Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes

OBJECTIVE

To investigate whether the dipeptidyl peptidase-4 inhibitor vildagliptin improves endothelium-dependent vasodilatation in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Sixteen subjects with type 2 diabetes (age 59.8 ± 6.8 years, BMI 29.1 ± 4.8 kg/m², HbA_1c 6.97 ± 0.61) on oral blood glucose–lowering treatment were included. Participants received vildagliptin 50 mg b.i.d. or acarbose 100 mg t.i.d. for four consecutive weeks in a randomized, double-blind, cross-over design. At the end of each treatment period, we measured forearm vasodilator responses to intra-arterially administered acetylcholine (endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator).

RESULTS

Infusion of acetylcholine induced a dose-dependent increase in forearm blood flow in the experimental arm, which was higher during vildagliptin (3.1 ± 0.7, 7.9 ± 1.1, and 12.6 ± 1.4 mL ⋅ dL⁻¹ ⋅ min⁻¹ in response to three increasing dosages of acetylcholine) than during acarbose (2.0 ± 0.7, 5.0 ± 1.2, and 11.7 ± 1.6 mL ⋅ dL⁻¹ ⋅ min⁻¹, respectively; P = 0.01 by two-way ANOVA). Treatment with vildagliptin did not significantly change the vascular responses to sodium nitroprusside.

CONCLUSIONS

Four weeks’ treatment with vildagliptin improves endothelium-dependent vasodilatation in subjects with type 2 diabetes. This observation might have favorable cardiovascular implications.Worldwide, almost 200 million people suffer from type 2 diabetes, and the prevalence is rapidly increasing (1). Type 2 diabetes causes a twofold excess risk for cardiovascular disease, partly independent from other risk factors (2). Ideally, pharmacotherapy for type 2 diabetes not only lowers blood glucose levels but also has glucose-independent beneficial cardiovascular effects.Endothelial dysfunction is considered an early marker of vascular complications, also in type 2 diabetes (3). Endothelial dysfunction comprises a number of functional alternations in the vascular endothelium, such as impaired endothelium-dependent vasodilatation, impaired barrier function, inflammatory activation, and stimulated coagulation (4). Endothelium-dependent vasodilatation, which is impaired in endothelial dysfunction, can be assessed by measuring responses to endothelium-dependent vasodilators such as acetylcholine (5).Recently, incretin-based therapy has been approved for the treatment of type 2 diabetes. Incretins are a group of gastrointestinal hormones, predominantly glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), that are secreted in response to food ingestion and stimulate insulin secretion (6). Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the incretin hormones to inactive metabolites (7). In addition to incretins, DPP-4 also inactivates chemokines, cytokines, and neuropeptides (8). In type 2 diabetes DPP-4 inhibitors reduce the breakdown of GLP-1 and improve metabolic control by increasing insulin secretion, improving β-cell function, and decreasing glucagon secretion (9).Apart from glycemic actions, GLP-1 has beneficial cardiovascular effects. GLP-1 has vasodilatory actions, which are believed to be mediated through a specific GLP-1 receptor in the vascular endothelium, and improves endothelial function in animals and humans (10,11). In addition, GLP-1 may have GLP-1 receptor-independent cardiovascular effects, which appear to be mediated by metabolites of GLP-1 (12). It is not known whether a pharmacological approach of increasing GLP-1 levels by inhibiting DPP-4, which changes the ratio between GLP-1 and its degradation product, exhibits the same vascular profile.DPP-4 inhibition affects not only GLP-1 levels, but also GIP breakdown, and perhaps also other substrates, such as chemokines and cytokines. Whether intervening in the breakdown of these other potential substrates affects endothelial function is unknown. Indirect evidence for a potential beneficial effect on endothelial function comes from a study demonstrating that the DPP-4 inhibitor sitagliptin increases endothelial progenitor cells in type 2 diabetes by inhibiting degradation of the chemokine stromal-derived factor 1-α (13).The fact is that meta-analyses summarizing the effects of DPP-4 inhibitors on major cardiovascular events in phase 2 and 3 studies all suggest a lower relative risk compared with placebo or other medication (14,15). These observations need to be confirmed in large cardiovascular outcome studies. The current study therefore aims to determine whether the DPP-4 inhibitor vildagliptin can improve endothelial function in patients with type 2 diabetes.     

