血脂异常对2型糖尿病患者胰岛素分泌功能的影响

目的 探讨血脂异常对T2DM患者胰岛素分泌功能的影响.方法 初诊的T2DM患者100例,未经调脂和降糖治疗,根据血脂水平分为血脂正常组(A组)、单纯TG升高组(B组)和混合血脂升高组(C组),以30名健康者作对照(NC组),采用HOMA-β评价β细胞分泌功能.结果 与NC组比较,A、B、C三组的HOMA-β均明显降低(P＜0.01);与A组比较,B、C组的HOMA-β降低(P＜0.01);B、C组之间比较差异无统计学意义(P＞0.05).HOMA-β相关因素回归分析显示TG为独立影响因素.结论 TG升高可降低T2DM患者的胰岛素分泌功能,TC没有独立于TG以外的降低胰岛素分泌功能的作用.     

Effects of bezafibrate on insulin secretion and peripheral insulin sensitivity in hyperlipidemic patients with and without diabetes

Although it has been reported that bezafibrate influences carbohydrate metabolism, this possibility has never been properly evaluated in a controlled clinical trial. In this study we attempted to evaluate the effects of bezafibrate on plasma lipoproteins, glucose tolerance, insulin secretion and peripheral insulin sensitivity in a group of hypertriglyceridemic patients with and without diabetes. Sixteen hyperlipidemic patients (10 males and 6 females) participated in the study. Eight had type IIB and 8 type IV hyperlipoproteinemia; 6 of them also had non-insulin dependent diabetes mellitus. The study was performed according to a double blind, crossover design: after 1 month wash-out period in which patients were on diet alone, they underwent, in a random order, a period of placebo therapy and another period in which they received a single daily dose of a long-acting bezafibrate preparation (400 mg) administered in the evening. Each treatment lasted 2 months. Total plasma and VLDL triglyceride concentrations were consistently reduced by bezafibrate (-46%, P less than 0.001; and -50%, P less than 0.001). Total and VLDL-cholesterol were also reduced by bezafibrate. The effects of bezafibrate on lipoproteins were similar in diabetic and non-diabetic subjects. Bezafibrate treatment did not influence fasting blood glucose concentration, glucose tolerance, peripheral insulin sensitivity or insulin secretion. In conclusion, the results of this controlled trial clearly indicate that bezafibrate can be successfully employed to lower plasma lipid levels in patients with non-insulin dependent diabetes mellitus and hyperlipidemia.     

脂代谢紊乱对2型糖尿病患者早期胰岛素分泌的影响

目的了解脂代谢紊乱对2型糖尿病（T2DM）患者早期胰岛素分泌功能的影响。方法93例未经调脂和降糖治疗的新诊T2DM患者根据血脂水平分为正常血脂组（B组）、单纯TG升高组（C组）和混合血脂升高组（D组），20例体检正常者为健康对照组（A组），根据OGTT结果计算和分析早期胰岛素分泌指数△I30／△G30和HOMA-IR。结果各组之间△I30／△G30比较：B、C、D组与A组之间差异有统计学意义（P〈0．01，P〈0．05和P〈0．05），C、D组与B组之间差异有统计学意义（P〈0．05），C组与D组之间差异无统计学意义（P〉0．05）；各组之间HOMA-IR比较：B、C、D组与A组之间差异有统计学意义（P〈0.05），D组与B组之间差异有统计学意义（P〈0.01），C组与B组之间差异无统计学意义（P〉005）。结论T2DM患者同时存在早期胰岛素分泌缺陷和胰岛素抵抗（IR），血脂异常与早期胰岛素分泌功能降低和IR相关。     

Insulin secretion and insulin action in Taiwanese with type 2 diabetes

In contrast to the United State, type 2 diabetes appears to be a common occurrence in non-obese Asians. In order to evaluate the possibility that this epidemiologic difference was indicative of a basic metabolic phenomenon, estimates of insulin secretion and insulin action were generated in 32 Chinese males, 16 with type 2 diabetes and 16 with normal glucose tolerance. Half of the individuals in each diagnostic category were obese (body mass index greater than 28 kg/m2) and half were non-obese (less than 26 kg/m2). Plasma glucose responses to a 75-g oral glucose challenge were significantly higher in patients with type 2 diabetes, but did not vary significantly within either group as a function of obesity. Plasma insulin concentrations were lower than normal when patients with type 2 diabetes were compared to their weight-matched controls. In addition, the absolute insulin values also varied as a function of body weight, with higher plasma insulin concentrations observed in the obese individuals. Insulin action was estimated by determination of the steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations during the last 60 min of a continuous 180-min intravenous infusion of somatostatin, crystalline insulin, and glucose. Under these conditions endogenous insulin secretion is suppressed, SSPI concentrations are similar in all individuals, and SSPG concentrations provide a quantitative estimate of insulin-stimulated glucose disposal. The results of these studies indicated that patients with type 2 diabetes had significantly elevated SSPG concentrations as compared to normals, and this was true whether the diabetic subjects were obese or non-obese.(ABSTRACT TRUNCATED AT 250 WORDS)     

