糖耐量损伤者瘦素受体基因Gln223Arg多态性研究

目的 探讨糖耐量受损者瘦素受体基因Gln223Arg多态性与血清瘦素水平及胰岛素抵抗的相关性.方法 从2007年1月至2009年8月在宁波市第二医院检验科进行糖耐量试验的门诊患者中筛选未接受任何抗糖尿病治疗且血常规及肝肾功能正常者.649名合格者据其糖耐量试验结果分为正常糖耐量组(n=298,男168名,女130名,平均年龄42岁)及糖耐量受损组(n=351,男188例,女163例,平均年龄46岁).检测甘油三酯、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、糖化血红蛋白、空腹血糖、胰岛素、瘦素、胰岛素抵抗及瘦素受体基因Gln223Arg多态性.采用t检验及χ~2检验分析瘦素受体基因Gln223Arg多态性与血清瘦素及胰岛素抵抗的相关性.结果 糖耐量受损组Gln223Gln基因型比例高于正常糖耐量组(χ~2=7.38,P<0.05),体重指数、甘油三酯、总胆固醇、低密度脂蛋白胆同醇、空腹血糖、糖化血红蛋白、胰岛素、胰岛素抵抗及瘦素水平显著高于正常糖耐量组(t值分别为13.168、10.816、6.704、16.459、26.553、9.521、17.108、28.122、5.829、6.602,均P<0.01).223Arg等位基因缺失的糖耐量受损患者总胆同醇、低密度脂蛋白胆固醇、胰岛素、胰岛素抵抗、瘦素高于携带该等位基因的糖耐量受损患者(t值分别为2.294、3.744、3.892、7.633、2.263、2.479,均P<0.05),但两者甘油三酯、高密度脂蛋白胆固醇、糖化血红蛋白及空腹血糖水平无显著差异(t值分别为0.343、-0.494、-1.175、1.404,均P>0.05).223Arg等位基因缺失(Gln223Gln)与男性糖耐量受损相关[比值比(OR)=2.32,P<0.01] ,与女性糖耐量受损无显著相关(OR=1.45,P>0.05).结论 瘦素受体基因Gln223Arg多态性与血脂、血清瘦素水平及男性糖耐量受损的发生、发展密切相关.     

Leptin gene and leptin receptor gene polymorphisms are associated with sweet preference and obesity

Leptin is an adipocyte-secreted hormone that regulates food intake and body weight, and that was recently reported to suppress sweet sensitivity in an animal model. We investigated the associations among sweet preference, obesity, and polymorphisms of the leptin gene (LEP) or leptin receptor gene (LEPR). A total of 3,653 residents randomly selected from among the citizens of Suita City, Osaka, Japan were enlisted as subjects, in whom we investigated sweet preference, clinical characteristics, including obesity and serum leptin level, and the polymorphisms of LEP and LEPR (G-2548A and A19G for LEP; R109K, R223Q, and rs3790439 for LEPR). We determined the associations among the parameters using logistic regression analysis, in order to consider potential confounding factors for sweet preference and/or obesity. The LEP A19G and LEPR R109K polymorphisms were associated with sweet preference, whereas the serum leptin level was not. Further, the LEPR 109KK genotype was found to be associated with obesity along with sweet preference. In conclusion, our results are the first to show associations of LEP and LEPR polymorphisms with sweet preference, and may provide useful information for diagnosis and treatment of lifestyle-related diseases.     

Hyperproinsulinaemia in impaired glucose tolerance is associated with a delayed insulin response to glucose

