噻唑烷二酮类药物对糖尿病肾病的直接作用及其机制

近年的研究显示 ,噻唑烷二酮类药物 (TZD)具有不依赖于胰岛素增敏作用的肾直接保护作用 ,在未降低糖尿病大鼠高血糖水平的情况下 ,TZD可减少清蛋白尿 ,抑制肾小球系膜肥大及细胞外基质 (ECM)增生。其可能的作用机制是 :在高血糖状态下 ,TZD通过激活肾小球中二酰基甘油激酶 (DGK) ,抑制二酰基甘油 (DAG) 蛋白激酶C(PKC) 细胞信号调节激酶 (ERK)通路活性而改善肾小球高滤过状态、抑制ECM蛋白的过度产生。也有研究认为 ,TZD与改善硫酸乙酰肝素原多糖 (HSPG)合成及硫酸化、从而抑制肾小球基膜 (GBM)外疏松层的阴离子位点有关。此外 ,TZD可能通过调节肾小球系膜细胞的表型转化达到肾保护作用。     

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY

Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation.

Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500?mmol?day^?1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone).

Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean?±?SD body weight falling from 270?±?54?lbs (123?±?25?kg) to 244?±?61 lbs (111?±?28?kg) (p?<?0.01). The weight loss observed was no different from that observed

in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263?±?54?lbs (120?±?25?kg) to 239?±?52?lbs (109?±?24?kg); p?<?0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control.

Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.     

Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors

SUMMARY

Objective: To compare the long-term effects on HbA_1c, lipid parameters, body weight, and hepatotoxicity after switching type 2 diabetes patients from troglitazone to either pioglitazone or rosiglitazone.

Methods: Of 125 study candidates from a previous prospective study, 100 patients (51 pioglitazone, 49 rosiglitazone) met criteria for comparing HbA_1c, lipids, body weight, and incidence of hepatotoxicity over 2 successive observation periods (3.1 and 12.6?months).

Results: Mean absolute HbA_1c decreased significantly, 0.53 and 0.27% in the pioglitazone and rosiglitazone groups, respectively, at the 12.6-month observation. Mean triglyceride (TG) decreased in the pioglitazone group at each interval with a cumulative decrease of 26.4% from baseline. In contrast, TG increased in the rosiglitazone patients by 43.3% at 3.1?months and then decreased (but remained above baseline) at 12.6?months. Mean high density lipoprotein (HDL) increased 22.1% with pioglitazone and 13.3% with rosiglitazone. In patients who had a baseline HDL < 35?mg/dL (0.91?mmol/L), pioglitazone-treated patients experienced a significant increase at each interval resulting in a 52.6% increase in HDL compared to a 26.9% increase for rosiglitazone patients. Patients in both treatment groups had similar weight increases at each interval and no hepatotoxicity was noted.

Conclusion: With pioglitazone or rosiglitazone, changes in glycemic control, lipid effects, and body weight appear to continue over time. Pioglitazone treatment resulted in decreased triglyceride levels, while rosiglitazone was associated with an increase in triglyceride levels. HDL increased in both treatment groups, but in patients with a baseline HDL < 35?mg/dL (0.91?mmol/L), pioglitazone improved the HDL to a greater extent than rosiglitazone.     

Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide

ABSTRACT

Objective: The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM.

Methods: References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included.

Results: T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA_1c) <?7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study.

Conclusions: Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.     

PPARγ activator,rosiglitazone: Is it beneficial or harmful to the cardiovascular system?

Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor γ which is used to improve insulin resistance in patients with typeⅡdiabetes.Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity.Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction,inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation,and the protection of myocardial injury during ischemic/reperfusion in different animal models.Previous clinical studies in typeⅡdiabetes patients demonstrated that rosiglitazone played an important role in protectingagainst arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system.Despite these benefits,inconsistent findings have been reported,and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system,including increased risk of acute myocardial infarction,heart failure and chronic heart failure.As a result,rosiglitazone has been recently withdrawn from EU countries.Nevertheless,the effect of rosiglitazone on ischemic heart disease has not yet been firmly established.Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease.     

