Rosiglitazone improves exercise capacity in individuals with type 2 diabetes

OBJECTIVE: Although exercise is recommended as a cornerstone of treatment for type 2 diabetes, it is often poorly adopted by patients. We have noted that even in the absence of apparent cardiovascular disease, persons with type 2 diabetes have an impaired ability to carry out maximal exercise, and the impairment is correlated with insulin resistance and endothelial dysfunction. We hypothesized that administration of a thiazolidinedione (TZD) agent would improve exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty participants with uncomplicated type 2 diabetes were randomly assigned in a double-blind study to receive either 4 mg/day of rosiglitazone or matching placebo after baseline measurements to assess endothelial function (brachial artery diameter by brachial ultrasound), maximal oxygen consumption (VO(2max)), oxygen uptake (VO(2)) kinetics, and insulin sensitivity by hyperinsulinemic-euglycemic clamp. Measurements were reassessed after 4 months of treatment. RESULTS: Participant groups did not differ at baseline in any measure. Rosiglitazone-treated participants (n = 10) had significantly improved VO(2max) (19.8 +/- 5.3 ml . kg(-1) . min(-1) before rosiglitazone vs. 21.2 +/- 5.1 ml . kg(-1) . min(-1) after rosiglitazone, P < 0.01), insulin sensitivity, and endothelial function. A change in VO(2max) correlated with improved insulin sensitivity measured by clamp (r = 0.68, P < 0.05) and with improved brachial artery diameter (r = 0.70, P < 0.05). Placebo-treated participants (n = 10) showed no changes in VO(2max) (19.4 +/- 5.2 ml . kg(-1) . min(-1) before rosiglitazone vs. 18.1 +/- 5.3 ml . kg(-1) . min(-1) after rosiglitazone, NS) or brachial artery diameter. CONCLUSIONS: This is the first known report showing that a TZD improved exercise function in type 2 diabetes. Whether this is due to the observed improvements in insulin sensitivity and/or endothelial function or to another action of the TZD class requires further exploration.     

Kinetic studies of plasma free fatty acid and triglyceride metabolism in man

Plasma transport of free fatty acids (FFA) and triglyceride fatty acids (TGFA) was studied in seven subjects with normal lipid metabolism, one case of total lipodystrophy, and one case of familial hyperlipemia (Type V). Studies were carried out after intravenous injection of radioactive FFA, of lipoproteins previously labeled in vitro in the triglyceride moiety, or both.Computer techniques were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for both FFA and TGFA. The results show that as much as 20-30% of FFA leaving the plasma compartment in normal subjects is transported to an exchanging extravascular pool and quickly reenters the plasma pool as FFA. The rate of irreversible delivery of FFA from plasma to tissues averaged 358 muEq/min in normals. The lipodystrophy patient, despite the virtual absence of adipose tissue (confirmed at autopsy), had a plasma FFA concentration and a total FFA transport, both more than twice normal. Total TGFA transport ranged from 25 to 81 muEq/min in four normal controls. The rate constant for TGFA turnover in the patient with Type V hyperlipemia was so small that total transport could not be quantified from the data available; the TGFA half-life was over 500 min.In two normal subjects given injections of autologous lipoproteins labeled in vitro with triolein-(14)C and simultaneously given oleic acid-(3)H, it was shown that the time course for the disappearance of the TGFA in the in vitro labeled samples conformed almost exactly to that of the physiologically labeled lipoprotein TGFA synthesized from injected FFA (as evidenced by the simultaneous fitting of both sets of data using the same multicompartmental model and the same rate constants). Radioactivity appeared in the plasma FFA fraction at a significant rate after injection of plasma labeled in vitro with TGFA. It was estimated that as much as 50% of the total TGFA transported underwent rapid and rather direct conversion to FFA in the two normal subjects studied this way. The kinetic data suggest that such conversion of TGFA to FFA was not preceded by any extensive dilution, such as would result from complete mixing with tissue triglyceride stores.     