Summary In subjects with impaired glucose tolerance hyperproinsulinaemia has been shown to be predictive for progression to Type II (non-insulin-dependent) diabetes mellitus. These findings are often interpreted as early indicators of an impaired beta-cell function. The aim of our study was to assess the potential determinants of hyperproinsulinaemia in subjects with impaired glucose tolerance. The study group consisted of 110 subjects, 45–74 years of age with mean 2 h plasma glucose concentrations between 8.6 and 11.1 mmol/l following two oral glucose tolerance tests. Subsequently, the hyperglycaemic clamp technique (10 mmol/l, with a priming infusion of 20 % glucose solution, 150 mg/kg) was used to assess the beta-cell function (time needed to reach the insulin peak) and insulin sensitivity (M/I value: glucose metabolised divided by insulin response, 150–180 min). Results showed that the intact-proinsulin:insulin ratio increased with increasing time needed to reach the insulin peak (0.065, 0.079 and 0.101; time needed to reach the insulin peak ≤ 5 min, 5 to 15 min, > 15 min; p < 0.05). The split-proinsulin:insulin ratio showed a similar association with the time needed to reach the insulin peak. These associations were independent of age, sex, body mass index and waist:hip ratio. In conclusion, this study shows that relative hyperproinsulinaemia is associated with an impaired beta-cell function in a study group of subjects with impaired glucose tolerance selected after two oral glucose tolerance tests. [Diabetologia (1999) 42: 177–180] Received: 5 June 1998 and in final revised form: 5 October 1998     

Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women

OBJECTIVE: Postmenopausal estradiol (E(2)) levels vary widely between individuals and this variation is an important determinant of diseases such as osteoporosis. It has been suggested that the estrogen receptor alpha (ESR1) gene may influence peripheral E(2) levels, but the role of common sequence variations in the ESR1 gene is unclear. METHODS: In 631 postmenopausal women and 528 men from the Rotterdam Study, a population-based, prospective cohort study of individuals aged 55 years and over, ESR1 PvuII-XbaI haplotypes were determined and correlated with plasma E2 levels. RESULTS: In women, haplotype 1 (T-A) was significantly associated with an allele-dose-dependent decrease in E(2). After adjusting for age, body mass index, years since menopause and testosterone levels, plasma E(2) levels decreased by 1.90 pmol/l per allele copy of this haplotype (P < 0.05). Extreme genotypes, representing 23 and 27% of the population, varied by 3.93 pmol/l. No association with plasma testosterone was observed. In a subset of 446 women, no association of genotype with plasma concentrations of dehydroepiandrosterone sulfate, androstenedione or estrone was seen. In men, none of the sex hormone levels was associated with the ESR1 PvuII-XbaI haplotypes. CONCLUSION: We have demonstrated a role for genetic variations in the ESR1 gene in determining post-menopausal E(2) levels in women.     

Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated with severe overweight among obese women.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Variations in the PPARgamma gene may affect the function of the PPARgamma and, therefore, body adipocity. We investigated the frequencies of the Pro12Ala polymorphism in exon B and the silent CAC478CAT polymorphism in exon 6 of the PPARgamma gene and their effects on body weight, body composition, and energy expenditure in obese Finns. One hundred and seventy obese subjects [29 men and 141 women; body mass index (BMI), 35.7 +/- 3.8 kg/m2; age, 43 +/- 8 yr; mean +/- SD) participated in the study. The frequencies of the Ala12 allele in exon B and CAT478 allele in exon 6 were not significantly different between the obese and population-based control subjects (0.14 vs. 0.13 and 0.19 vs. 0.21, respectively). The polymorphisms were associated with increased BMI [Pro12Pro, 34.5 +/- 3.8; Pro12Ala, 34.8 +/- 3.1; Ala12Ala, 39.2 +/- 4.6 kg/m2 (P = 0.011); CAC478CAC, 34.5 +/- 3.8; CAC478CAT, 34.5 +/- 3.3; CAT478CAT, 37.7 +/- 4.1 kg/m2 (P = 0.046)]. In addition, the women with both Ala12Ala and CAT478CAT genotypes (n = 5) were significantly more obese compared with the women having both Pro12Pro and CAC478CAC genotypes (n = 85; BMI, 40.6 +/- 3.3 vs. 34.4 +/- 3.9 kg/m2; P = 0.001), and they had increased fat mass (46.8 +/- 9.1 vs. 36.8 +/- 7.5 kg; P = 0.005). In conclusion, the Pro12Ala and CAC478CAT polymorphisms in the PPARgamma gene are associated with severe overweight and increased fat mass among obese women.     