2型糖尿病微血管病变患者的胰岛素分泌功能分析

目的 探讨2型糖尿病微血管病变患者的胰岛分泌功能情况及相关因素。方法 应用馒头餐－胰岛素释放试验对115例2型糖尿病患者,其中有微血管并发症56例,无微血管并发症59例,以及正常对照组25例进行血糖、胰岛素测定,计算血糖、胰岛素曲线面积、胰岛素敏感性指数、胰岛素分泌指数,并进行了比较。结果 糖尿病两组各时相血糖值及血糖面积均非常显著高于正常对照组;糖尿病有微血管病变组各时相血糖值及血糖面积高于无微血管病变组（P均＜0．001）。糖尿病有微血管病变且各时相胰岛素值及胰岛素面积均显著低于无微血管病变组（P均＜0．01）,糖尿病有微血管病变组胰岛素分泌指数显著低于无微血管病变组（P＜0．001）。多元Logistic逐步回归分析显示,微血管变与糖尿病病程呈显著正相关,与胰岛素分泌指数呈显著负相关。结论 2型糖尿病微血管病变患者存在严重的持续性高血糖。糖尿病病程的延长,严重的胰岛分泌功能障碍为2型糖尿病微血管病变的主要危险因素。     

Abnormalities in insulin secretion in type 2 diabetes mellitus

Type 2 diabetes mellitus is a multifactorial disease, due to decreased glucose peripheral uptake, and increased hepatic glucose production, due to reduced both insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including absence of pulsatility, loss of early phase of insulin secretion after glucose, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. beta-cell dysfunction is genetically determined and appears early in the course of the disease. The interplay between insulin secretory defect and insulin resistance is now better understood. In subjects with normal beta-cell function, increase in insulin is compensated by an increase in insulin secretion and plasma glucose levels remain normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate leads to a progressive elevation in plasma glucose levels, then to overt diabetes. When permanent hyperglycaemia is present, progressive severe insulin secretory failure with time ensues, due to glucotoxicity and lipotoxicity, and oxidative stress. A marked reduction in beta-cell mass at post-mortem examination of pancreas of patients with type 2 diabetes has been reported, with an increase in beta-cell apoptosis non-compensated by neogenesis.     

Indomethacin decreases insulin secretion in patients with type 2 diabetes mellitus

In healthy subjects, basal endogenous glucose production (EGP) is partly regulated by paracrine intrahepatic factors. Administration of indomethacin, an inhibitor of prostaglandin synthesis, resulted in a transient stimulation of EGP without changes in glucoregulatory hormone concentrations. It is unknown whether similar paracrine factors influence basal EGP in type 2 diabetes mellitus. The effects of 150 mg indomethacin, a nonendocrine stimulator of glucose production in healthy adults, and placebo on EGP were measured in a randomized placebo-controlled study in patients with type 2 diabetes mellitus (3 men and 3 women; mean age, 58.5 years; mean body mass index, 28.6 kg x m(-2)). EGP was measured before and for 6 hours after administration of placebo/indomethacin, by a primed, continuous infusion of [6,6-2H2]glucose. After indomethacin, plasma glucose and EGP increased in all subjects by 14% (P < .05) and 48% (P < .05), respectively. In the control experiment, plasma glucose and EGP declined gradually in all subjects by 22% (P < .001) and 17% (P = .004), respectively. The stimulation of glucose production coincided with the inhibition of insulin secretion by 52% within 1 hour after administration of indomethacin (P < .001). In the control experiment, insulin secretion decreased gradually by 18% after 6 hours (P < .001). Thus, indomethacin inhibits insulin secretion and stimulates EGP in type 2 diabetes.     