吡格列酮干预对2型糖尿病患者尿细胞间粘附分子-1排泄的影响

目的观察吡格列酮对2型糖尿病患者尿细胞间粘附分子-1(ICAM-1)排泄的影响,探讨其肾脏保护机制。方法 98例2型糖尿病患者(完成为90例)随机分为吡格列酮干预组(DP组,44例)和磺酰脲类药物干预组(DS组,46例),分别加用吡格列酮和磺酰脲类药物。治疗前和治疗后第12周,测定两组的空腹血糖(FBG)、糖化血红蛋白(HbA1c)水平及尿白蛋白/肌酐(Alb/Cr)和尿ICAM-1/Cr比值。结果 (1)基础状态时,DP组和DS组FBG、HbA1c水平及尿Alb/Cr和ICAM-1/Cr比值均高于NC组(P<0.01),但DP组和DS组间上述各相关差异无统计差异(P>0.05);(2)治疗后,DP组和DS组FBG及GHbA1c水平较基线值明显下降(P<0.01),两组间各指标差异无统计意义(P>0.05);(3)与治疗前相比,DP组尿Alb/Cr水平明显降低,差异显著(P<0.01),而DS组尿Alb/Cr水平仅轻度降低,差异无显著性(P>0.05);(4)治疗后,DP组尿ICAM-1/Cr明显下降(P<0.01),DS组有所下降,但无统计意义(P>0.05);与DS组比较,治疗后DP组尿ICAM-1/Cr水平显著降低(P<0.05);5)DP组和DS组患者尿ICAM-1/Cr水平与尿Alb/Cr水平呈正相关(r=0.705,P<0.01)。结论吡格列酮可降低尿ICAM-1的排泄,减轻肾组织局部增强的炎性反应,对糖尿病患者肾脏起到保护作用。     

二甲双胍和噻唑烷二酮类分别与达因-35联用治疗多囊卵巢综合征的疗效比较

目的:比较二甲双胍和噻唑烷二酮类(TZDs)分别与达因-35联用治疗多囊卵巢综合征(PCOS)的临床疗效。方法:随机将53例患者分成两组,A组予以二甲双胍治疗3个月后与达因-35共用3个月,B组予以TZDs治疗3个月后和达因-35共用3个月,总治疗期6个月,比较治疗前后内分泌激素、体重指数、血糖、排卵率等的改变。结果:两组治疗后胰岛素(INS)、胰岛素抵抗指数(HOMA-IR)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、睾酮(T)及黄体生成素(LH)均明显降低(P<0.05,P<0.01)。A组降低体重优于B组,B组改善胰岛素抵抗优于A组。两组在排卵率和妊娠率方面无显著差异(P>0.05),双胍组4例自发性妊娠,TZDs组也有4例自发性妊娠。随访1年,8例婴儿发育均无异常。结论:二甲双胍和TZDs分别与达因-35联用,均能改善PCOS患者的胰岛素抵抗及内分泌紊乱,肥胖的PCOS患者推荐首选二甲双胍+达因-35,体重正常者或胰岛素抵抗严重者选用TZDs+达因-35。     

Evaluation of eating disorders and their association with glycemic control and metabolic parameters in adult patients with type 2 diabetes mellitus

