Impact of the short-term, intense exercise on postprandial glycemia in type 2 diabetic patients treated with gliclazide

BACKGROUND: Physical activity is crucial for treatment of diabetes. However, intensive exercise brings the risk for metabolic decompensation; therefore, predicting its effect on glycemia is of great importance. MATERIALS AND METHODS: Fourteen type 2 diabetic patients (47.9+/-1.6 years; mean+/-S.E.M.), treated with gliclazide, and 14 healthy controls (45.1+/-1.0 years) were subjected to standard graded submaximal (90% HR(max)) exercise treadmill testing for 2 h after standardized breakfast. Blood glucose, lactate, insulin, and proinsulin concentrations were measured on fasting and during the periexercise period up to 120 min after the effort. Glucagon, growth hormone, cortisol, and catecholamines were determined up to 60 min of the recovery period. RESULTS: After exercise, glycemia decreased from the preexercise value of 11.3+/-1.4 to 8.0+/-1.1 mmol/l at 120 min (P<.001) in the diabetic group, while in controls, it did not change significantly. Shift in glycemia during and after exercise in the diabetic group was dependent on preexercise glycemia, according to the quadratic polynomial regression model, whereas a simple negative correlation between these indices was found in the control group. Insulinemia tended to decrease from the midexercise maximum of 488+/-116 to 261+/-71 pmol/l at the 120th min in diabetic patients. Neither hypoglycemia nor deficit in response of counterregulatory hormones was observed. CONCLUSIONS: In the type 2 diabetic patients treated with gliclazide, short-term, intensive, submaximal exercise, performed 2 h after a meal, causes reduction of hyperglycemia during the recovery period. Preexercise glycemia was found to be a primary predictor of the shift in glycemia under the exercise, according to the polynomial regression model.     

Characteristics of pancreatic beta-cell secretion in Type 2 diabetic patients treated with gliclazide and glibenclamide

The aim of the present cross-over study was to compare the beta-cell response to gliclazide and glibenclamide administered orally during and following a hyperglycaemic clamp in sulphonylurea treated Type 2 diabetes. Nine patients (6 males), aged 61.4 (S.D. 6.9) years with a body mass index of 27.5 (3.1) kg m(-2) and HbA(1c) at baseline of 7.2 (0.9)% were included. Eight healthy control subjects underwent the same tests. Patients received 80-240 mg gliclazide or 5-15 mg glibenclamide for 6 weeks. Thirty minutes after administration of 160 mg of gliclazide or 10 mg of glibenclamide a 1-h hyperglycaemic clamp (11.0 mmol l(-1)) was begun, and followed by a 3.5-h observation period. Nadir blood glucose levels were 4.2 (1.0), 4.3 (1.2) and 3.4 (1.0) mmol l(-1) for glibenclamide gliclazide and controls, respectively (both P=0.07 vs. controls). Glucose levels decreased slowly and linearly in people with diabetes and reached nadirs after 204 (8) and 198 (18) min, respectively, after cessation of glucose infusion, while in controls, glucose levels declined steeply to a nadir at 98 (47) min (P<0.003 vs. both drugs). No first phase insulin secretion peak was observed in people with diabetes. Insulin levels remained elevated during the 3-h observation period in SU treated patients but, in control subjects decreased to baseline values within 2 h of the clamp. The proinsulin to C-peptide ratio increased during the observation period. In conclusion, the effects of glibenclamide and gliclazide on insulin secretion are very similar in patients with Type 2 diabetes who are in moderate glycaemic control, with a slow rise to lower amplitude, poor responsiveness to falling glucose levels, and raised proinsulin to C-peptide ratio.     