Aminophylline stimulates insulin secretion in patients with type 2 diabetes mellitus

In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone concentrations. To evaluate the modulatory role of adenosine on endogenous glucose production and basal insulin secretion in type 2 diabetes, aminophylline, a potent adenosine receptor antagonist, was administered intravenously to 5 patients with type 2 diabetes mellitus in a saline-controlled study. Endogenous glucose production was measured before and during 6 hours after administration of aminophylline/saline by primed, continuous infusion of [6,6-(2)H(2)]glucose. During both experiments, the decrease in plasma glucose concentration was similar (16% v 18% from basal, not significant [NS]). After aminophylline administration, basal endogenous glucose production was transiently inhibited within 15 minutes to 70% from basal, whereas it did not change significantly in the control experiment (P =.02). The inhibition of glucose production coincided with stimulation of insulin secretion to 144% from basal 90 minutes after the administration of aminophylline (P =.008). In the control experiment insulin secretion decreased gradually by 29% during 6 hours. We conclude that aminophylline inhibits endogenous glucose production in type 2 diabetes by stimulation of insulin secretion. Paracrine factors, such as adenosine, may be involved in the regulation of basal insulin secretion in type 2 diabetes mellitus.     

Effects of nateglinide on the secretion of glycated insulin and glucose tolerance in type 2 diabetes

AIMS: Glycation of insulin has been demonstrated within pancreatic beta-cells and the resulting impaired bioactivity may contribute to insulin resistance in diabetes. We used a novel radioimmunoassay to evaluate the effect of nateglinide on plasma concentrations of glycated insulin and glucose tolerance in type 2 diabetes. METHODS: Ten patients (5 M/5 F, age 57.8+/-1.9 years, HbA(1c) 7.6+/-0.5%, fasting plasma glucose 9.4+/-1.2 mmol/l, creatinine 81.6+/-4.5 microM/l) received oral nateglinide 120 mg or placebo, 10 min prior to 75 g oral glucose in a random, single blind, crossover design, 1 week apart. Blood samples were taken for glycated insulin, glucose, insulin and C-peptide over 225 min. RESULTS: Plasma glucose and glycated insulin responses were reduced by 9% (P=0.005) and 38% (P=0.047), respectively, following nateglinide compared with placebo. Corresponding AUC measures for insulin and C-peptide were enhanced by 36% (P=0.005) and 25% (P=0.007) by nateglinide. CONCLUSIONS: Glycated insulin in type 2 diabetes is reduced in response to the insulin secretagogue nateglinide, resulting in preferential release of native insulin. Since glycated insulin exhibits impaired biological activity, reduced glycated insulin release may contribute to the antihyperglycaemic action of nateglinide.     

中国新诊断2型糖尿病胰岛素分泌和胰岛素抵抗特点调查

目的 研究中国新诊断2型糖尿病患者胰岛素分泌功能(IS)及胰岛素抵抗(IR)状况.方法 对405例新诊断2型糖尿病患者和40名糖耐量正常者(对照组)测量身高、体重;行口服葡萄糖耐量试验(OGTT)及胰岛素释放试验.按空腹血糖(FPG)水平分为4组,与对照组比较.93例FPG≥8.3mmol/L者应用格列齐特(达美康)缓释片进行干预治疗1～3个月,血糖达标后重复OGTT并计算干预后的IR及IS.结果 (1)随着FPG水平的升高,糖尿病各组IR、IS逐级恶化:在FPG≥9.7mmol/L组,胰岛素敏感性为正常组的30%,IS仅为正常组的5%;(2)在FPG<9mmol/L组,IR能解释70%的血糖水平变化,而在FPG高于≥9mmol/L组,IS能解释60%的血糖变化;(3)格列齐特缓释片干预治疗IR及IS有了显著的改善.结论 新诊断2型糖尿病的IR及IS随空腹血糖升高而恶化,但是IS恶化更为严重;这种双重恶化在高血糖状态得到纠正后在相当程度上是可逆的.     