Fibrinolytic dysfunction in insulin-resistant women with previous gestational diabetes

BACKGROUND: Women with a history of gestational diabetes (p-GDM) are at increased risk of developing type 2 diabetes mellitus (DM2) later in life, and therefore at increased risk for future cardiovascular disease. MATERIALS AND METHODS: Three months after delivery we investigated the plasma levels of plasminogen activator inhibitor type 1 (PAI-1), tissue plasminogen activator (t-PA), fibrinogen and von Willebrand factor (vWF) in 74 women with p-GDM and 20 healthy females with normal glucose tolerance during and after pregnancy, as well as the relation of fibrinolytic parameters to insulin resistance and glycaemic control. All women underwent an oral (OGTT) as well as an intravenous glucose tolerance test (FSIGT). Mathematical model analysis disclosed that 50% (n=37 each) of the p-GDM subjects had normal (NIS) or impaired (IIS) insulin sensitivity. Parameters of interest were determined using commercially available test systems. RESULTS: Women with p-GDM and IIS had significantly increased body fat mass (BFM) (P相似文献   

Parental diabetes in Taiwanese diabetic women with and without previous gestational diabetes

Background    Gestational diabetes mellitus (GDM) is reported to be associated with maternal but not paternal diabetes. This study examined the relative contribution of maternal and paternal diabetes among type 2 diabetic women with and without a GDM history.
Materials and methods    A total of 48 502 type 2 diabetic women from a national sample were interviewed by telephone. Among them, 510 reported a GDM history. Parental diabetes was compared between patients with and without a GDM history considering the confounding effects of age, body mass index, smoking, hypertension, duration of diabetes and insulin use.
Results    Patients with a GDM history were younger in age, had younger age of onset, longer duration of diabetes, slightly lower body mass index, higher prevalence of insulin use and lower prevalence of hypertension, but smoking rates were similar. The percentages of parental diabetes of nil, mother only, father only and both father and mother for those without a GDM history were 76·2, 15·2, 5·8 and 2·8%, respectively; and were 47·8, 26·8, 17·5 and 7·9%, respectively, for those with a GDM history ( P  < 0·001). The adjusted odds ratios for patients with versus without a GDM history for parental diabetes of nil, mother only, father only, and both father and mother were 1·000, 1·210 (0·948–1·544), 1·783 (1·341–2·371) and 2·094 (1·440–3·045), respectively.
Conclusions    Although maternal diabetes is more commonly seen, the disproportionately higher paternal diabetes in patients with a GDM history suggests an important role for paternal diabetes on the development of GDM into type 2 diabetes mellitus.     

Birth weight of women with gestational diabetes.

OBJECTIVE: Epidemiological observations have suggested a relationship between type 2 diabetes and a low birth weight. However, there are many confounding variables and problems with retrospective data collection. Women with gestational diabetes mellitus (GDM), who are likely to develop type 2 diabetes in the future, may help clarify these observations. RESEARCH DESIGN AND METHODS: Consecutive women with GDM (n = 138) were included in the study if they had a singleton pregnancy delivered between 37 and 41 weeks of gestation, if they had themselves been born in the local hospital, and if their own delivery data were available. With respect to their own births, a matched group was obtained by considering the next female delivery of the same gestational age. RESULTS: For women with GDM, the mean (+/- 1 SD) birth weight was 3,293 +/- 493 g and the ponderal index was 27.0 +/- 2.4. Their values were not significantly different from the matched group, which had a birth weight of 3,315 +/- 460 g and a ponderal index of 27.0 +/- 2.5. After adjusting for the gestational age of delivery, the birth weight of women with GDM did not show a U-shaped distribution. CONCLUSIONS: After adjustment for the gestational age of delivery, women with GDM do not themselves have either a lower or higher birth weight than a matched group. These data suggest that women with GDM are either not a good surrogate for investigating the relationship between birth weight and type 2 diabetes or that correction for the gestational age of delivery removes the most important confounding variable. It is also possible that modern dietary changes may have altered the relationship.     

