胰岛素泵快速控制新诊断2型糖尿病患者高血糖状态对胰岛β细胞功能的影响

目的了解胰岛素泵对胰岛β细胞功能的影响。方法对新诊断51例2猁糖尿病（TgDM）患者FBG≥15mmol／L者，分别行胰岛素强化治疗和口服降糖药治疗，观察其血清C肽浓度的变化。结果强化组治疗4天血糖达标后血清C肽曲线下面积无明显变化，继续皮下注射胰岛素治疗半年后明显升高（P〈0．001）。口服降糖药组亦有改善（P〈0．01）。但半年后两组结果显示：应用胰岛素组优于口服降糖药组（P〈O．001）。结论胰岛素泉数日快速控制严重高血糖不能消除高血糖毒性对胰岛β细胞功能的抑制，对新诊断的FBG≥14mmol／L的T2DM患者胰岛素治疗应废持续数月以期改善胰岛功能。     

罗格列酮对老年2型糖尿病患者胰岛β细胞功能影响

目的观察罗格列酮对磺脲类降糖药继发性失效(SF)的老年2型糖尿病(T2DM)患者的胰岛β细胞功能影响。方法选择69例SF的T2DM患者,根据年龄分为老年组(≥60岁,37例)、中青年组(<60岁,32例),分别加用罗格列酮或胰岛素治疗24周,治疗前后分别测糖化血红蛋白(HbA1c)、空腹血糖(FBG)、空腹胰岛素(FIns)、血脂、稳态模型的胰岛素抵抗指数(HOMA-IR)、HOMAβ胰岛细胞分泌指数(HOMA-IS),胰岛素敏感指数(ISI)、糖负荷30min净增胰岛素/净增血糖比值(ΔI30/ΔG30)并进行比较。结果治疗后各组HbA1c、FBG、HOMA-IR均明显下降,HOMA-IS、ISI均明显升高,差异有统计学意义(P<0.01),治疗后罗格列酮组FIns较治疗前有所升高(P<0.05),而胰岛素组无明显变化,治疗后各组ΔI30/ΔG30均较治疗前升高(P<0.05或P<0.01)。结论本研究表明罗格列酮有助于诱导β细胞功能的恢复,这种作用对老年患者同样有效。     

Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes

AIMS/HYPOTHESIS: The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function. METHODS: This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors. RESULTS: Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P < 0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P < 0.0001) relative to placebo. CONCLUSION: Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.     

Measurements of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes

OBJECTIVE: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization. Research DESIGN AND METHODS: Participants with T2DM (n = 16) who had a baseline hemoglobin A(1c) of 7.1 +/- 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min x m(2) insulin infusions. RESULTS: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2-fold, respectively, reduced fasting plasma glucose and postprandial plasma glucose by 1.3 +/- 0.3 mmol/liter and 1.6 +/- 0.3 mmol/liter (both P <0.01), and improved glucose responsiveness of insulin secretion by 50% (P < 0.01). Vildagliptin lowered postprandial glucagon by 16% (P <0.01). Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (P < 0.01). CONCLUSIONS: Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.     

Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia

Aim: To assess the 2‐year efficacy and tolerability of vildagliptin (50 mg once daily) in patients with type 2 diabetes (T2DM) and mild hyperglycaemia. Methods: This was a multicentre, randomized, double‐blind, placebo‐controlled trial comprising a 52‐week core study with a 4‐week, active treatment–free washout followed by a 52‐week extension study with another washout period conducted in 131 drug‐naïve patients with T2DM and mild hyperglycaemia [glycosylated haemoglobin (HbA_1c) 6.2–7.2%]. All patients received lifestyle counselling at each study visit. Efficacy and tolerability were assessed during visits at weeks 0 (core study baseline), 4, 8, 12, 16, 24, 32, 40 and 52 of active treatment; at week 56 (i.e. after the first washout period); at weeks 68, 80, 96 and 108 and at week 112 (i.e. after the second washout period). Standard meal tests were also performed at weeks 0, 24, 52, 56, 80, 108 and 112 to assess postprandial glycaemia and β‐cell function, which was quantified by glucose area under the curve (AUC_{0–2 h})/insulin secretory rate (ISR) AUC_{0–2 h} (ISR/G). Changes from baseline and between‐treatment differences (placebo‐adjusted changes from baseline during vildagliptin treatment) were analysed by ancova . Results: The placebo‐adjusted change from week 0 in HbA_1c was ?0.3 ± 0.1% after 1 year of vildagliptin treatment (p < 0.001) and ?0.5 ± 0.2% after 2 years (p = 0.008). The placebo‐adjusted change from core study baseline in fasting plasma glucose, in glucose AUC_{0–2 h} and in the β‐cell function parameter, ISR/G, tended to be greater after 2 years than after 1 year of treatment with vildagliptin. Even after a 4‐week washout, the placebo‐adjusted change from week 0 to week 112 in ISR/G was 3.2 ± 1.6 pmol/min/m²/mM (p = 0.058) and the placebo‐adjusted difference in the change from week 0 to week 112 in HbA_1c was ?0.3 ± 0.1% (p = 0.051). The incidences of adverse events (AEs), serious AEs and discontinuations because of AEs were similar in the two treatment groups, and hypoglycaemic episodes were reported by no patient receiving vildagliptin and by two patients receiving placebo. Conclusions: In drug‐naïve patients with mild hyperglycaemia, 2‐year treatment with vildagliptin 50 mg once daily attenuated the progressive loss of glycaemic control seen in patients receiving only lifestyle counselling (and placebo). This appears to be because of a corresponding attenuation of the deterioration of β‐cell function as assessed by ISR/G.     