Association of gliclazide and left ventricular mass in type 2 diabetic patients

Diabetes is a state of increased oxidant stress and there is evidence that oxidation may play a role in the genesis of higher left ventricular mass. Gliclazide has been shown to possess free radical scavenging properties. We assessed whether gliclazide may have a beneficial effect on left ventricular mass via reducing 8-iso-prostaglandin F(2alpha) concentrations, a reliable marker of oxidant injury. A total of 41 patients were randomized into two groups. All patients had been taking glibenclamide for more than 3 months before being randomized to switch either an equipotent dose of gliclazide (n=21) or to continue on glibenclamide (n=20). Baseline characteristics were similar in both groups. At 6 months, gliclazide-treated patients showed a significant regression in left ventricular mass index compared with the glibenclamide-treated group (-16% versus 3%, P=0.003). Gliclazide patients had significantly lower plasma 8-iso-prostaglandin F(2alpha) compared with baseline (299+/-101 pg/ml versus 400+/-112 pg/ml, P=0.001) and the glibenclamide-treated patients (299+/-101 pg/ml versus 388+/-114 pg/ml, P=0.01) after 6-month therapy. The magnitude of left ventricular mass index regression correlated univariately with the magnitude of inhibition of 8-iso-prostaglandin F(2alpha) formation (r=0.74, P<0.0001). Multivariate analysis revealed that regression of left ventricular mass index significantly correlated with the changes of 8-iso-prostaglandin F(2alpha) (P<0.0001, adjusted R(2)=0.55). Our findings demonstrated for the first time that in addition to its primary hypoglycemia, gliclazide may have an additional effect on reducing left ventricular mass, possibly through attenuation of free radical formation.     

肥胖2型糖尿病肾病患者动态血糖分析

目的探讨肥胖2型糖尿病（T2DM）肾病患者的动态血糖特点。方法80例肥胖T2DM患者根据24h尿白蛋白排泄率（24hUAER）分为糖尿病肾病（DN）组和单纯2型糖尿病（T2DM）组,每组40例;另选健康体检者15名组成正常对照（NC）组。动态血糖监测系统（CGMS）监测三组72h血糖变化,并进行对比分析。结果DN组血糖波动系数（BGFC）、日内血糖波动最大幅度、2hPG均明显大于T2DM组及NC组（P均〈0．05）,DN组BGFC与24hUAER正相关（r=0．356、P〈0．05）。结论血糖波动与肥胖2型糖尿病肾病相关。     

Normal insulin response to short-term intense exercise is abolished in Type 2 diabetic patients treated with gliclazide

BackgroundPhysical activity is an essential component of diabetes management; however, exercise is associated with the risk for metabolic decompensation. The aim of the study was to analyze insulin response to the short-term intense exercise in middle-aged Type 2 diabetic patients treated with gliclazide.Materials and MethodsFourteen Type 2 diabetic patients (47.9±1.6 years, mean±S.E.M.), treated with gliclazide, and 14 healthy controls (45.1±1.0 years) were submitted to standard graduated submaximal (90% HR_max) exercise treadmill testing at 2 h after standardized breakfast. Serum glucose, insulin, proinsulin, C peptide, growth hormone, insulin-like growth factor-1, and cortisol concentrations; and plasma lactate, glucagon, epinephrine, and norepinephrine concentrations were measured during the periexercise period up to the 60th min of the recovery period.ResultsSignificant hemodynamic (heart rate, systolic, and diastolic blood pressure), metabolic (lactate concentration), and hormonal (epinephrine and norepinephrine levels) responses to the exercise were similar in patients and healthy subjects. Glucose, insulin, and proinsulin levels were higher in the diabetic group at the preexercise and at all the next analyzed time points. The insulin concentration increased during the postprandial period in both groups and decreased subsequently during the exercise only in the control group, without concurrent C peptide decline. The C peptide-to-insulin ratio increased during the exercise and decreased immediately postexercise only in the control group.ConclusionsThe initial decrease of the insulin serum concentration during short-term intense exercise in normal middle-aged men is primarily related to the increased clearance of the hormone. Normal insulin response to the exercise was abolished in Type 2 diabetic patients treated with gliclazide.     

Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide

Multicentric study was conducted to evaluate the efficacy of glimepiride in the oral hypoglycemic agents therapy of type 2 diabetic patients treated with glibenclamide so far, and to claim an adequate use of this new generation sulfonylurea. In 66 diabetic outpatients, glibenclamide was switched to glimepiride. After 6 months' therapy, a significant reduction in fasting plasma IRI was observed in relatively hyperinsulinemic patients. In addition, weight reduction was achieved in patients with insulin resistance during this study. These findings suggest that glimepiride improves insulin resistance in hyperinsulinemic patients treated with glibenclamide. Also, glimepiride is favored especially for overweight, insulin-resistant patients inadequately controlled by glibenclamide.     

Effects of combination of insulin and acarbose compared with insulin and gliclazide in type 2 diabetic patients

In this prospective study we aimed to compare insulin plus acarbose with insulin plus gliclazide with respect to their effect on insulin requirement, lipid profiles and body mass index (BMI) while achieving good glycemic control. Forty patients with type 2 diabetes mellitus who were on conventional insulin therapy (subcutaneous insulin therapy consisting of regular and NPH insulin, two times a day) were included in the study. They were randomized to double blind treatment with insulin in combination with gliclazide or acarbose for 6 months. For both groups, acceptable glycemic control was achieved at the end of study period. The mean HbA_1c levels decreased from 8.32±0.26 to 7.13±0.18% in acarbose group and 8.6±0.15 to 7.48±0.21% in the gliclazide group. The difference between groups was not significant (P 0.29). In the acarbose group, total cholesterol and LDL concentration decreased significantly while other parameters did not change. In the gliclazide group, HDL levels decreased significantly from 46.6±2.48 mg/dl to 41.3±2.09 mg/dl (P 0.001) BMI increased significantly from 27.60±1.21 kg/m² to 28.69±1.26 kg/m². (P 0.003) Total daily insulin dose was not changed in the acarbose group significantly, but increased from 42.6±2.73 to 49.27±3.58 U/day, which was significant in gliclazide group of (P 0.016). In the acarbose group, there were no significant differences between responders and nonresponders with respect to fasting and stimulated C-peptide, HbA_1c levels and baseline BMI values. But in the gliclazide group, baseline BMI values were significantly higher in the nonresponding group compared to responders (P 0.02). In conclusion, combination of insulin with acarbose can be a good alternative for type 2 diabetic patients on insulin therapy; seems more beneficial than combination with gliclazide; may have advantage of achieving good glycemic control without increasing insulin dose and BMI; also may have the advantage of providing a decrease in LDL level, which are all important to prevent atherosclerosis. Received: 29 January 1999 / Accepted in revised form: 19 May 1999     

Glycated albumin is low in obese, type 2 diabetic patients

This study is to clarify whether obesity status affects glycated albumin (GA) and HbA1c levels in adults with type 2 diabetes. One hundred and seven individuals with type 2 diabetes without advanced complications participated in this study. The relationship between HbA1c, GA, hemoglobin (Hb), albumin (ALB), absolute value of GA (aGA) and Body Mass Index (BMI) were examined using Pearson's correlation coefficient. The comparison of each parameter was conducted using unpaired t-test between the obese (BMI> or =25) and the non-obese (BMI<25) group. Additionally the multiple regression analyses to find factors related with GA (i.e. BMI, HbA1c, age, ALB and the insulin therapy) were performed. HbA1c level and BMI showed very weak correlation (r=-0.04; p=0.65). However, GA, aGA and BMI showed a significant negative correlation (r=-0.28; p=0.004, r=-0.22; p=0.024). The GA and aGA values of the obese group were significant lower than those in the non-obese group. In multiple regression analysis, BMI (beta=-0.24; p=0.001) was negatively, and HbA1c (beta=3.65; p<0.001) was positively correlated with GA. In conclusion, the current analysis demonstrated a need of careful evaluation of GA values in obese diabetic patients in daily practice. Further researches are required to elucidate the underlying mechanisms.     