Impaired early insulin secretion in Japanese type 2 diabetes with metabolic syndrome

Although it is widely believed that type 2 diabetics with metabolic syndrome (MS) have insulin resistance, the beta-cell function of these patients is largely unknown. We evaluated the characteristics of insulin secretion in Japanese type 2 diabetics with MS after minimizing the influence of glucotoxity. A 75-g OGTT was performed in 192 diabetic subjects and 275 subjects with normal glucose tolerance (NGT). Although there was no significant difference of the AUC (insulin(0-120)) between the MS group and the NGT group, the insulinogenic index (I.I.) was significantly lower in MS patients compared with NGT subjects. The BMI, maximum BMI, waist circumference, and VFA were all positively correlated with I.I. in the MS group (r=0.298-0.376). By stepwise multiple regression analysis, the BMI was shown to be an independent determinant of I.I. in the MS group (standardized regression coefficient: 0.376, p=0.0004), and it accounted for 13% of the variance in I.I. The impaired I.I. was also found in the MS group with untreated type 2 diabetes. These results indicate that early insulin secretion is impaired in type 2 diabetics with MS. The positive association between BMI and I.I. in diabetics with MS may be explained by beta-cell compensation for reduced insulin sensitivity.     

Effects of Goshajinkigan on insulin resistance in patients with type 2 diabetes

We investigated the effects of Goshajinkigan (GJG), a Chinese herbal medicine, on insulin sensitivity in patients with type 2 diabetes using the homeostasis model assessment of insulin resistance (HOMA-R) and the euglycemic insulin clamp procedure. Daily oral administration of GJG (7.5 g/day) was performed for 1 month in 71 type 2 diabetes patients: the GJG treatment group. HOMA-Rs were calculated before and after 1 month of GJG treatment and compared with those of 44 controls who were matched in terms of sex, age, body mass index (BMI) and HbA1c levels with the experimental group. In 64 patients out of the GJG treatment group, HOMA-R was calculated 1 month after discontinuation of treatment. In addition, euglycemic clamp was conducted in eight patients before and after the GJG treatment. HOMA-R was 4.78+/-0.37 (means+/-S.E.) before GJG treatment and significantly decreased to 4.02+/-0.25 after GJG treatment (P=0.019). No significant change was observed in the control group. HOMA-R returned to the pre-treatment level (P=0.018) 1 month after GJG treatment discontinuation. Glucose infusion rates and metabolic clearance rates determined by the high-dose euglycemic clamp increased after 1 month of GJG treatment (from 9.6+/-1.1 to 11.1+/-0.7 mg/kg/min, P=0.045 and from 7.9+/-0.8 to 9.1+/-0.8 ml/kg/min, P=0.046, respectively). These results indicate that GJG administration might be useful for improving insulin resistance in patients with type 2 diabetes.     

Characterization of insulin secretion and resistance in type 2 diabetes of adolescents

CONTEXT: Type 2 diabetes (T2D) in obese children is an emerging problem, including in Europe. Its presentation at diagnosis very often differs from that in adults. OBJECTIVE: The objective of this study was to investigate the relative contributions of the two components of T2D, insulin resistance and insulin secretion, early in the history of the disease in adolescents. PATIENTS AND METHODS: Six obese adolescents with T2D were included 2 months to 4.3 yr after diagnosis (five girls and one boy; median age, 15.4 yr; median body mass index, 4.4 sd). Peripheral and hepatic insulin sensitivity was evaluated with euglycemic hyperinsulinemic (40 mU/m(2).min) clamp. First-phase insulin release was evaluated after iv glucose stimulation. A graded iv glucose infusion and an arginine test were performed to measure insulin secretion. RESULTS: All patients showed decreased peripheral glucose uptake to the same extent. Five patients showed hepatic insulin resistance. First-phase insulin release was very low in two patients. Three patients showed an exaggerated insulin response under graded glucose infusion and preserved secretion under arginine stimulation. Three other patients, with elevated fasting plasma glucose levels, demonstrated a very low insulin response under glucose stimulation and a low insulin response under arginine stimulation. CONCLUSIONS: These data emphasize that together with marked insulin resistance, the failure of beta-cell function is a major component in the course of T2D in childhood.     