Diabetes and abnormal glucose tolerance in women with previous gestational diabetes

OBJECTIVE: In Spanish women with gestational diabetes mellitus (GDM), we aimed to study the progression to diabetes and abnormal glucose tolerance (AGT) and identify predictive factors. RESEARCH DESIGN AND METHODS: In 696 women with GDM and 70 control women, glucose tolerance was evaluated postpartum and at 5-year intervals. RESULTS: In the GDM group, the cumulative risk for diabetes and AGT was 13.8 and 42.4% after 11 years compared with 0 and 2.8% in control women, respectively (P < 0.05). Independent predictive factors for diabetes were previous hyperglycemia, four abnormal glucose values on the diagnostic oral glucose tolerance test (OGTT) or overt diabetes during pregnancy, 2-h blood glucose on the diagnostic OGTT >/=11.7 mmol/l, gestational age at diagnosis <24 weeks, and prepregnancy BMI >/=26.4 kg/m(2). All of these factors (some with different cutoff points) in addition to fasting glycemia were predictors of AGT also. The risk was nonlinear. Four abnormal glucose values on the diagnostic OGTT or overt diabetes during pregnancy was the strongest predictive factor for diabetes (relative risk 3.92), and prepregnancy BMI was the predictive factor with the highest attributable fraction in the whole group (13.3%). When first postpartum OGTT data were included in the analysis, predictors changed, but the overall prediction was similar. CONCLUSIONS: Spanish women with GDM have an increased risk of diabetes and AGT. Predictive factors display a nonlinear relationship. The strongest predictive factor for diabetes was four abnormal glucose values on the diagnostic OGTT or overt diabetes during pregnancy; the factor with the highest attributable fraction in the whole group was prepregnancy BMI.     

Impaired vascular nitric oxide bioactivity in women with previous gestational diabetes

BACKGROUND: Dysfunction of the vascular endothelium, preceding vascular morbidity and type 2 diabetes, is present in women with previous gestational diabetes (GDM). However, it is unknown whether excess weight, insulin resistance, and asymmetric dimethylarginine (ADMA)--an endogenous nitric oxide (NO) synthase inhibitor--also contribute to the vascular changes observed in these patients. The aim of this study was therefore to identify factors other than GDM that impair vascular function. METHODS: Seven overweight and five non-overweight women with previous GDM were included in this study. Vascular function was assessed from forearm blood-flow responses to the endothelium-dependent vasodilator acetylcholine (ACh), the endothelium-independent vasodilator glyceryltrinitrate, the vasoconstrictor norepinephrine and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). ADMA was measured in venous blood, and insulin resistance was estimated from a modified intravenous glucose tolerance test. Twenty healthy male volunteers served as a historical control group. RESULTS: Vasodilation of forearm resistance vessels in response to ACh was impaired in overweight women when compared with non-overweight women (P < 0.05); similarly, vasoconstrictor reactivity tended to be smaller in the overweight group. In addition, there was a significant relationship between vascular responsiveness to ACh and L-NMMA, body-mass index, serum ADMA concentrations and stimulated glucose levels (all P < 0.05). ACh responses and ADMA levels in non-overweight women were similar to those of healthy controls. CONCLUSION: Factors such as obesity, increased ADMA levels and insulin resistance appear to be strong contributors to endothelial dysfunction observed in women with GDM.     

