The effect of pirenzepine on growth hormone and blood glucose levels in type I diabetes mellitus. A controlled study in patients on basal bolus insulin treatment

Increased GH levels in Type I diabetes mellitus have been implicated in the pathogenesis of metabolic complications such as the so-called dawn phenomenon. GH secretion is under control of cholinergic mechanisms. In 21 Type I diabetic patients the effect of oral administration of the anticholinergic drug pirenzepine in addition to intensive insulin therapy on GH and blood glucose levels was studied. At 21.30, 08.00 and 12.00 h, all patients received in random order 50 mg of pirenzepine or placebo po. Blood for determination of GH, blood glucose, cortisol and C-peptide levels were obtained at 3-h intervals. Serum levels of plasma glucose and GH were significantly lower under pirenzepine than under placebo (P less than 0.05 and P less than 0.01, respectively). Serum levels of cortisol, free insulin and C-peptide were comparable on the test and the control day. Our data indicate that in Type I diabetes mellitus the anticholinergic drug pirenzepine is effective in decreasing both GH and blood glucose levels.     

Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression

Our previous work demonstrated that berberine (BBR) increases insulin receptor (InsR) expression and improves glucose utility both in vitro and in animal models. Here, we study the InsR-up-regulating and glucose-lowering activities of BBR in humans. Our results showed that BBR increased InsR messenger RNA and protein expression in a variety of human cell lines, including CEM, HCT-116, SW1990, HT1080, 293T, and hepatitis B virus-transfected human liver cells. Accordingly, insulin-stimulated phosphorylations of InsR β-subunit and Akt were increased after BBR treatment in cultured cells. In the clinical study, BBR significantly lowered fasting blood glucose (FBG), hemoglobin A_1c, triglyceride, and insulin levels in patients with type 2 diabetes mellitus (T2DM). The FBG- and hemoglobin A_1c-lowering efficacies of BBR were similar to those of metformin and rosiglitazone. In the BBR-treated patients, the percentages of peripheral blood lymphocytes that express InsR were significantly elevated after therapy. Berberine also lowered FBG effectively in chronic hepatitis B and hepatitis C patients with T2DM or impaired fasting glucose. Liver function was improved greatly in these patients by showing reduction of liver enzymes. Our results confirmed the activity of BBR on InsR in humans and its relationship with the glucose-lowering effect. Together with our previous report, we strongly suggest BBR as an ideal medicine for T2DM with a mechanism different from metformin and rosiglitazone.     

Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a meta-analysis

AimsThe efficacy of the once-daily prandial GLP-1 receptor agonist lixisenatide plus basal insulin in T2DM was assessed by pooling results of phase III trials.MethodsA meta-analysis was performed of results from three trials in the GetGoal clinical program concerning lixisenatide or placebo plus basal insulin with/without OADs. The primary endpoint was change in HbA_1c from baseline to week 24. Secondary endpoints were change in PPG, FPG, insulin dose, and weight from baseline to week 24. Hypoglycemia rates and several composite endpoints were assessed.ResultsLixisenatide plus basal insulin was significantly more effective than basal insulin alone at reducing HbA_1c at 24 weeks. Composite and secondary endpoints were improved significantly with lixisenatide plus basal insulin, with the exception of FPG, which showed no significant difference between the groups. Lixisenatide plus basal insulin was associated with an increased incidence of hypoglycemia versus basal insulin alone.ConclusionsLixisenatide plus basal insulin resulted in significant improvement in glycemic control versus basal insulin alone, particularly in terms of controlling PPG. Prandial lixisenatide in combination with basal insulin is a suitable option for treatment intensification in patients with T2DM insufficiently controlled with basal insulin, as these agents have complementary effects on PPG and FPG, respectively.     

Intramuscular versus subcutaneous injection of unmodified insulin: consequences for blood glucose control in patients with type 1 diabetes mellitus