Metabolic abnormalities in obese patients with impaired glucose tolerance

It is not clear whether the glucose tolerance test diagnosis of Impaired Glucose Tolerance introduced in the recent revisions of diagnostic criteria is associated with abnormalities of intermediary metabolism other than glucose. Intermediary metabolite concentrations have therefore been studied fasting and in response to oral glucose in 35 patients referred with morbid obesity accompanied by either normal glucose tolerance (18 patients) or Impaired Glucose Tolerance (17 patients). When fasting obese patients with Impaired Glucose Tolerance had significantly higher blood total ketone body concentrations, 0.24 (0.19-0.30) vs 0.14 (0.12-0.16) mmol l-1 (antilog of mean-SE to mean + SE) (p less than 0.05), and lower blood glycerol concentrations, 0.14 +/- 0.01 vs 0.18 +/- 0.01 mmol l-1 (mean +/- SE) (p less than 0.05), than obese patients with normal glucose tolerance. There were no significant differences in fasting insulin, 16 (15-18) vs 14 (12-15) mU l-1, or glucose levels, 5.3 +/- 0.2 vs 5.1 +/- 0.2 mmol l-1. After oral glucose there was an exaggerated rise in glucose, insulin, lactate, and pyruvate in patients with Impaired Glucose Tolerance.     

Leptin response to oral glucose tolerance test in obese and nonobese premenopausal women

The objective of this study was to investigate the serum leptin response to oral glucose stimulation in a group of obese and nonobese normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese (BMI: 37.7 +/- 6.3 kg/m2) and 14 nonbese (BMI: 21.5 +/- 1.0 kg/m2) age-matched, healthy premenopausal women were included in the study. Serum glucose, insulin, and leptin levels were measured at 30 min intervals during the 120 min of an oral glucose tolerance test (OGTT). Mean serum glucose, insulin, and leptin levels were significantly higher in the obese group compared to nonobese subjects during OGTT. Except for a 120 min decrement noted in obese women, no changes occurred in serum leptin levels during oral glucose stimulation in both groups. As a conclusion, absence of a significant elevation in serum leptin levels during OGTT in our obese subjects compared to nonobese subjects may be related to their normal metabolic variables despite being abdominally obese and insulin resistant.     

肥胖和非肥胖糖耐量受损患者胰岛素敏感性和1相胰岛素分泌研究

目的研究肥胖和非肥胖糖耐量受损(IGT)患者的胰岛素敏感性和β细胞1相胰岛素分泌功能,以探讨在IGT患者中肥胖对胰岛素抵抗和1相胰岛素分泌的影响。方法共有99位受试者(包括正常对照者32名,肥胖IGT44例,非肥胖IGT23例)接受了口服75 g葡萄糖耐量试验(OGTT)和胰岛素改良的减少样本数(采血样12次)的Bergman微小模型技术结合静脉葡萄糖耐量试验(FSIGTT)。胰岛素抵抗由FSIGTT中胰岛素敏感性指数(SI)加以评估,而OGTT中糖负荷后30 min胰岛素增值与血糖增值之比值[ΔI30/ΔG30=(I30 min-I0 min) /(G30 min-G0 min)]和FSIGTT中急性胰岛素分泌反应(AIRg)则用以评价胰岛β细胞分泌功能。处理指数(DI =AIRg×SI)用于评价AIRg是否代偿机体的胰岛素抵抗。结果与正常对照组[(7.52±10.89)×10-4]相比,二组IGT患者之SI明显降低,而肥胖IGT组的SI[(1.72±1.11)×10-4]较非肥胖组[(3.15±1.49)×10-4]更低(均P<0.01); AIRg和ΔI30/ΔG30在正常组(412±191,14.45±8.47)和肥胖IGT组(378±235,17.02±11.30)之间差异无统计学意义,但均大于非肥胖组(196±160,8.93±6.69,均P<0.01);与正常组(2 851±1 180)相比,DI指数在二组IGT显著降低(595±485,584±517),但后二组间此值差异无统计学意义。SI与2 h胰岛素、体重指数、尿酸和胆固醇呈显著的负相关性(校正r2=0.603,P<0.01);而AIRg与ΔI30/ΔG30显著正相关,与空腹血糖负相关(校正r2=0.479,P<0.01)。结论IGT患者存在胰岛素抵抗和β细胞功能异常。与非肥胖IGT患者相比,肥胖IGT患者胰岛素抵抗程度更为严重,但胰岛β细胞胰岛素1相分泌相对充分。     

Analysis of the relationship between PPAR-gamma 2 gene variants and severe insulin resistance in obese patients with impaired glucose tolerance.