Incidence and significance of islet cell antibodies in women with previous gestational diabetes

Islet cell antibodies (ICAs) are markers for patients at risk for insulin-dependent diabetes and are associated with progressive beta-cell destruction. This prospective study was performed to estimate the incidence of these antibodies in 187 women with previous gestational diabetes. With a specific protein A monoclonal antibody (MoAb) assay, the incidence of ICAs was only 1.6% (3 of 187). Oral and intravenous glucose tolerance tests were performed in these 3 women and compared with 6 women with previous gestational diabetes without ICAs and 5 control women. Glucose tolerance was impaired only in the 3 women with ICAs, who also had an increase (P less than 0.03) in fasting plasma glucose and a decrease (P less than 0.03) in early first-phase insulin response. We conclude that the more specific MoAb method indicates a lower incidence of ICA in women with a history of gestational diabetes than previously reported and that a decreased first-phase insulin response is associated with the presence of ICAs, suggesting progressive islet cell damage.     

妊娠期糖尿病妇女产后2型糖尿病发生及预防的研究进展

随着糖尿病(diabetes mellitus,DM)发病率及相关病死率在全球范围内的不断上升,严重威胁人类健康,DM预防已成为世界各国共同关注的健康问题。同时,文献显示妊娠期     

Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes

OBJECTIVE

To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women.

RESEARCH DESIGN AND METHODS

Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m²) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight.

RESULTS

Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (−7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (−2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss.

CONCLUSIONS

Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.The recent withdrawal of sibutramine from the market leaves only two Food and Drug Administration–approved pharmacologic agents for the treatment of obesity, phentermine and orlistat (1). From this limited armamentarium, clinicians attempt medical management of a chronic disease that has substantial economic, physical, and emotional consequences. Although many studies have shown that weight loss can be achieved through highly supervised dietary interventions, weight regain following these interventions is almost universal (2–4). A recent meta-analysis showed that 25–88% (mean 54%) of weight loss achieved immediately after the intervention was maintained after 1 year of unsupervised follow-up (5). After 2 years, the percentage of maintained weight loss diminishes even more (6). In contrast, bariatric surgery is the most successful intervention for achieving long-term weight loss in morbid obesity (7). However, widespread use of a surgical intervention for obesity is problematic because many people who would benefit do not choose this approach, nor is it routinely available to individuals with BMI <39.9 kg/m² and no other metabolic complications. Given the lack of long-term success with dieting, the invasive nature of bariatric surgery, and the limited pharmacologic options for the medical management of obesity, studies designed to investigate weight loss with agents approved for other primary indications have potentially high clinical value.Glucagon-like peptide (GLP)-1 is an incretin hormone secreted by the enteroendocrine L cells of the small intestine in response to food intake. The major physiologic effects of GLP-1 include increased postprandial insulin secretion, decreased postprandial glucagon secretion, and delayed gastric emptying (8). Early studies of human GLP-1 showed that continuous peripheral infusion was associated with decreased appetite and increased satiety (9). Continuous infusion of GLP-1 also was shown to improve insulin sensitivity, glycemic control, and β-cell function in individuals with type 2 diabetes (10). Incretin mimetics evolved as therapeutic options for the treatment of type 2 diabetes primarily because of their effects on insulin and glucagon secretion, with weight loss as an additional benefit.Weight loss ranging from 2 to 6 kg has been a consistent finding in studies designed to investigate the glycemic benefits of incretin mimetics in individuals with type 2 diabetes (11–14). There are very limited data on weight loss in nondiabetic individuals treated with these agents (15,16). To evaluate the effects of exenatide treatment in obese, nondiabetic women, we designed a randomized, placebo-controlled, crossover study. To minimize the placebo effect and study the effect of exenatide in a real-world setting, we did not include any lifestyle modifications, and we discouraged any change in diet or physical activity. To avoid confounding factors of body fat distribution, we enrolled only women.     

