研究揭示的高瘦素 高胰岛素血症或胰岛素抵抗之间的     

The degree of hyperinsulinemia and impaired glucose tolerance predicts plasma leptin concentrations in women only: a new exploratory paradigm

Plasma leptin has been shown to correlate positively with many indices of obesity, as well as insulin resistance. For a given body weight, the levels are higher in women than in men, but the reasons for this difference are not clear. Insulin has been shown to stimulate leptin production by adipose tissue in vivo and in vitro. Previous studies have reported that leptin levels are similar in diabetic and nondiabetic individuals. However, these studies were not performed in newly diagnosed diabetics, and other variables (such as gender) could have confounded the results. Therefore, the goal of the present cross-sectional study is to examine the effect of metabolic variables (such as glucose and insulin) on plasma leptin concentrations in men and women separately. We measured leptin levels in 48 subjects (17 with newly diagnosed type 2 diabetes mellitus, 13 with impaired glucose tolerance [IGT], and 18 normal individuals). The 3 groups were well matched for gender, age, and body mass index (BMI). When adjusted for the BMI and gender, a statistically significant gender-related difference in mean plasma leptin was observed across the 3 glucose tolerance subgroups (P < .03 by analysis of covariance [ANCOVA]). More specifically, plasma leptin levels were, on average, 44% lower in women with diabetes or IGT versus normal women (P < .02). No such between-group difference was observed in the men. In univariate analysis in the same female subgroup, plasma leptin correlated positively with fasting insulin (rs = +.43, P < .06) and negatively with 2-hour post-75-g glucose load plasma glucose concentration (rs = -.54, P < .02). In a multiple regression model controlling for the BMI in the female subgroup, circulating insulin and glucose concentrations 2 hours after the 75-g glucose load were good predictors of fasting plasma leptin (r = +.38, P = .02 and r = -.70, P < .001, respectively). Leptin levels in women appear to be influenced independently and to an important degree by ambient plasma glucose and plasma insulin concentrations. These findings suggest that the synthesis of leptin by adipose tissue is more susceptible to in vivo regulation by insulin and glucose in women than in men. Plasma leptin concentrations were also lower in women with IGT or type 2 diabetes versus normal women, suggesting that fasting and/or postprandial hyperglycemia interferes with the stimulatory effect of plasma insulin on the synthesis of leptin by adipose tissue in women only.     

Decreased soluble leptin receptor levels in women with polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level. DESIGN: We assessed the correlation of metabolic and endocrine parameters with leptin and sOB-R levels in 122 PCOS women (aged 27 +/- 5.7 years) and 81 healthy controls (aged 25 +/- 4.0 years). METHODS: Leptin and sOB-R levels were measured using ELISA kits. In addition, anthropometric variables, body fat and endocrine parameters were evaluated and a glucose tolerance test performed to assess indices of insulin resistance and glucose metabolism. RESULTS: In PCOS patients, no correlation was found between leptin or sOB-R and parameters of hyper-androgenism. However, as expected, body mass index (BMI), body fat, waist circumference and indices of insulin resistance were significantly correlated with leptin in PCOS subjects and controls. In a subgroup analysis of lean, overweight and obese PCOS patients, significant differences were found in leptin (29.7 +/- 20.7 vs 45.4 +/- 25.0 vs 67.7 +/- 28.8 ng/ml, P < 0.0001) and sOB-R (8.0 +/- 3.4 vs 6.4 +/- 2.5 vs 5.7 +/- 2.3 ng/ml, P < 0.05). Compared with BMI-matched controls, lean PCOS patients had lower sOB-R levels (8.0 +/- 3.4 vs 12.7 +/- 4.7 ng/ml, P < 0.0001) and higher free leptin indices (4.5 +/- 3.9 vs 2.8 +/- 2.2, P = 0.0285). CONCLUSION: Taking into account that low sOB-R levels supposedly compensate diminished leptin action, PCOS per se might cause leptin resistance.     

Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia.