Mutations in the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene may cause obesity and insulin resistance. Therefore we investigated whether known variants in the PPAR-gamma 2 gene are associated with obesity and extreme insulin resistance in obese patients with impaired glucose tolerance (IGT). The Pro115 Gln, Pro12Ala, Pro467Leu, Val290Met and a silent polymorphism C478 T were examined in 48 subjects with IGT and insulin resistance (IR), characterized by euglycemic hyperinsulinemic clamps, and in 52 healthy insulin sensitive (IS) controls. We found one proband in the IR group with the Pro115 Gln variant. This subject showed a lower whole body glucose uptake (18 micromol/kg per min) compared to the entire IR group (29 micromol/kg per min). The body weight of the proband (BMI 28.5 kg/m2) was within the average of the IR group (30.3 +/- 0.8 kg/m2). The Pro12Ala variant was not associated with differences in BMI, in the degree of insulin resistance between the IR and IS group. The Pro467Leu, Val290Met mutations and the silent polymorphism CAC478CAT were not detected in any group. In conclusion, the Pro115 Gln variant, but not the Pro12Ala mutation in the PPAR-gamma 2 gene, could be a rare cause of severe insulin resistance.     

Screening for insulin receptor gene DNA polymorphisms associated with glucose intolerance in a Scandinavian population

Summary The significance of insulin receptor gene variants in the aetiology of Type 2 (non-insulin-dependent) diabetes mellitus has been investigated by analysis of restriction fragment length polymorphisms in a genetically homogeneous Swedish population. Seven polymorphisms were analysed, spanning functionally important regions of the insulin receptor locus. Four of these polymorphisms were mapped more accurately within the gene compared to previous studies. The genotype distribution was compared in 76 Type 2 diabetic patients and 84 healthy control subjects. No significant differences were found in the distribution of genotypes between diabetic and control subjects at the p< 0.01 level. In order to study the possible association between quantitative measures of glucose metabolism and these DNA polymorphisms, the fasting glucose and insulin concentrations were compared in the different genotype groups of control subjects and mildly diabetic patients treated with diet. No differences in fasting glucose or insulin concentrations were found at the p< 0.005 level of significance. In conclusion, no significant associations were found between insulin receptor gene DNA polymorphisms and glucose intolerance.     

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.     

Adipocytes in subjects with impaired fasting glucose and impaired glucose tolerance are resistant to the anti-lipolytic effect of insulin

Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two intermediate states in the transition from normal glucose metabolism to type 2 diabetes. Insulin clamp studies have shown that subjects with IGT have increased insulin resistance in skeletal muscle, while subjects with IFG have near normal muscle insulin sensitivity. Because of the central role of altered free fatty acid (FFA) metabolism in the pathogenesis of insulin resistance, we have examined plasma free fatty acid concentration under fasting conditions, and during OGTT in subjects with IGT and IFG. Seventy-one NGT, 70 IGT and 46 IFG subjects were studied. Fasting plasma FFA in IGT subjects was significantly greater than NGT, while subjects with IFG had similar fasting plasma FFA concentration to NGT. However, fasting plasma insulin concentration was significantly increased in IFG subjects compared to NGT while subjects with IGT had near normal fasting plasma insulin levels. The adipocyte insulin resistance index (product of fasting plasma FFA and FPI) was significantly increased in both IFG and IGT subjects compared to NGT. During the OGTT both IFG and IGT subjects suppressed their plasma FFA concentration similarly to NGT subjects, but the post-glucose loads were significantly increased in both IFG and IGT subjects. These data suggest that both subjects with IFG and IGT have increased resistance to the antilipolytic action of insulin. However, under basal conditions, fasting hyperinsulinemia in IFG subjects is sufficient to offset the adipocyte insulin resistance and maintain normal fasting plasma FFA concentration while the lack of increase in FPI in IGT subjects results in an elevated fasting plasma FFA.     