BackgroundThere is little data on the prevalence and effects of eating disorders in patients with T2DM.AimsTo evaluate the presence of eating disorders (ED) and their association with glycemic control and metabolic parameters in adult patients with type 2 diabetes mellitus (T2DM).MethodsA cross-sectional study was conducted in the endocrinology outpatient unit of our tertiary care centre between January 2017 to December 2018. Eating Attitudes Test (EAT-26) and Binge Eating Scale (BES) questionnaires were used to screen for ED in adults with T2DM (group 1) and controls without T2DM (group 2). Cut off scores ≥18 on BES was considered as a positive screen for Binge eating disorder in participants with and without T2DM. A score of ≥30 on EAT-26 was defined as abnormal for participants with T2DM and ≥20 for those without T2DM. Formal psychiatric assessment was done to diagnose ED in those who screened positive on the basis of scores on BES or EAT-26 or both. Demographic, anthropometric and relevant medical details like duration of treatment, glycemic control, complications were recorded.ResultsA total of 512 individuals (256 in each group) participated in this study. Out of these, 10.9% of individuals with T2DM and 14.1% of those without T2DM screened positive for ED, with no significant difference in the two groups. After a detailed psychiatric assessment, two patients (0.8%) in each group were confirmed to have ED. Participants with T2DM who were on thiazolidinediones had higher odds (2.2) of screening positive for an ED.(p = 0.03).ConclusionsOur study reveals that eating disorders are not very common in our clinical population of T2DM, and the prevalence is comparable to BMI matched individuals without T2DM. The prevalence rates of eating disorders are lower (in both controls and patients with T2DM) than those reported from developed western countries.     

Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes

Type 2 diabetes mellitus is a complex metabolic disease that can cause serious damage to various organs. Among the best-known complications, an important role is played by cognitive impairment. Impairment of cognitive functioning has been reported both in type 1 and 2 diabetes mellitus. While this comorbidity has long been known, no major advances have been achieved in clinical research; it is clear that appropriate control of blood glucose levels represents the best current (although unsatisfactory) approach in the prevention of cognitive impairment. We have focused our attention on the possible effect on the brain of antidiabetic drugs, despite their effects on blood glucose levels, giving a brief rationale on the mechanisms (e.g. GLP-1, BDNF, ghrelin) that might be involved. Indeed, GLP-1 agonists are currently clinically studied in other neurodegenerative diseases (i.e. Parkinson’s and Alzheimer’s disease); furthermore, also other antidiabetic drugs have proven efficacy in preclinical studies. Overall, promising results are already available and finding new intervention strategies represents a current need in this field of research.     

A study on lifestyle adjustment and insulin sensitizing treatment in PCOS-IR women

Objective:To compare the efficacy of lifestyle adjustment,metformin and rosiglitazone on women with polycystic ovary syndrome and insulin resistance(PCOS-IR)Methods:A randomized controlled trial(RCT)was carried out in Peking Union Medical College Hospital(PUMCH),One hundred and six women with PCOS were randomly allocated to three intervention groups:lifestyle adjustment,lifestyle adjustment plus metformin,lifestyle adjustment plus rosiglitazone group,patients were treated with lifestyle adjustment(diet and exercise),lifestyle adjustment plus metformin(500mg three times daily),lifestyle adjustment plus rosiglitazone(4mg once daily)for three months.Sixty patients completed treatments,basal body temperature(BBT),total testosterone as well as fasting serum insulin and lipid levels were measured and compared in all patients before and after lifestyle adjustment.Results:No significant differences were found in the baseline characteristics among three groups.In lifestyle adjustment group 51%(22/43)patients completed treatment,23%(5/22)patients resumed ovulation.In lifestyle adjustment plus metformin group 58%(21/36)patients completed treatment,43%(9/21)patients resumed ovulation.In lifestyle adjustment plus rosiglitazone group 63%(17/27)patients completed treatment,59%(10/17)patients resumed ovulation.Ovulation rate was significantly higher in lifestyle adjustment plus rosiglitazone group than that in weight loss group.There was no significant difference among three groups in body mass index(BMI),waist circumference,waist-hip ratio(WHR),sex hormone,serum fasting insulin and lipid levels after treatment.Conclusions:Lifestyle adjustment,metformin and rosiglitazone treatment can improve ovulation each.