OBJECTIVE: Regulation of growth hormone (GH) receptor expression and hence tissue GH sensitivity may be important for the conflicting results found in treatment studies with recombinant growth hormone in chronic heart failure (CHF). Growth hormone-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor and is closely related to measures of body composition and, specifically, to size of visceral fat tissue. Leptin, the adipocyte specific (ob) gene product, has been proposed as the signal linking adipose tissue and GHBP/GH-receptor expression. CHF has recently been shown to be a hyperleptinaemic and insulin-resistant state regardless of aetiology. This study aimed to examine the influence of leptin on GHBP in CHF patients with and without cardiac cachexia compared with healthy control subjects. METHODS: We studied 47 male patients with CHF (mean age 61+/-2 years, New York Heart Association (NYHA)-class 2.7+/-0.1, left ventricular ejection fraction (LVEF) 28+/-2%, peak oxygen consumption 16.8+/-0.9 ml/kg/min) and 21 male healthy controls of similar age. Of the CHF patients, 19 were cachectic (cCHF; non-oedematous weight loss >7.5% over at least 6 months) and 28 non-cachectic (ncCHF; similar for age and LVEF). Insulin sensitivity was assessed by an intravenous glucose tolerance test using the minimal model approach. RESULTS: Compared with healthy controls, patients had elevated levels of leptin (7.6+/-0.7 vs 4.8+/-0.7 ng/ml, P<0.05), insulin (76.2+/-8.9 vs 41.4+/-6.0 pmol/l, P<0.01), and reduced insulin sensitivity (2.43+/-0.2 vs 3.48+/-0.3 min(-1).microU.ml(-1).10(4), P<0.005) but similar GHBP levels (901+/-73 vs 903+/-95 pmol/l). Leptin levels were increased in ncCHF (9.11+/-1.0 ng/ml, P=0.001) but were not different from normal in cCHF (5.32+/-0.7 ng/ml, P>0.5). After correction for total body fat mass, both ncCHF and cCHF were hyperleptinaemic (41.8+/-3.8 and 37.9+/-0.38 vs 24.4+/-2.1 ng/ml/100 g, ANOVA P=0.001). In both patients and controls there was a direct correlation between leptin levels and GHBP (r=0.70 and r=0.71 respectively, both P<0.0001). This relationship was stronger than between GHBP and several parameters of body composition (body mass index (BMI), total and regional body fat mass or % body fat) and held true when sub-groups were tested individually (ncCHF r=0.62, P<0.001; cCHF r=0.79, P<0.0001). In multivariate regression analysis in all CHF patients, serum leptin levels emerged as the strongest predictor of GHBP, independent of age, BMI, total and regional fat mass or % body fat, fasting insulin level and insulin sensitivity. CONCLUSION: Fat mass corrected leptin levels are elevated in CHF patients with and without cachexia. Reduced total fat mass may account for lower leptin levels in cachectic CHF patients compared with non cachectic patients. Leptin strongly predicts GHBP levels in CHF regardless of its hyperleptinaemic state or severely altered body composition as in cardiac cachexia. Leptin could be the signalling link between adipose tissue and GHBP/GH receptor expression in CHF.     

Plasma leptin concentration in patients with Type 2 diabetes: relationship to cardiovascular disease risk factors and insulin resistance.

AIMS: The aim of this study was to evaluate the relationship of obesity, leptin, insulin resistance and C-reactive protein (CRP) with coronary heart disease (CHD) risk factors in patients with Type 2 diabetes mellitus (DM) with CHD compared with those with Type 2 DM without CHD. METHODS: Leptin, CRP (high sensitivity assay), fasting plasma insulin, glucose, HbA(1c) and full lipid profile were determined in 58 Type 2 diabetic patients with CHD and 87 Type 2 DM patients without CHD. RESULTS: were compared between those with and without CHD. Univariate correlation as well as logistic regression analyses were used to relate these markers with traditional CHD risk factors. RESULTS: Leptin showed significant correlations with BMI (r = 0.59; P < or = 0.0001), waist circumference (r = 0.45; P < 0.0001), CRP (r = 0.36; P < 0.0001), and fasting insulin (r = 0.53; P < 0.0001) as well as with systolic (r = 0.23; P = 0.007) and diastolic (r = 0.23; P = 0.007) blood pressure. However, when those with and without CHD were compared only age (P < 0.0001), duration of diabetes (P < 0.001) and degree of microalbuminuria (P = 0.02) were significantly higher in patients with CHD. Leptin (P = 0.49), CRP (P = 0.19) and lipid parameters were not significantly different between the two groups. CONCLUSION: Our study confirms a relationship between leptin and CRP with CHD risk factors. The lack of significant difference when patients with and without CHD are compared may be due to the potential confounding effects of treatment with aspirin and statins.     