Using the perpendicular injection technique lean diabetic patients may often inject insulin intramuscularly (IM). Guided by ultrasound measurements of the subcutaneous (SC) thickness of the thigh, the aim of the present study was to re-evaluate the absorption kinetics of unmodified insulin from IM and SC injection sites and to evaluate the consequences of IM injection of unmodified insulin for blood glucose control in Type 1 diabetic patients. T50% values (time until 50% of the injected insulin is absorbed from the injection site) of SC injected, radioactively labelled, human unmodified insulin (125I-Actrapid) were 338 +/- 13 (+/- SE) min, 289 +/- 27 min, and 287 +/- 27 min during rest, light physical activity, and strenuous exercise, respectively. Intramuscularly injected unmodified insulin was absorbed faster, T50% 232 +/- 20 min, 113 +/- 13 min, and 112 +/- 5 min during the same levels of physical activity in the same order. When unmodified insulin (Actrapid) was given IM 30 min before breakfast, lunch, and dinner together with intermediate-acting insulin (Protaphane) SC at 2200 h, a more physiological profile of plasma free insulin and a more stable blood glucose profile was obtained than with SC administration into the thigh. The coefficient of variation of blood glucose concentration during the study (3 days each route) was lower with IM than with SC injection of unmodified insulin (33 +/- 4 vs 43 +/- 3%, p less than 0.01). No difference in frequency of hypoglycaemic attacks was found and patients claimed that IM injection was no more painful than SC injection. These data suggest that IM injection of soluble insulin into the thigh is beneficial.     

胰岛素抗体阳性和阴性的2型糖尿病患者血糖波动水平比较

目的探讨胰岛素自身抗体（IAA）阳性和阴性的2型糖尿病（T2DM）患者的血糖波动情况,分析影响IAA产生的有关因素。方法连续纳入2009年5月至2012年3月华西医院内分泌科住院的T2DM患者62例,所有患者均应用动态血糖监测系统进行72h血糖监测,并检测糖化血红蛋白（HbAlc）、IAA、血脂、肝肾功能。根据IAA检查结果,将患者分为抗体阳性组（3l例）和抗体阴性组（31例）。记录两组受试者的空腹血糖、血糖水平的标准差、早餐后血糖波动、午餐后血糖波动（PPGEAL）、晚餐后血糖波动、平均餐后血糖波动（MPPGE）、平均血糖波动幅度（MAGE）,最大血糖波动幅度（LAGE）、日间血糖平均绝对差。并通过患者的年龄、性别、治疗方式、体质量指数、高血压病史及高血脂病史预测胰岛素抗体产生的相关性,采用多元逐步回归方法建立上述指标的多元logistic回归方程。结果抗体阳性组患者的平均血糖标准差,MAGE,LAGE,PPGEAL均大于抗体阴性组,差异有统计学意义（P值分别为O．031,0．010,0．021,0．030）;但两组患者的其他指标均没有统计学意义（P〉0．05）;多元logistic逐步回归分析显示,治疗方式与IAA产生的风险性有关。结论IAA阳性较IAA阴性T2DM患者的日内血糖波动幅度更大,两组日间血糖波动幅度无明显差异。使用外源性胰岛素治疗与胰岛素抗体的产生具相关性,使用胰岛素注射治疗的患者产生胰岛素抗体的风险性是口服降糖药治疗患者的5．525倍。     

Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus

Aim: Colesevelam lowers glucose and low‐density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. Methods: In this 12‐week, randomized, double‐blind, placebo‐controlled study, subjects with type 2 diabetes and haemoglobin A_1c(HbA_1c) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of ³H‐labelled glucose followed by a 2‐step hyperinsulinemic–euglycemic clamp. Two 75‐g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co‐administration of colesevelam. A final OGTT was conducted at week 12. HbA_1c and fasting plasma glucose (FPG) levels were evaluated pre‐ and post‐treatment. Results: Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady‐state glucose disposal rate. At baseline, co‐administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC_g) but not incremental AUC_g. At week 12, neither total AUC_g nor incremental AUC_g were changed from pre‐treatment values in either group. Post‐load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC_i) and incremental AUC_i did not differ between groups. Both HbA_1c and FPG improved with colesevelam, but treatment differences were not significant. Conclusions: Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.     

Assessment of basal insulin requirement using fasting tests in insulin-treated patients with type 2 diabetes mellitus.

AIMS: Characterizing the time course of the rise of blood glucose concentrations in the fasting state during the day and night in patients with type 2 diabetes. METHODS: 40 consecutive insulin-treated patients with type 2 diabetes underwent fasting tests on two different days with either no breakfast and lunch (fasting time of 20 hours) or no dinner (fasting time of 21 hours). Glucose-lowering medication was stopped prior to the test according to the half-life of the medication prescribed. At the start of the fasting tests, blood glucose concentrations were lowered to below 7 mmol/L using an insulin infusion. RESULTS: 26 men and 14 women were included in the study. Mean (+/-SD) age was 61+/-10 years, BMI 31+/-7 kg/m (2), and HbA1c 7.5+/-1%. Diabetes duration was 14+/-8 years and duration of insulin therapy had been prescribed for a mean of 6+/-6 years. During the daytime fast, plasma glucose concentrations rose by a mean of 0.8+/-1.6 mmol/L. During the nighttime fast, plasma glucose concentrations increased particularly after midnight, by 4.3+/-2.1 mmol/L, i.e. significantly more than during the daytime fast. CONCLUSIONS: Fasting blood glucose concentrations in the majority of insulin-treated patients with type 2 diabetes increase markedly after midnight. No similar increase is observed during the day. Thus, for most patients with type 2 diabetes, an intermediate- or long-acting insulin injected at bedtime with a peak action six to eight hours after injection should be appropriate.     