Visceral fatness and insulin sensitivity in women with a previous history of gestational diabetes mellitus

OBJECTIVE: The purpose of this study was to investigate the insulin sensitivity and visceral fatness in women with previous gestational diabetes mellitus (GDM), who are prone to develop type 2 diabetes. RESEARCH DESIGN AND METHODS: A 75-g oral glucose tolerance test (OGTT) performed 1 year postpartum identified 21 GAD(-) women with previous GDM and impaired glucose tolerance (GDM-IGT). Sixty age- and BMI-matched women with normal glucose tolerance (GDM-NGT) were selected by 1:3 matching to the GDM-IGT group. Another 18 women with normal glucose metabolism during a previous pregnancy and no family history of diabetes were recruited as the normal control group. Age and BMI matching was performed using a range of +/-1.0 years and +/-1.0 kg/m(2), respectively. Total body fat was measured by tetrapolar bioelectrical impedance, and visceral fat was determined using a single cut of a computed tomography scan. Insulin sensitivity was determined by the minimal model technique using the frequently sampled intravenous glucose tolerance test. RESULTS: One year postpartum, visceral fat was greater in the GDM-IGT group than in the age- and BMI-matched GDM-NGT or normal control groups. The insulin sensitivity index was lower in the GDM-IGT group than in the GDM-NGT or normal control groups. beta-Cell function, as measured by the acute insulin response to glucose, was also lower in GDM-IGT. CONCLUSIONS: High body fat content, especially visceral fat content, and a low insulin response to glucose seem to contribute simultaneously to the development of impaired glucose metabolism in Korean women with previous GDM.     

Implications of new diagnostic criteria for abnormal glucose homeostasis in women with previous gestational diabetes.

OBJECTIVE: To determine the consequences of applying revised American Diabetes Association (ADA) (1997) and World Health Organization (WHO) (1998) recommendations for the classification of glucose intolerance in women with previous gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: There were 192 women with previous GDM who took an oral glucose tolerance test (OGTT) 1-86 months after delivery and were classified by WHO (1985), ADA (1997, fasting glucose), and revised WHO (1998) guidelines. RESULTS: Among the 165 women without a preexisting diagnosis of diabetes, WHO-1985 and ADA-1997 provided similar estimates of diabetes prevalence (13.3% vs. 11.5%) but widely differing estimates of impaired glucose homeostasis (31.5% impaired glucose tolerance [IGT] by WHO-1985 vs. 10.9% impaired fasting glucose by ADA-1997 criteria). Overall, 56 women (34%) showed a classification discrepancy between WHO-1985 and ADA-1997 criteria, including 44 with normal fasting glucose by ADA-1997 criteria, but abnormal 2-h glucose by WHO-1985 criteria (40 IGT, 4 diabetes). The cardiovascular risk profile of these women was more favorable than that of 18 women with impaired fasting glucose. WHO-1998 recommendations reproduced ADA-1997 findings when used as a fasting screen, but behaved similarly to WHO-1985 criteria when 2-h glucose values were also analyzed. CONCLUSIONS: All criteria produced similar estimates of diabetes prevalence. However, analyses based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) failed to identify 60% of women with abnormal 2-h glucose levels. Screening women with previous GDM (and by analogy, other groups at high risk of diabetes) with a single fasting glucose has low sensitivity for the detection of abnormal glucose tolerance. Recent guidelines recommending this approach require reevaluation.     

妊娠期糖尿病妇女产后糖代谢异常与胰岛β细胞功能缺陷的关系

目的探讨妊娠期糖尿病（GDM）产后6～12个月糖耐量异常或糖尿病的风险因素和可能的机制。方法186例确诊为GDM的孕妇,于产后6周行75g葡萄糖耐量试验（OGTT）。结果异常的妇女于产后6～12个月进行第二次随访。记录年龄,身高,体重,腰围,血压。再行75gOGTT,并检测各点的胰岛素水平,同时检测高敏C反应蛋白,血脂。计算葡萄糖负荷后30min胰岛素增值与葡萄糖增值的比值（Δins/ΔBG）,并回顾其妊娠和分娩时母亲和胎儿资料。结果14例于产后6～12个月存在糖代谢异常,占总随访例数的7.5%。对比糖代谢异常者与恢复正常者血糖、血脂、胰岛素水平、体重指数、高敏C反应蛋白（hs-CRP）以及妊娠和分娩时产妇和胎儿资料,显示GDM产后6～12个月高血糖的妇女有明显降低的空腹胰岛素和更高的孕期餐后血糖,胰岛β细胞功能明显降低。而体重指数、腰围、血压、血脂、hs-CRP亦无差异。年龄、不良孕产史、家族史以及妊娠期母婴并发症的发生率和胎儿体重亦无差异。结论内在的胰岛β细胞功能缺陷可能是GDM孕妇产后6～12个月糖代谢异常的主要危险因素,而与炎症和代谢综合征风险因素无明显关系。     

Acute effects of weight reduction on cholesterol metabolism in obese type 2 diabetes.