糖适平治疗2型糖尿病的CGMS动态变化临床观察

目的探讨糖适平治疗2型糖尿病的CGMS与多项目指标临床相关性。方法近年诊断2型糖尿病患者22例，应用美国产动态血糖监测系统（CGMS Mini Med Inc），测量药物治疗后不间断连续血糖监测曲线，与本药药代动力学水平做一动态分析。结果口服糖适平2．5h时血糖水平曲线最低平，与其他时段血糖水平曲线差异有极显著性（P〈0．001）。其中每日6am口服本药，2．5h时血糖水平曲线为24h时最低平，与其他时段血糖水平曲线差异有极显著性（P〈0．001）。口服糖适平7．5h后血糖水平曲线渐次升高，直至再次口服本药后血糖水平曲线渐次降低直至口服糖适平2．5h时血糖水平曲线最低平。每日服药1次，24h血糖水平曲线较不服药者血糖水平曲线明显低平（P〈0．001）。结论每日6am口服本药为最佳服药时间，口服本药2．5h时降糖作用最强；本药可在体内持续作用7．5～24h。     

The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5'-nucleotidase: findings in a study of ecto-5'-nucleotidase gene-deficient mice

OBJECTIVE: Evidence from in vitro, in vivo, and clinical studies indicates that adenosine mediates, at least in part, the antiinflammatory effects of methotrexate (MTX), although the biochemical events involved have not been fully elucidated. This study was undertaken to investigate whether MTX exerts antiinflammatory effects in mice that lack ecto-5'-nucleotidase (ecto-5'-NT) (CD73) and are unable to convert AMP to adenosine extracellularly, in order to determine whether adenosine is generated intracellularly and transported into the extracellular space or is generated from the extracellular dephosphorylation of AMP to adenosine. METHODS: Male CD73 gene-deficient mice and age-matched wild-type mice received intraperitoneal injections of saline or MTX (1 mg/kg/week) for 5 weeks. Air pouches were induced on the back by subcutaneous injection of air; 6 days later, inflammation was induced by injection of carrageenan. RESULTS: Fewer leukocytes, but higher levels of tumor necrosis factor alpha (TNFalpha), accumulated in the air pouches of vehicle-treated CD73-deficient mice compared with those of wild-type mice. As expected, MTX treatment reduced the number of leukocytes and TNFalpha levels in the exudates and increased exudate adenosine concentrations in wild-type mice. In contrast, MTX did not reduce exudate leukocyte counts or TNFalpha levels or increase exudate adenosine levels in CD73-deficient mice. CONCLUSION: These results demonstrate that the antiinflammatory actions of MTX are mediated, at least in part, by increased release of adenine nucleotides that are hydrolyzed extracellularly to adenosine via an ecto-5'-NT-dependent pathway.     

Effect of liraglutide on glucagon secretion in obese type 2 diabetic patients

<正>Objective To investigate the effect of liraglutide on glucagon release in obese type 2 diabetes (T2DM).Methods A multi-center,prospective,and self-comparison study was conducted in four hospitals in Qingdao.Twenty-four patients with T2DM were selected and trea-     

Systemic resistin is increased in type 2 diabetic patients treated with loop diuretics

Increased serum resistin was found in rodent models of obesity and insulin resistance, whereas contradictory results have been obtained in human studies. In humans, resistin is primarily released by monocytes/macrophages, suggesting that soluble levels may be associated with macrophage activation. Here, systemic and monocyte-released resistin levels were found to be similar in type 2 diabetic (T2D) patients, overweight controls and normal-weight controls. When adjusted for body mass index and age, serum resistin modestly correlated with gamma-glutamyltransferase levels, fasting glucose and interleukin-6. Systemic resistin was marginally increased in T2D patients treated with beta-blockers or urate-lowering drugs and was considerably higher in patients treated with loop diuretics. Monocyte-released resistin was even reduced by the loop diuretic furosemide, excluding the possibility that this drug may directly stimulate resistin synthesis. In summary, the current data indicate that changes accompanying renal dysfunction but not obesity or type 2 diabetes are associated with increased serum resistin.     