重组人门冬胰岛素注射液对2型糖尿病患者餐后血糖影响的观察

目的比较重组人门冬胰岛素注射液(IASP)和可溶性人胰岛素(HSI)对2型糖尿病病人餐后血糖的影响。方法2002-102003-05对中日友好医院的42例已接受每日多次人胰岛素治疗的2型糖尿病患者经过2周的导入期治疗后随机分为两组,分别以IASP和HSI治疗4周,比较两组餐后1h、2h血糖的变化。结果经过4周的治疗,IASP组餐后1h血糖下降幅度显著大于HSI组[(2·1±2·0)mmol/L对(0·9±1·9)mmol/L,P<0·05],两组空腹血糖、餐后2h血糖和果糖胺的水平差异无显著性。HSI组治疗期间发生1例低血糖事件,两组均未发生严重低血糖事件和其他严重不良事件。结论与人HSI相比,IASP注射液能更有效地降低餐后1h血糖,安全性和耐受性良好。     

新诊断1型糖尿病患者外周血自然杀伤细胞的变化特点

目的 探讨新诊断1型糖尿病患者外周血自然杀伤细胞数目和功能的变化情况.方法 收集2009年到2011年瑞金医院收治新诊断1型糖尿病患者外周全血标本43份,同时收集性别、年龄匹配的正常对照健康志愿者外周全血标本21份,2型糖尿病对照组14例,Ficoll方法分离外周血单个核细胞( PBMC),流式细胞术(FACS)测定PBMC主要细胞亚群比例,流式细胞分选仪分离正常人和1型糖尿病患者自然杀伤细胞.实时荧光定量PCR检测自然杀伤细胞激活的主要效应分子γ-干扰素(IFN-γ)、perforin 及自然杀伤细胞激活性受体NKp46、NKp30基因mRNA表达水平.结果 与正常对照相比,自然杀伤细胞是1型糖尿病患者所有细胞亚群中改变最明显的一群细胞,细胞数目明显降低[( 102±86)/μl对(355±264)μl,P＜0.01];与正常对照自然杀伤细胞相比,1型糖尿病患者的自然杀伤细胞NKp46、perforin基因表达明显下调(P＜0.05),NKp30、IFN-γ基因在1型糖尿病患者的自然杀伤细胞中表达无明显改变(P＞0.05).结论 新诊断1型糖尿患者存在自然杀伤细胞数目和功能明显下降,自然杀伤细胞介导的免疫功能障碍可能在1型糖尿病的病程中发挥着非常重要的作用.     

Correlation between basal metabolic rate,visceral fat and insulin resistance among type 2 diabetes mellitus with peripheral neuropathy

BackgroundBasal Metabolic Rate (BMR) means the amount of energy utilized by body in physical and psychological resting rate, after a night sleep, awake without any previous physical activity post meal (10 h after last meal) & neutral environment. In people with type 2 diabetes mellitus (T2DM) there is an increase in BMR which is said to be associated with the level of glycaemic control. So, the objective of the study was to find out the correlation between BMR, Insulin resistance and Visceral fat in T2DM with peripheral neuropathy.Materials & methodsA total of 50 participants with T2DM with peripheral neuropathy were included. Age group of 30–75 years were selected for the study. Participants with a known history of neurological disease, locomotor disability, and pregnancy were excluded from the study. Demographic details of the participants like duration of diabetes mellitus, age, Fasting Blood Glucose, Fasting Insulin, HOMA-IR, Glycated Haemoglobin (HBA1c), Neuropathy and Blood pressure values were noted. We measured Basal Metabolic Rate (BMR) by using Mifflin-St Jeor predictive equation in T2DM with peripheral neuropathy.ResultsThe mean age of the participants is 60.16 ± 10.62. The mean duration of T2DM 13.44 ± 11.92. In the present study we found a statistical significant correlation between BMR and HOMA IR (r = 0.913*; p = 0.000), BMR & Fasting blood sugar (FBS) (r = 0.281*; p = 0.048), BMR and Visceral fat (VF) (r = 0.332*; p = 0.018).ConclusionBasal metabolic rate is correlated to Homa-IR, visceral fat, fasting blood sugar and musculoskeletal mass among T2DM with peripheral neuropathy.     