初诊2型糖尿病短期胰岛素强化治疗后胰岛β细胞功能的动态变化

目的观察短期持续胰岛素输注（CSII）对初诊断2型糖尿病（T2DM）患者胰岛β细胞功能的影响,探讨强化治疗的时间。方法对32名FPG≥11mmol/L的初诊断T2DM患者行CSII14d。治疗前、治疗第4天和第15天分别进行OGTT（OGTT组）和精氨酸刺激试验（AST组）,比较两组治疗前后血糖（PG）、稳态模型评估法胰岛素抵抗指数（HOMA-IR）、β细胞功能指数（HOMA-β）、胰岛素分泌指数等指标的变化。结果治疗后两组PG、HOMA-IR降低,HOMA-β增加,14d较3d各指标改善显著;3d后△C30/△G30无升高,△C120/△G120明显升高;14d后两者均升高,差异有统计学意义。治疗3d和14d后精氨酸刺激急性C肽反应无明显变化。结论短期CSII强化治疗FPG明显升高的初诊断T2DM,能显著改善β细胞功能,14d疗效较好。但对非葡萄糖刺激的胰岛素分泌可能无明显影响。     

高血糖对2型糖尿病患者胰岛β细胞功能的抑制作用

目的了解高血糖状态对2型糖尿病患者胰岛β细胞分泌功能的影响。方法应用口服葡萄糖耐量试验（OGTT）观察28例新发2型糖尿病（T2DM）患者在前后不同血糖状态下的胰岛β细胞的分泌功能。结果胰岛素和C肽释放倍数随空腹血糖的下降而升高（P<0.05）;胰岛β细胞功能指数（HOMA-β）与空腹血糖水平呈负相关（P<0.01）。结论空腹高血糖可抑制胰岛β细胞的分泌功能,短期降糖治疗后胰岛β细胞功能可显著改善。     

2型糖尿病患者肺功能改变及影响因素研究

目的检测2型糖尿病患者的肺功能,探讨肺是否为糖尿病病变的靶器官。方法检测120例2型糖尿病患者和40例健康者的肺通气功能、弥散功能以及糖化血红蛋白（HbAlc）并进行比较,40例有并发症糖尿病患者给予胰岛素强化治疗4周后再次检测以了解治疗前后的肺功能变化。结果2型糖尿病组患者肺通气功能及弥散功能均较正常对照组明显降低（P〈0．05）,有并发症组肺通气功能及弥散功能较无并发症组明显降低（P〈0．05）,治疗后患者的一氧化碳弥散量（DLCO）及HbAlC较治疗前有所好转,并与变化相关。结论2型糖尿病患者肺功能受损,肺脏是糖尿病病变的靶器官之一,控制血糖是防治糖尿病患者肺功能损害的重要措施。     

Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin

Aim: To compare the tolerability and efficacy of vildagliptin to pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy over 1‐year duration. Methods: This 52‐week, multicentre, randomized, active‐controlled study compared vildagliptin (50 mg b.i.d., n = 295) and pioglitazone (30 mg daily, n = 281) in patients with inadequate glycaemic control [haemoglobin A1c (HbA_1c) 7.5–11%] receiving a stable dose of metformin (≥1500 mg). The primary objective was to demonstrate non‐inferiority of vildagliptin at 24 weeks in the change in HbA_1c from baseline. The objective of the additional 28 weeks of the study was to assess long‐term safety, while also assessing mean change from baseline to study end in HbA_1c, fasting plasma glucose and body weight. Results: When added to a stable dose of metformin (mean baseline dose approximately 2 g/day), the non‐inferiority of HbA_1c lowering of vildagliptin to pioglitazone over 24 weeks was established at the non‐inferiority margin of 0.3% (between‐group difference = 0.1%). During the remaining 28 weeks, comparable HbA_1c decreases were recorded in both groups. Overall adverse event (AE) rates were similar in both groups, as was the occurrence of peripheral oedema. Hypoglycaemia occurred rarely in both groups. Serious AEs occurred more frequently with pioglitazone group. While mean body weight increased significantly in the pioglitazone group (+2.6 kg) from baseline, there was no significant weight gain with vildagliptin (+0.2 kg). Conclusions: When added to metformin, vildagliptin demonstrates favourable safety and tolerability over 1 year. Vildagliptin provided additional HbA_1c lowering to that achieved with metformin alone and comparable to that achieved with pioglitazone, with only pioglitazone causing weight gain.     

格列吡嗪缓释片与格列齐特对2型糖尿病患者胰岛素抵抗和胰岛β细胞功能的影响

目的　探讨应用磺脲类降糖药物格列吡嗪缓释片 (商品名瑞易宁 )及格列齐特 (商品名达美康 )对 2型糖尿病患者的胰岛 β细胞功能及胰岛素抵抗的影响。 方法　 1 51名 2型糖尿病患者分为瑞易宁及达美康治疗组 ,测定治疗前后空腹血糖 (FPG) ,空腹血清免疫反应胰岛素 (IRI)、真胰岛素 (SI)、胰岛素原(PI)水平 ,计算PI占总胰岛素比例 ,并比较治疗前后HOMA模型中胰岛素抵抗指数 (HOMA IR)及 β细胞功能指数 (HOMA IS)的变化 ,分析血糖下降对胰岛素抵抗的影响。结果　 (1 )两治疗组FPG均较治疗前有显著下降 ,两组间比较差异无显著性。 (2 )治疗后两组HOMA IS均有较明显上升 ,瑞易宁组上升 70 % ;达美康组上升 60 % ,但两组间比较差异无显著性。两组HOMA IR治疗后较治疗前均下降 ,瑞易宁组下降1 5 % ,达美康组下降 1 6 % ,但两组间比较差异无显著性。治疗后HOMA IR的下降与空腹及餐后血糖的下降相关。 (3)患者治疗前空腹PI水平为 (1 1 .93± 2 .2 7) pmol/L ,SI水平为 (55 .32± 1 .66)pmol/L ,PI的比例为 1 9.6 %。治疗后 ,服瑞易宁者空腹PI及SI水平均略有下降 ,但无统计学差异 ;服达美康者空腹血清PI及SI水平均略有上升 ,亦无统计学差异 ;PI在PI与SI总和中所占的比例与治疗前比较差异无显著性。结论　应用HOMA     

Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea

Aim: To compare the efficacy and tolerability of vildagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled [haemoglobin A_1c (HbA_1c) 7.5 to 11%] with prior sulphonylurea (SU) monotherapy. Methods: This 24‐week, multicentre, randomized, double‐blind, placebo‐controlled study assessed the effects of the dipeptidyl peptidase‐4 inhibitor vildagliptin (50 mg given once or twice daily) vs. placebo added to glimepiride (4 mg once daily) in 515 patients with T2DM. Adjusted mean changes from baseline to end‐point (AMΔ) in HbA_1c, fasting plasma glucose, fasting lipids and body weight were compared by analysis of covariance. Results: The between‐group difference (vildagliptin ? placebo) in AMΔ HbA_1c was ?0.6 ± 0.1% in patients receiving vildagliptin 50 mg daily and ?0.7 ± 0.1% in those receiving 100 mg daily (p < 0.001 vs. placebo for both). Greater efficacy was seen in patients ≥65 years of age (?0.7 ± 0.1% and ?0.8 ± 0.2% for 50 and 100 mg daily respectively) and in patients with baseline HbA_1c > 9% (Δ = ?1.0 ± 0.2% and ?0.9 ± 0.2% for 50 and 100 mg daily respectively). Relative to placebo, patients receiving vildagliptin also had improvements in β‐cell function and postprandial glucose, with small changes in fasting lipids and body weight. The incidences of adverse events (AEs) (67.1, 66.3 and 64.2%) and serious AEs (2.9, 2.4 and 5.1%) were similar in patients receiving 50 mg vildagliptin, 100 mg vildagliptin or placebo respectively. The incidence of hypoglycaemic events was low but slightly higher in the group receiving vildagliptin 100 mg (3.6%) than in the group receiving vildagliptin 50 mg (1.2%) or placebo (0.6%). Conclusions: In patients with T2DM inadequately controlled with prior SU monotherapy, addition of vildagliptin (50 or 100 mg daily) to glimepiride (4 mg once daily) improves glycaemic control and is well tolerated. Addition of vildagliptin 50 mg daily to SU monotherapy may be a particularly attractive therapy in elderly patients.     