空腹血清游离脂肪酸与2型糖尿病的关系

目的 2型糖尿病(T2DM)患者血清游离脂肪酸(FFA)水平的变化及与糖代谢、胰岛素抵抗各指标间的相关性,并探讨影响T2DM的危险因素。方法通过口服糖耐量试验(OGTT)筛选105例未经药物治疗的T2DM患者和66名健康人(正常对照组),分别测定其血浆葡萄糖(PG)和胰岛素(Ins)水平,计算胰岛素抵抗指数(HOMA-IR)和胰岛素分泌指数(HOMA-IS),同时检测空腹血清FFA。对血清FFA浓度与性别、年龄、体重、体重指数(BMI)、0～3 h PG和Ins以及HOMA-IR、HOMA-IS进行相关性分析。以T2DM是否发病为因变量Y(T2DM组=1,正常对照组=0),性别、年龄、体重、BMI、HOMA-IR、HOMA-IS和FFA为自变量,做Logistic回归分析。结果 T2DM组HOMA-IR、HOMA-IS和血清FFA水平与正常对照组比较差异均有统计学意义(P<0.01、P<0.001)。相关分析发现,空腹血清FFA与0 h PG、0.5 h PG、1 h PG、2 h PG、3 h PG、3 h Ins、HOMA-IR呈弱正相关(r分别为0.340、0.281、0.282、0.307、0.302、0.193、0.225,P均<0.05)。Logistic回归分析显示血清FFA是T2DM的重要风险因素[OR=14.05,95%可信区间(CI):1.87～105.55]。结论血清FFA水平升高可能影响机体糖动态平衡,与胰岛素抵抗和T2DM发病密切相关。     

Premenopausal advantages in postprandial lipid metabolism are lost in women with type 2 diabetes

OBJECTIVE: Women with type 2 diabetes appear to lose the protection against cardiovascular disease afforded by estrogens. We examined the effects of menopausal status on postprandial clearance of dietary fat in healthy and diabetic women. RESEARCH DESIGN AND METHODS: Fasting subjects (premenopausal and postmenopausal control subjects, premenopausal and postmenopausal diabetic women, all n = 8) were given a meal containing the stable isotope 1,1,1-(13)C-tripalmitin, with blood and breath sampled for 6 and 24 h, respectively, in the postprandial period. Lower levels of (13)C-palmitic acid ((13)C-PA) in the triglyceride fraction implies more efficient chylomicron clearance, lower levels of (13)C-PA in the nonesterified fatty acid (NEFA) fraction implies improved dietary NEFA entrapment, and higher levels of (13)CO(2) in the breath denote more efficient of oxidation of dietary-derived lipid. RESULTS: In diabetic women, there were no differences between the pre- and postmenopausal groups for any of these parameters. In contrast, premenopausal control subjects, compared with postmenopausal control subjects, had lower (13)C-PA in the triglyceride fraction area under the curve (AUC) (premenopausal median [range] 25.2 [12.1-49.4 mmol/l] per 6 h, postmenopausal 48.5 [15.5-77.2 mmol/l] per 6 h; P < 0.01) and higher (13)CO(2) levels in the breath AUC (premenopausal 22.5 [18.0-31.5%] of administered dose, postmenopausal 17.2 [11.2-31.5%] of administered dose; P < 0.01) with no difference between groups in levels of (13)C-PA in the NEFA fraction AUC. CONCLUSIONS: The premenopausal advantage in clearance of dietary lipid is not seen in premenopausal diabetic women. This is likely to promote an atherogenic lipoprotein profile and may contribute to the loss of cardiovascular disease protection seen in diabetic women.     

Elevated plasma glucose and lowered triglyceride levels from omega-3 fatty acid supplementation in type II diabetes

We studied the effect of omega-3 fatty acids (omega 3FA) on glucose homeostasis and lipoprotein levels in eight type II (non-insulin-dependent)-diabetic subjects ingesting 8 g/day omega 3FA for 8 wk as marine-lipid concentrate capsules. After omega 3FA supplementation, fasting plasma glucose levels increased 22% (P = .005) and meal-stimulated glucose increased 35% (P = .036). The percentage of glucose elevation correlated with percentage ideal body weight (r = .73, P = .04). No significant changes were seen in fasting or meal-stimulated plasma insulin, glucose disposal, or insulin-to-glucagon ratios. Very-low-density lipoprotein cholesterol and triglyceride (TG) levels showed consistent reductions of 56% (P less than .001) and 42% (P less than .001), respectively, after omega 3FA supplementation. Total cholesterol levels decreased 7% (P less than .05) without alteration in low- or high-density lipoprotein cholesterol. Thus, omega 3FA supplementation at a dose of 8 g/day significantly improves plasma TG levels but increases fasting and meal-stimulated glucose concentrations in the type II diabetic patient not treated with insulin or sulfonylurea agents. Marine-lipid concentrate capsules supplying large amounts of omega 3FAs should be used cautiously in the type II diabetic patient.     

Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes

Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKbeta, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKbeta activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin ( approximately 7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-(2)H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a approximately 25% reduction in fasting plasma glucose, associated with a approximately 15% reduction in total cholesterol and C-reactive protein, a approximately 50% reduction in triglycerides, and a approximately 30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by approximately 20% and approximately 50%, respectively. Aspirin treatment also resulted in a approximately 20% reduction in basal rates of hepatic glucose production and a approximately 20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKbeta represents a new target for treating type 2 diabetes mellitus.     

2型糖尿病患者胰岛素抵抗与血清游离脂肪酸浓度的关系

目的探讨2型糖尿病(T2DM)患者空腹与餐后2 h游离脂肪酸(FFA)浓度和胰岛素抵抗的关系。方法测定100例T2DM患者(根据亚洲糖尿病论坛的推荐分为控制良好和控制不良2组)及50名正常对照者的糖化血红蛋白(HbA1c)、空腹胰岛素(FINS)、空腹血糖(FPG)、餐后2 h血糖(2 h PG)、空腹FFA及餐后2 hFFA。以稳态模式评估胰岛素抵抗指数(HOMA-IR)。结果与对照组比较,T2DM组的FPG、2 h PG、FFA、2 h FFA、HbA1c、HOMA-IR均明显增高(P<0.01)。T2DM控制不良组各项指标均高于控制良好组(P<0.05),FFA、2 h FFA与HOMA-IR、HbA1c、FPG、2 h PG均呈明显的正相关(r分别为0.910、0.876,0.851、0.759,0.908、0.746,0.769、0.674,P<0.01)。结论 T2DM患者体内FFA浓度的增高与胰岛素抵抗存在明显相关性,与T2DM的发病机制有密切关系。     

罗格列酮对2型糖尿病游离脂肪酸的影响

目的观察罗格列酮对2型糖尿病游离脂肪酸（FFA）的影响。方法60例2型糖尿病患者,随机分为罗格列酮组与二甲双胍组。治疗前和治疗3个月后,测量身高和体质量,计算体质量指数（BMI）,观察空腹血糖（FBS）、甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、FFA、糖化血红蛋白（HbA1c）的变化。结果治疗后两组FBS、HbA1c均下降。罗格列酮组FBS治疗前后（10．34±3．08）mmol／L vs（7．75±1．46）mmol／L（P〈0．01）,HbA1c（8．85±2．28）％vs（7．28±1．33）％（P〈0．01）;二甲双胍组FBS（9．51±2．89）mmol／Lvs（7．36±1．40）mmol／L（P〈0．01）,HbA1c（9．26±2．45）％vs（7．61±1．23）％（P〈0．01）。但两组之间比较无统计学意义（P〉0．05）。罗格列酮组治疗前后FFA（0．65±0．24）mmol／Lvs（0．54±0．19）mmol／L（P〈0．05）。而二甲双胍组治疗前后FFA无明显下降。结论罗格列酮治疗降低FFA的水平,有助于减少2型糖尿病大血管并发症的发生。     

Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus.

Hyperglycemia, hyperinsulinemia, and insulin resistance cause vascular disease in type 2 diabetes mellitus. Dietary treatment alone often fails and oral drugs or insulin enhance hyperinsulinemia. In previous studies, an intravenous bolus of recombinant human insulin-like growth factor-I (rhIGF-I) caused normoglycemia in insulin-resistant diabetics whereas rhIGF-I infusions lowered insulin and lipid levels in healthy humans, suggesting that rhIGF-I is effective in insulin-resistant states. Thus, eight type 2 diabetics on a diet received on five treatment days subcutaneous rhIGF-I (2 x 120 micrograms/kg) after five control days. Fasting and postprandial glucose, insulin, C-peptide, proinsulin, glucagon, triglyceride, insulin-like growth factor-I and -II, and growth hormone levels were determined. RhIGF-I administration increased total IGF-I serum levels 5.3-fold above control. During the control period mean (+/- SD) fasting glucose, insulin, C-peptide, and total triglyceride levels were 11.0 +/- 4.3 mmol/liter, 108 +/- 50 pmol/liter, 793 +/- 250 pmol/liter, and 3.1 +/- 2.7 mmol/liter, respectively, and decreased during treatment to a nadir of 6.6 +/- 2.5 mmol/liter, 47 +/- 18 pmol/liter, 311 +/- 165 pmol/liter, and 1.6 +/- 0.8 mmol/liter (P < 0.01), respectively. Postprandial areas under the glucose, insulin, and C-peptide curve decreased to 77 +/- 13 (P < 0.02), 52 +/- 11, and 60 +/- 9% (P < 0.01) of control, respectively. RhIGF-I decreased the proinsulin/insulin ratio whereas glucagon levels remained unchanged. The magnitude of the effects of rhIGF-I correlated with the respective control levels. Since rhIGF-I appears to improve insulin sensitivity directly and/or indirectly, it may become an interesting tool in type 2 diabetes and other states associated with insulin resistance.     