地特胰岛素联合利拉鲁肽治疗血糖控制不佳2型糖尿病患者的临床观察

目的 评价地特胰岛素联合利拉鲁肽治疗血糖控制不佳的T2DM患者疗效. 方法 选取预混胰岛素治疗血糖控制不佳的T2DM患者32例,采用地特胰岛素联合利拉鲁肽治疗方案,比较治疗前后各项指标,采用动态血糖监测系统(CGMS)评价血糖漂移水平、血糖曲线下面积(AUCPG)和低血糖发生率等情况. 结果 治疗后BMI[(27.25±2.32)vs(26.50±2.30)kg/m2]、SBP[(137.22±17.42)vs (126.55±10.08) mmHg]、DBP[(85.00±9.54)vs(78.22±6.45) mmHg]、FPG[(10.19±2.99)vs(6.52±1.24)mmol/L]、2 hPG[(15.61±4.37)vs(10.51±1.36) mmol/L]、HbA1c[(8.57±1.64)％vs(7.26±1.11)％]、TC[(5.11±1.51)vs(4.19±0.48) mmol/L]、LDL-C[(3.13±0.73)vs(2.55±0.64)mmol/L]和胰岛素抵抗指数(HOMA-IR)[(3.79±1.98)vs(2.60±1.63)]较治疗前下降(P＜0.05或P＜0.01),FC-P[(2.72±1.57)vs(4.73±2.39) ng/ml]、2 hC-P[(6.93±2.20) vs(13.33±3.39) ng/ml]和HDL-C[(1.00±0.27)vs(1.21±0.19) mmol/L]较治疗前上升(P＜0.01).CGMS结果显示,治疗后血糖平均值[(7.90±0.33)vs(6.90±0.10) mmol/L]、血糖漂移系数[(1.87±0.25)vs(1.07±0.11)]、血糖漂移最大幅度[(8.22±1.69)vs(1.22±0.69)mmol/L]、血糖＞7.8 mmol/L AUCpG[(27.46±6.20)vs (17.46±2.30)]及血糖＞11.1 mmol/L AUCPG[(6.20±3.52)vs(2.02±0.25)]、低血糖发生率(45.45％vs3.12％)较治疗前降低(P＜0.01). 结论 地特胰岛素联合利拉鲁肽可有效降低患者BMI、血压、血糖、血脂、HOMA-IR和血糖漂移水平,且低血糖发生率低.     

Acute changes in blood glucose do not alter blood glutathione synthesis in adolescents with poorly controlled type 1 diabetes mellitus

Depletion of blood glutathione (GSH), a key antioxidant, is associated with type 1 diabetes mellitus (T1D) and contributes to the pathophysiology of diabetes complications. The aim of the current study was to determine whether acute normalization of blood glucose would restore GSH kinetics in adolescents with poorly controlled T1D. Ten 16.9 ± 1.5-year-old (SE) adolescents who had had T1D for 8.5 ± 1.9 years and were free of complications but were in poor control (hemoglobin A(1c), 9.2% ± 0.5%) received two 5-hour intravenous infusions of L-[3,3-(2)H(2)]cysteine in the postabsorptive state on 2 separate days after blood glucose had been maintained overnight at 246 ± 24 mg/dL (hyperglycemia) or 118 ± 23 mg/dL (euglycemia) using intravenous insulin infusion. Blood GSH fractional synthesis rates were determined by mass spectrometry from (2)H(2)-cysteine incorporation into GSH. Neither blood GSH (551 ± 169 vs 541 ± 232 μmol/L, P = .629) nor GSH fractional synthesis rate (84% ± 30% vs 82% ± 33% d(-1), P = .965) was altered by the short-term change in glycemic control. This finding suggests that, in adolescents with poorly controlled T1D, either (a) blood glucose per se does not regulate GSH metabolism or (b) GSH may only respond to sustained, more chronic changes in blood glucose level.     