短期胰岛素泵强化治疗对新诊断2型糖尿病患者胰岛素分泌和敏感性的影响

目的 探讨短期胰岛素泵强化治疗对新诊断2型糖尿病患者胰岛素敏感性和胰岛素分泌功能的影响.方法 选取2006年6月至2007年2月在本院就诊的新诊断2型糖尿病患者10例进行为期2周的胰岛素泵强化治疗,在治疗前和停泵24 h后分别进行两次静脉葡萄糖耐量试验(IVGTT)和高胰岛素-正葡萄糖钳夹试验.结果 (1)在治疗前所有糖尿病患者均缺乏急性胰岛素分泌(AIR),经2周强化治疗使血糖正常后,所有患者AIR均有了不同程度地恢复[(7.63±4.73 vs 0.83±1.96)mU/L,P＜0.01)].AIR恢复较好的患者略为年轻和肥胖.(2)糖耐量正常志愿者平均葡萄糖输注率(GIR)为(8.26±2.48)mg·kg-1·min-1,而初发2型糖尿病患者在胰岛素泵强化治疗前GIR为(2.30±0.81)mg·kg-1·min-1(与正常者比,P＜0.01),胰岛素泵强化治疗后GIR升高到(5.33±1.43)mg·kg-1·min-1(P＜0.01).GIR升高显著的患者腰围和体重指数低、治疗前的平均血糖高.结论 短期胰岛素泵强化治疗使血糖"正常化",同时可改善胰岛细胞功能,提高胰岛素敏感性.     

Undercarboxylated osteocalcin can predict insulin secretion ability in type 2 diabetes

It has been reported that there is an intimate relationship between diabetes and bone metabolism including undercarboxylated osteocalcin (ucOC). In contrast, data on the relationship between ucOC and glucose metabolism are limited in type 2 diabetes. We recruited 50 Japanese patients with type 2 diabetes, and examined the association with ucOC on the insulin secretion, evaluated by both glucagon loading test and meal tolerance test. UcOC was shown to correlate positively with the change in C‐peptide response in the glucagon loading test and C‐peptide response after eating a meal (P = 0.025, P = 0.047). Therefore, ucOC reflects the reserve capacity of β‐cell function, such as the bolus insulin secretion ability in patients with type 2 diabetes.     

High-density lipoprotein subspecies between patients with type 1 diabetes and type 2 diabetes without / with intensive insulin therapy

The reduced levels of high-density lipoprotein (HDL) 2-cholesterol (C) in diabetes and other metabolic disorders associated with a high risk of cardiovascular disease are well established. Few studies, however, have compared the HDL subspecies in type 1 diabetes (T1D) with those in type 2 diabetes (T2D) with or without insulin. We examined HDL subspecies in 27 T1D with insulin, 33 T2D with insulin or insulin plus oral-anti-diabetic drugs (OADs), 36 T2D with OADs or diet/exercise, and 25 non-diabetic controls. Insulin was injected four times daily in a basal-bolus manner for both T1D and T2D. Plasma levels of C, apolipoprotein (apo) AI, and AII were determined in HDL2 and HDL3 by the single precipitation method. HDL-C levels were significantly higher in T1D and lower in T2D, compared with the controls. Insulin-treated T2D had higher HDL-C than non-insulin-treated T2D. T1D had higher HDL2-C and HDL2-apo AI levels than T2D. Insulin-treated T2D had higher HDL2-C and HDL2-apo AI levels than non-insulin-treated T2D. All of these differences were more pronounced for men than for women. HDL3 levels were comparable among controls,T1D and T2D. HDL2-C levels were inversely associated with BMI, HbA1c, triglyceride, small dense LDL-C, and LDL-C. Multiple regression analysis revealed that HDL2-C was independently associated with triglyceride, LDL-C, and intensive insulin therapy but not with HbA1c. In conclusion, these results suggest that intensive insulin therapy is associated with alterations of HDL subspecies, irrespective of the type of diabetes.     

Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus

This study assessed the synergistic effects of nateglinide (a non-sulfonylurea D-phenylalanine derivative) and meals on insulin secretion in 24 patients with type 2 diabetes. Oral doses of 60 and 180 mg or 120 and 240 mg were administered to two cohorts of subjects 10 min before meals (or fasting) three times daily for 7 days, with washout intervals between treatment periods. Dose-dependent increases in plasma insulin occurred, with the peak effect within 2 h after treatment. Significantly greater insulin secretion was observed when nateglinide was taken before a meal compared to nateglinide given in the fasted state or in response to just the meal. Nateglinide lowered plasma glucose concentrations significantly vs. placebo at all doses, and doses of 120 and 240 mg were more effective than 60 mg (P < 0.05). Adverse event rates were similar for nateglinide and placebo, and no hypoglycemic episodes or serious adverse events were reported during the study. Nateglinide (120 mg) was the maximum effective dose in this study and was shown to be a safe and well tolerated therapy for control of mealtime glucose excursions in patients with type 2 diabetes. Results indicate that a synergistic interaction occurs between nateglinide and elevated mealtime plasma glucose concentrations to stimulate insulin secretion.