Absence of lymphocyte ecto-5'-nucleotidase in infants with reticuloendotheliosis and eosinophilia (Omenn's syndrome)

Lymphocytes from three infants with reticuloendotheliosis and eosinophilia ( Omenn 's syndrome) and immunodeficiency were assayed for 5'-nucleotidase activity. B and T lymphocytes from all three patients were totally deficient in ecto-5'-nucleotidase activity, but had normal levels of cytoplasmic 5'-nucleotidase. In contrast, cultured lymphocytes expressed normal ectoplasmic and cytoplasmic activities, suggesting that the lymphocyte-restricted enzyme deficiency was not likely a primary genetic defect. The deficiency of lymphocyte ecto-5'- nucleotidase was not associated with any abnormality of deoxynucleoside metabolism. The absence of lymphocyte ecto-5'-nucleotidase may be a characteristic feature of this syndrome and may help to distinguish this disease from others with similar manifestations.     

Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients

Circulating endothelial progenitor cells (EPCs) play an important role in the development and progression of diabetic vascular complications. The aim of this study was to investigate the effects of gliclazide plus metformin (GLIMET) compared with metformin alone (MET) on number and function of circulating EPCs in T2DM patients. Patients with newly diagnosed T2DM were randomly divided into two groups, receiving the following treatments for 16 weeks: MET group (assuming metformin 500-2500 mg/day, n=24) and GLIMET group [assuming gliclazide (modified release, 30-60 mg/day)+metformin (250-1000 mg/day), n=23]. Circulating EPCs were quantified by flow cytometry, and the ability to uptake LDL and stain for lectin were used as another method of characterizing EPCs ex vivo. The functions of circulating EPCs were evaluated by colony-forming units (CFU) and migration. The status of oxidative stress was analyzed by serum-free malonaldehyde (MDA) and superoxide dismutase (SOD). There were no significant differences in clinical characteristics and number and function of circulating EPCs between two groups at baseline. Glycemic responses were similar after treatments. Compared with MET group, GLIMET group was associated with an increase in circulating EPCs number, DiLDL-lectin-positive EPCs, and migration. The mean improvements in MDA and SOD of GLIMET group were more strongly upregulated than those of MET group. This study demonstrated that both metformin mono-treatment and metformin plus gliclazide combination treatment provided with improvements in number and function of circulating EPCs. Compared with metformin mono-treatment, early use of combination therapy with gliclazide plus metformin made more effective improvements in circulating EPCs.     

Deficiency of CD73/ecto-5'-nucleotidase in mice enhances acute graft-versus-host disease

Extracellular ATP and adenosine have immunoregulatory roles during inflammation. Elevated extracellular ATP is known to exacerbate GVHD, and the pharmacologic activation of the adenosine A2A receptor is protective. However, the role of endogenous adenosine is unknown. We used gene-targeted mice and a pharmacologic inhibitor to test the role of adenosine generated by CD73/ecto-5'-nucleotidase in GVHD. In allogeneic transplants, both donor and recipient CD73 were protective, with recipient CD73 playing the dominant role. CD73 deficiency led to enhanced T-cell expansion and IFN-γ and IL-6 production, and the migratory capacity of Cd73-/- T cells in vitro was increased. However, the number of regulatory T cells and expression of costimulatory molecules on antigen-presenting cells were unchanged. A2A receptor deficiency led to increased numbers of allogeneic T cells, suggesting that signaling through the A2A receptor via CD73-generated adenosine is a significant part of the mechanism by which CD73 limits the severity of GVHD. Pharmacologic blockade of CD73 also enhanced graft-versus-tumor activity. These data have clinical implications, as both the severity of GVHD and the strength of an alloimmune antitumor response could be manipulated by enhancing or blocking CD73 activity or adenosine receptor signaling depending on the clinical indication.