Efficacy and safety of nateglinide plus vildagliptin combination therapy compared with switching to vildagliptin in type 2 diabetes patients inadequately controlled with nateglinide

Aims/Introduction

To investigate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase‐4 inhibitor, as add‐on to nateglinide, compared with switching to vildagliptin in Japanese type 2 diabetes patients poorly controlled with nateglinide.

Materials and Methods

A total of 40 patients inadequately controlled with nateglinide were randomized to the switching group (n = 20, switching from nateglinide to vildagliptin) or combination group (n = 20, nateglinide plus vildagliptin). A meal tolerance test was carried out at weeks 0 and 24.

Results

The mean changes in glycated hemoglobin from baseline to week 24 were −1.2 ± 0.3% and −0.3 ± 0.5% in patients of the combination and switching groups, respectively, and the difference between the groups was statistically significant (P < 0.001). The mean changes in area under the curve of glucose from 0 to 180 min (AUC_0–180 min) from baseline to week 24 was −361 ± 271.3 mmol·min/L in patients of the combination group compared with 141 ± 241.9 mmol·min/L in those of the switching group (P < 0.001). The incidence of hypoglycemic events was low (three in the combination group), and none of the patients developed severe hypoglycemia. Although the addition of vildagliptin to nateglinide did not significantly increase insulin secretion relative to glucose elevation (ISG) after meal load (ISG_0–180 min: AUC_0–180 min insulin / AUC_0–180 min glucose) in comparison with that in baseline, the mean ISG_0–30 min 24 weeks after addition of vildagliptin to nateglinide was significantly higher than that at baseline. In contrast, switching from nateglinide to vildagliptin reduced the mean ISG_0–180 min, relative to baseline.

Conclusions

The combination therapy of vildagliptin and nateglinide is effective and safe in Japanese type 2 diabetes, and the improved glycemic control is as a result of augmentation of nateglinide‐induced early phase insulin secretion. This trial was registered with UMIN (no. ID000004010).     

Characterization of the chlorpropamide-alcohol-flush in patients with type 1 and type 2 diabetes

Summary The aim of the present paper was to evaluate the prevalence of the chlorpropamide-alcohol-flush (CPAF) in patients with type 2 and with type 1 diabetes. Ninety-seven patients with type 2 diabetes and 33 with type 1 diabetes drank 40 ml vermouth 12 h after placebo and again 12 h after 1 tablet of chlorpropamide (250 mg) or 12 h after the last of repeated administrations of chlorpropamide (250 mg b.i.d. for 2 days). Skin temperature was recorded in all patients by a thermocouple probe connected to the left cheek. In 47 patients serum concentrations of chlorpropamide and of its metabolite CBSU were also determined. The prevalence of CPAF was similar in type 1 and type 2 diabetes, was greater in women than in men, and was significantly greater after repeated administrations than after one single administration of chlorpropamide. The increase of skin temperature during a 30-min period was significantly higher in patients with CPAF than in patients without CPAF. Serum concentrations of chlorpropamide and of its metabolite CBSU were more elevated after 4 than after 1 tablet of chlorpropamide, but were not significantly different in patients with and without CPAF. These data indicate that both genetic factors and the amount of chlorpropamide used affect the appearance of CPAF. To assess the possible role of serotonin and of dopamine in the CPAF, some patients with CPAF were tested again after treatment with metergoline, an antiserotonin agent, or with bromocriptine, a dopamine-agonist. Neither drug influenced the CPAF, indicating that the two neurotransmitters are not involved in the CPAF.     