Does parity increase insulin resistance during pregnancy?

AIMS: To study the effect of parity on impairment of insulin sensitivity during pregnancy and on the risk of gestational diabetes (GDM). METHODS: We studied the relationship between parity and peripheral insulin sensitivity index (ISI(OGTT)) or GDM in 1880 caucasian women, who underwent a 100-g, 3-h oral glucose tolerance test (OGTT) between the 24th and 28th gestational week and in 75 women who underwent an OGTT in two consecutive pregnancies. A proxy for beta-cell function (basal plasma C peptide/fasting plasma glucose; CP/FPG) was also measured. RESULTS: By univariate analysis parity was related to decreased ISI(OGTT) and to increased CP/FPG in those with parity > 3 and likewise GDM, diagnosed in 124 women (6.58%), was linearly related to parity (P = 0.0034) and strongly age dependent. The relationships between parity and ISI(OGTT), CP/FPG and GDM were no longer significant after adjustment for age, pregestational body mass index (BMI), and weight gain. GDM was significantly related to age and pregestational weight, while ISI(OGTT) and CP/FPG were inversely related to prepregnancy BMI or weight gain. In comparison with the index pregnancy, the subsequent pregnancy was characterized by an increase in actual and prepregnancy BMI, in 2 h area under curve (AUC) glucose and by a decrease in ISI(OGTT) (P = 0.0001). The longer the time interval between pregnancies and the higher the increment in pregestational BMI or in weight gain during the pregnancy, the greater were the ISI(OGTT) decrease and 2-h AUC glucose increase. CONCLUSIONS: Parity is not directly linked to insulin sensitivity deterioration, to CP/FPG increase during pregnancy, or to GDM appearance, although it is linked through the mediation of progressive ageing and weight gain either before or during pregnancy, when there is a sufficiently long time interval between pregnancies.     

High plasma leptin concentrations in hypertensive men but not in hypertensive women.

OBJECTIVE: Previous studies on humans have reported higher leptin levels in women than in men, independent of body fat, and leptin has been correlated with insulin resistance in men but not in women. Since insulin resistance is thought to play a role in raising blood pressure, we investigated sex differences in leptin concentrations between hypertensive and normotensive individuals. METHODS: Ninety-two nondiabetic hypertensive patients (48 men and 44 women) and 92 age, body mass index (BMI)-matched normotensive control individuals were studied. Fasting plasma glucose, insulin, leptin and lipoprotein concentrations, glucose and insulin responses to 75 g oral glucose tolerance test (OGTT) and insulin suppression tests were determined. RESULTS: Fasting plasma leptin concentrations were higher in hypertensive men than in normotensive men (5.1 +/- 0.5 versus 3.9 +/- 0.4 ng/ml, P = 0.015). However, fasting plasma leptin concentrations were not significantly different between hypertensive and normotensive women (11.8 +/- 1.0 versus 10.9 +/- 1.0 ng/ml, P = 0.440). Fasting plasma leptin concentrations showed good correlation with BMI, body fat, fasting plasma insulin concentrations, and insulin area to OGTT in both men and women (all P < 0.001). However, fasting plasma leptin concentrations were related to steady-state plasma glucose (SSPG) concentrations, a measure of insulin sensitivity by insulin suppression test, in men only (P < 0.001). After adjustment for body fat amount, age and duration of hypertension, fasting plasma leptin levels still correlated significantly with SSPG concentrations in men. These four variables together accounted for a 67.9% variation in fasting plasma leptin levels in men. In women, body fat amount was the only significant determinant for plasma leptin levels. These four variables accounted for a 78.2% variation in plasma leptin levels in women. CONCLUSIONS: Our study confirmed a sex difference in leptin levels both in hypertensive and normotensive subjects. Higher plasma leptin concentrations in hypertensive men but not in hypertensive women when compared with normotensive control individuals was also demonstrated. These observations are consistent with the findings that plasma leptin is correlated with insulin sensitivity in men but not in women. Further studies are needed to understand the causes and consequences of sex effects on leptin in blood pressure regulation.