Failure to adequately adapt reduced insulin sensitivity with increased insulin secretion in women with impaired glucose tolerance

Summary To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58–59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and >25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i. v. arginine at all three glucose levels and the slope_AIR, i. e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p=0.015, and at >25 mmol/l p=0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74% (AIR at 14 mmol/l glucose) and 57% (AIR at >25 mmol/l glucose), respectively, in women with IGT. Also the slope_AIR was lower in IGT than in NGT (p=0.025); the increase in slope_AIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - AIR acute insulin response - AGR acute glucagon response     

Leptin concentrations during oral glucose tolerance test (OGTT) in obese and normal weight women.

OBJECTIVE: To examine possible changes of leptin concentrations after the acute administration of glucose orally (OGTT). DESIGN: Seventy-five grams of glucose were administered per os in one group of obese and normal weight individuals and concentrations of glucose, insulin and leptin were measured at 0, 30, 60, 90 and 120 min. In an age matched control group of individuals with similar BMI water was given and leptin concentrations were measured before and after 30, 60, 90 and 120 min. SUBJECTS: Twenty-seven obese women aged 34+/-1.57 y with BMI 37.1+/-0.8 kg/m2 and 16 normal weight women, aged 32+/-1.13 y with BMI 23.6+/-0.3 kg/m2 formed the experimental group, while 10 obese and 10 normal weight females with similar age and BMI were used as controls. MEASUREMENTS: Weight, height, BMI, body fat, glucose, insulin and leptin at baseline and during OGTT. Variations of the above parameters were calculated from the area under the curve (AUC). RESULTS: Fasting leptin concentrations and AUC were higher in obese than in normal weight women. In obese women, leptin increased significantly in comparison to its basal concentrations 30 and 60 min after the glucose loading. Insulin was also increased, as expected. No correlation was found between insulin and leptin concentrations after glucose loading. Basal concentrations of leptin did not correlate with those of glucose and insulin. No changes in leptin concentrations were found in normal weight women after OGTT. However, a significant positive correlation was found between insulin and basal leptin. Finally, leptin concentrations did not change in obese and normal weight controls after water administration. CONCLUSION: A significant increase in leptin concentrations was found 30 and 60 min after glucose loading in obese individuals. No such increase was found in normal-weight women.     

空腹血糖异常、糖耐量减低患者血清胰岛素水平的变化及其意义

目的 观察空腹血糖异常(IFG)、糖耐量减低(IGT)患者血清胰岛素水平的变化。方法 对50例空腹血糖和糖耐量正常者(NGT)、40例IFC和80例IGT患者行口服葡萄糖耐量试验(0GTT)，用氧化酶法检测血糖，用放免法测定血清空腹及餐后2小时胰岛素。结果 IFG、IGT组空腹血糖、空腹胰岛素水平及胰岛素敏感指数较NGT组明显升高(P＜0.05或P＜0．01)，IFG组胰岛素敏感指数与IGT组比较无显著性差异(P＞0．05)。结论 在IFG、IGT状态下已经存在胰岛素抵抗，而且在程度上两者间并没有显著性差异，应早期干预治疗。     

Differences in insulin resistance and pancreatic B‐cell function in obese subjects with isolated impaired glucose tolerance and isolated impaired fasting glucose

Aims To investigate changes in insulin action and insulin secretion in obese subjects with different categories of impaired glucose regulation (IGR): impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and combined IFG/IGT (CGI). Methods A total of 222 subjects underwent an oral glucose tolerance test and a frequently sampled intravenous glucose tolerance test (FSIGTT); 100 had normal glucose tolerance (subdivided into 32 lean NGT, 68 obese NGT), and 122 were obese with IGR (82 IGT, 14 IFG and 26 CGI). The insulin sensitivity index (S_I) was assessed by Bergman's minimal model method with FSIGTT; insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S_I, was used to determine whether AIRg was adequate to compensate for insulin resistance. Results S_I was similar in NGT and IGR obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT, significantly reduced in IGT, and further reduced in IFG and CGI subjects as compared with obese NGT subgroups. DI was reduced in NGT obese individuals. Within the obese IGR subgroups, IFG and CGI subjects had even lower DI value than IGT subjects. Conclusions Obese Chinese subjects with IGR have a similar degree of insulin resistance but differ in insulin secretion. Subjects with IFG and CGI have a more prominent deficiency in insulin secretion than subjects with IGT.     

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.