正常糖耐量、糖耐量受损及新诊断2型糖尿病人群胰岛β细胞功能的变化

胰岛β细胞功能自NGT到IGT再到T2DM呈进行性下降，所依证据是HOMA—β，△I30／△G30、前胰岛素和C肽的比值(PI／CP)。PI／CP可能是测定胰岛β细胞功能的较好指标。     

铁过负荷对2型糖尿病患者糖脂代谢和胰岛β细胞功能的影响

目的 探讨铁过负荷对2型糖尿病患者糖脂代谢和胰岛β细胞功能的影响.方法 302例2型糖尿病患者根据血清铁蛋白水平分为铁蛋白升高组.比较两组的空腹和餐后2小时的血糖、C肽、糖化血红蛋白(HbA1C)、血清总胆固醇、甘油三酯的水平.结果 铁蛋白升高组的空腹和餐后2小时血糖、HbA1C高于铁蛋白正常组,餐后2小时C肽低于铁蛋白正常组.结论 铁过负荷可能对2型糖尿病患者的胰岛β细胞功能和血糖控制产生负面影响.     

胰岛β细胞功能紊乱与2型糖尿病

胰岛β细胞功能受损和胰岛素抵抗是2型糖尿病的两大致病机制。β细胞功能，尤其早时相胰岛素分泌，对维持正常葡萄糖代谢有重要作用。在从正常糖耐量向糖尿病进展的过程中，β细胞功能呈进行性下降，早期应用促进或模拟早时相胰岛素分泌的药物保护β细胞功能有助于延缓糖尿病的进展。     

The effect of hyperinsulinemia and hyperglycemia on endothelial function in pregnant patients with type-2 diabetes

We studied endothelial function (flow mediated vasodilation, FMD) during hyperinsulinemia and hyperglycemia in pregnant women with type-2 diabetes, in the second and third trimester. We found that hyperglycemia reduces FMD in late pregnancy.     

Beta cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive patients with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial

Aims/hypothesis

Traditional blood glucose lowering agents do not prevent the progressive loss of beta cell function in patients with type 2 diabetes. The dipeptidylpeptidase (DPP)-4 inhibitor vildagliptin improves beta cell function both acutely and chronically (up to 2?years). Whether this effect persists after cessation of treatment remains unknown. Here, we assessed the insulin secretory capacity in drug-naive patients with type 2 diabetes after a 52?week treatment period with vildagliptin or placebo, and again after a 12?week washout period.

Methods

This study was conducted at a single university medical centre, and was a double-blind, randomised clinical trial in 59 drug-naive patients with type 2 diabetes and mild hyperglycaemia to either vildagliptin 100?mg (n?=?29) or placebo (n?=?30). Randomisation was performed by a validated 1:1 system. Neither patient, nor caregiver, was informed about the assigned treatment. Inclusion criteria were drug-naive patients ??30?years, with HbA_1c ??7.5% and BMI of 22?C45?kg/m². The mildly hyperglycaemic patient population was chosen to minimise glucose toxicity as a confounding variable. Beta-cell function was measured during an arginine-stimulated hyperglycaemic clamp at week?0, week?52 and after a 12?week washout period. All patients with at least one post-randomisation measure were analysed (intent-to-treat).

Results

Fifty-two week vildagliptin 100?mg (n?=?26) treatment increased the primary efficacy variable, combined hyperglycaemia and arginine-stimulated C-peptide secretion (AIR_arg), by 5.0?±?1.8?nmol/l?×?min, while it decreased by 0.8?±?1.8?nmol/l?×?min with placebo (n?=?25) (between-group difference p?=?0.030). No significant between-group difference in AIR_arg was seen after the 12?week washout period. The between-group difference adjusted mean 52?week changes from baseline was ?0.19?±?0.11, p?=?0.098 and ?0.22?±?0.23%, p?=?0.343 for HbA_1c and fasting plasma glucose, respectively. There were no suspected drug treatment-related serious adverse events.

Conclusions/interpretation

One year treatment with vildagliptin significantly increased beta cell secretory capacity. This effect was not maintained after the washout, indicating that this increased capacity was not a disease modifying effect on beta cell mass and/or function.

Trial registration:

ClinicalTrials.gov NCT00260156

Funding:

This study was sponsored by the Novartis Pharmaceutical Cooperation.