2型糖尿病病人外周血细胞凋亡的多因素分析

目的　探讨 2型糖尿病 (DM2 )患者外周血淋巴细胞 (PBL )凋亡的影响因素。方法　用琼脂糖凝胶电泳法测定 5 3例 2型糖尿病病人 (其中 2 6例无血管并发症组 ,2 7例伴血管并发症 )患者及 48例正常对照组 PBL凋亡率 ,并行多因素分析。结果　 2型糖尿病组细胞凋亡、一氧化氮(NO)、糖化血红蛋白 (Hb A1C)等九项指标明显高于正常对照组 ,无血管并发症组较有血管并发症组更显著 ,逐步回归分析显示 ,PBL凋亡与 NO、HBA1C呈显著正相关。结论　 DM2 PBL凋亡与NO、Hb A1C水平升高及血管病变的发生发展关系密切     

Lower fasting blood glucose, glucose variability and nocturnal hypoglycaemia with glargine vs NPH basal insulin in subjects with Type 1 diabetes

Background and aimsTo compare switching from NPH insulin (NPH) to insulin glargine (glargine) with continuing NPH for changes in fasting blood glucose (FBG) in patients with Type 1 diabetes on basal–bolus therapy with insulin lispro as bolus insulin. Secondary objectives included self-monitoring blood glucose, mean daily blood glucose (MDBG) and mean amplitude glucose excursion (MAGE) values alongside changes in HbA_1c and safety profiles.Methods and resultsThis was a 30-week, parallel, open-label, multicentre study. Seven-point profiles were used to calculate MDBG and MAGE. Hypoglycaemia and adverse events were recorded by participants. FBG improved significantly with both glargine (baseline–endpoint change: −28.0 mg/dL; 95% CI: −37.3, −18.7 mg/dL; p < 0.001) and NPH (−9.8 mg/dL; 95% CI: −19.1, −0.5 mg/dL; p = 0.0374). The improvement was significantly greater with glargine than NPH (mean difference: −18.2 mg/dL; 95% CI: −31.3, −5.2 mg/dL; p = 0.0064). MDBG (−10.1 mg/dL; 95% CI: −18.1, −2.1 mg/dL; p = 0.0126) and MAGE (−20.0 mg/dL; 95% CI: −34.5, −5.9 mg/dL; p = 0.0056) decreased significantly with glargine, but not NPH although endpoint values were no different with the two insulins. Baseline to endpoint change in HbA_1c was similar (−0.56 vs −0.56%) with no differences at endpoint. Overall hypoglycaemia was no different, but glargine reduced nocturnal hypoglycaemia (“serious episodes” with BG < 42 mg/dl, p = 0.006) whereas NPH did not (p = 0.123), although endpoint values were no different.ConclusionSwitching from NPH to glargine is well tolerated and results into lower FBG, and lower glucose variability while reducing nocturnal hypoglycaemia. These data provide a rationale for more aggressive titration to target with glargine in Type 1 diabetes.     

Morning versus bedtime isophane insulin in type 2 (non-insulin dependent) diabetes mellitus.

Morning versus bedtime administration of NPH insulin was compared in 12 subjects with Type 2 diabetes and overt fasting hyperglycaemia. Subjects were studied at baseline (diet alone) and after 2 months on each of the two insulin programmes in a random crossover design, in which dosage was increased until at least one daily preprandial blood glucose was consistently in the range of 3.9 to 6.0 mmol l-1. Mean (+/- SEM) daily total insulin dosage was equivalent for the morning (0.36 +/- 0.03 units kg-1) and for the bedtime (0.37 +/- 0.03 units kg-1) insulin administration schedules. Glycaemic control was improved on both insulin regimens, but was better on bedtime than morning insulin. Fasting plasma glucose (mmol l-1) was 12.0 +/- 0.7 (baseline), 8.6 +/- 0.7 (morning), and 4.6 +/- 0.3 (bedtime), respectively. Mean 24 h plasma glucose (mmol l-1) was 13.3 +/- 1.3, 9.0 +/- 0.7, and 7.8 +/- 0.7. Glycated haemoglobin (%) was 7.65 +/- 0.35, 6.23 +/- 0.26, and 5.81 +/- 0.32. The improvement of basal glycaemia is a consequence of increased basal metabolic clearance of glucose (baseline, 47.6 +/- 3.1 ml m-2 min-1; morning 63.5 +/- 5.4, bedtime 103.5 +/- 7.1). There was no change in hepatic glucose output. It is concluded that bedtime administration of intermediate acting insulin results in increased basal insulinaemia, leading to improved basal glycaemia and consequent improved overall metabolic control, compared to morning insulin administration. Therefore, bedtime may be the preferable timing of insulin therapy for patients with Type 2 diabetes and overt fasting hyperglycaemia.