BACKGROUND: Weight reduction in obese type 2 diabetes increases the absorption efficiency of cholesterol and serum plant sterol levels from baseline. However, there is no information on the effects of acute restriction of calories and lack of dietary cholesterol and plant sterols on serum cholesterol precursor and plant sterols and on cholesterol metabolism. Thus, 10 obese (BMI>30 kg/m(2)) type 2 diabetes subjects consumed very low energy diet virtually free of cholesterol, cholestanol and plant sterols for 3 months. Methods: Serum sterols were measured with gas-liquid chromatography. RESULTS: Body weight was reduced by 15.5+/-1.7 kg (p<0.001), serum cholesterol by 21+/-3%, triglycerides 45+/-5%, glucose 23+/-3%, insulin 59+/-5% and HbAIc by 8+/-2%, whereas serum sex hormone binding globulin increased by 108+/-25% (p<0.05-0.001 for all). Serum desmosterol and lathosterol to cholesterol ratios (indicators of cholesterol synthesis) were significantly decreased by 20% suggesting that cholesterol synthesis was suppressed. Serum squalene ratio was unchanged. Despite lack of dietary plant sterols and cholestanol, serum campesterol and sitosterol ratios (indicators of cholesterol absorption efficiency) only tended to decrease, whereas serum cholestanol ratio, also an absorption indicator, was increased by 33+/-3% (p<0.001), and its ratios to campesterol and sitosterol were increased by 60% and 31%, suggesting that sterol absorption efficiency might have been increased and their turnover reduced. CONCLUSIONS: In obese type 2 diabetes, restriction of calories and dietary sterols improved markedly control of diabetes, decreased serum cholesterol precursor sterols suggesting that cholesterol synthesis was decreased, but only tended to decrease serum values of plant sterols probably due to their release from the adipose tissues associated with their impaired turnover.     

Total sialic acid and associated elements of the metabolic syndrome in women with and without previous gestational diabetes

OBJECTIVE: Inflammatory markers predict type 2 diabetes and relate to the metabolic syndrome. Gestational diabetes mellitus (GDM) predicts type 2 diabetes and may be part of this syndrome. To examine the association of inflammatory markers with GDM, we investigated total sialic acid (TSA) in women with and without previous GDM. RESEARCH DESIGN AND METHODS: All women with GDM and a random sample of women from one center of the Brazilian Study of Gestational Diabetes were invited to return 7 years after their index pregnancy. After an interview, an oral glucose tolerance test and anthropometry were performed. A total of 46 women with and 50 women without previous GDM completed the protocol. RESULTS: Mean TSA was significantly higher in women with (71.8 +/- 11.1 mg/dl) than without (67.5 +/- 9.8 mg/dl) previous GDM (P < 0.05). In a linear regression model, TSA was 4 mg/dl (P < 0.05) higher in women with previous GDM, after adjustment for BMI, fasting insulin sensitivity, and number of years spent in school. In a similar model, current 2-h plasma glucose levels were associated with higher TSA levels after adjustment for waist-to-hip ratio and the log of triglycerides. TSA was strongly correlated with individual components and aggregates (r = 0.55, P < 0.001) of the metabolic syndrome. CONCLUSIONS: Increased TSA levels are associated with previous GDM and are strongly linked to the metabolic syndrome. These findings in young women suggest that a chronic mild systemic inflammatory response is an early feature of the metabolic syndrome and that GDM may be a window for its investigation.     

Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 micrograms/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 micrograms/min) and verapamil (10-300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.