2型糖尿病患者高血清游离脂肪酸水平与胰岛素抵抗的相关性研究

目的探讨2型糖尿病(T2DM)患者血清游离脂肪酸(FFA)水平与胰岛素抵抗的相关性。方法选取102例T2DM患者作为T2DM组,依据糖化血红蛋白(HbA1c)水平分为控制良好和控制不良组,选取62例健康体检者作为健康对照组,检测各组的HbA1c、三酰甘油(TG)、空腹血糖(FBS)、餐后2h血糖(PPBS)、空腹胰岛素(FINS)、空腹FFA及餐后2h游离脂肪酸(2hFFA)。以稳态模式评估胰岛素抵抗指数(HOMA-IR)。结果T2DM组HbA1c、TG、FBS、PPBS、FFA、2hFFA及HOMA-IR均较健康对照组明显升高(P0.05)。T2DM控制不良组各指标均高于控制良好组(P0.05)。FFA、2hFFA与其他指标均呈明显正相关(r0.5,P0.01)。结论T2DM患者体内FFA水平显著升高,与胰岛素抵抗存在明显相关性。     

老年2型糖尿病患者血清抵抗素、游离脂肪酸水平研究

目的探讨血清抵抗素、游离脂肪酸与老年糖尿病及胰岛素抵抗的关系。方法测量老年(年龄>60岁)2型糖尿病患者82例(老年糖尿病组),成年(年龄<60岁)2型糖尿病患者70例(成年糖尿病组),老年健康体检者50例(对照组)空腹血清抵抗素、游离脂肪酸、空腹血糖及胰岛素水平,计算胰岛素抵抗指数。结果老年糖尿病组血清抵抗素、游离脂肪酸水平高于对照组与成年糖尿病组(P<0.05或P<0.01)。老年糖尿病组胰岛素抵抗程度较成年糖尿病组明显,并伴有脂代谢紊乱。结论血清抵抗素、游离脂肪酸与老年糖尿病尤其是老年胰岛素抵抗密切相关。     

The kinetics of plasma free fatty acid and triglyceride transport in patients with idiopathic hypertriglyceridaemia and their relation to carbohydrate metabolism

Abstract. Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.—Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.—Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.—In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.—The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.—The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.     

血清游离脂肪酸水平调查及在2型糖尿病患者中的应用

目的研究北京医院健康体检者的游离脂肪酸（FFA）水平及血脂分布特征，揭示FFA水平与2型糖尿病（DM）的关系。方法测定256名健康体检者和93例2型DM患者的血清糖（Glu）和总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL—C）、低密度脂蛋白胆固醇（LDL—C）、FFA含量，将测得的数据按性别分组进行分析，并分析2型DM组与健康组的差异。结果在健康体检人群中，男性血脂水平为TC（4．33±0．74）mmol／L、HDL—C（1．36±0．29）mmol／L、LDL—C（2．05±0．65）mmol／L、TG（0．91±0．32）mmol／L、FFA（401．11±158．64）μEq／L；女性血脂水平为TC（4．28±0．65）mmol／L、HDL—C（1．42±0．27）mmol／L、LDL—C（2．08±0．61）mmol／L、TG（0．78±0．25）mmol／L、FFA（446．50±165．59）μEq／L。男女2组血脂水平差异无统计学意义。与健康组比较，2型DM组Glu、FFA、TC、TG和LDL—C升高，HDL—C降低，差异有统计学意义（P〈0．01）。结论北京医院健康体检者血脂水平的性别差异不明显，FFA参考范围为96—740μEq／L。     

老年2型糖尿病病人餐后甘油三脂水平与大血管并发症的相关关系

目的　研究老年 2型糖尿病病人餐后甘油三脂水平与大血管并发症的关系。方法　 40例 2型糖尿病病人以空腹和餐后 4h甘油三脂水平分组 :空腹及餐后TG正常组 (11例 )为A组 ,空腹TG正常 ,餐后增高组 (15例 )为B组 ,空腹TG增高组 (14例 )为C组 ,分析其大血管并发症发生情况。结果　大血管并发症发生率依次为 2 7 2 7%、73 33 %、78 5 7%。A组与B组大血管并发症比较P <0 0 5 ,B组与C组比较P >0 0 5。结论　空腹TG正常 ,餐后TG增高的大血管并发症发生率与餐后正常者差异有显著意义     

TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.     

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.