9th International Conference on Obesity,NIDDM, Adipogenesis and Insulin Resistance

The 9th International Conference on Obesity, NIDDM, Adipogenesis and Insulin Resistance was held between 3rd and 5th April, 2000 in London, UK. The three day conference was attended by more than 100 delegates from both academic and industrial institutions. Conference topics covered the use of genetics in obesity and diabetes, etiology and implications of treatment for obesity, progress in identification of new obesity and Type 2 diabetes drug targets, islet cell targets, progress in drugs for insulin enhancement and sensitisation, adipogenesis and insulin resistance. Below are meeting highlights closely related to new drug developments and drug target identification in these therapeutic areas.     

Therapeutic potential of A1 adenosine receptor ligands: a survey of recent patent literature

Background: In recent years, a number of companies, universities and other institutions have invested in research on new molecules acting as agonists, antagonists and enhancers on A₁ adenosine receptors (ARs) and in the evaluation of their new therapeutic applications. Objective: To review recent patenting activity on this topic. Methods: The first part of this article describes the compounds patented, subdivided by functional activity, and the second part the most relevant therapeutic applications or new uses for A₁ AR ligands, with a focus on compounds in or soon to be in clinical trials. Conclusion: Although a number of potential therapeutic applications are proposed in the recent literature, at present, in the authors' opinion, very few A₁ ligands are close to coming on the market, probably due to limited selectivity towards the target tissue or organ.     

Aspects of the treatment of Turner syndrome

Several issues have to be considered when taking care of girls and women with Turner syndrome. During childhood, short stature is the primary concern and treatment with growth hormone (GH) is now widely used, often in conjunction with the androgen, oxandrolone. Recent studies indicate that doses used previously in the treatment of short stature have been too small. Induction of puberty should be performed at an appropriate age with reference to the peers of the patient. In adulthood, female sex hormone substitution should be offered to possibly prevent the increased morbidity seen in Turner syndrome, which consists of increased risk of fractures and osteoporosis, a clustering of diseases like ischaemic heart disease, hypertension, stroke and Type 2 diabetes, the latter entities being involved in the insulin resistance syndrome. Furthermore, hypothyreosis are often seen and the risk of Type 1 diabetes may also be increased. Congenital malformations of the heart are frequently seen in Turner syndrome, possibly increasing the risk of dissecting aorta aneurism. Liver enzymes are often elevated in Turner syndrome and there may be an increased risk of cirrhosis of the liver. Mortality does seem to be increased in Turner syndrome and women with the ‘pure’ 45,X karyotype do seem to be most severely affected. In the clinical practice of Turner syndrome, a careful monitoring of glucose and bone metabolism, weight, thyroid function and blood pressure should be performed. A cardiovascular risk profile should be determined and the patient informed concerning risks and benefits from sex hormone replacement therapy. Based on the available literature, sex hormone replacement therapy is highly recommended, although at present there are no longitudinal data documenting the long-term positive effect of sex steroid substitution. However, hypogonadism is expected to explain at least part of the decreased lifespan found in Turner syndrome. Since general physicians encounter Turner patients infrequently, it is recommended that the care and treatment of Turner syndrome is centralised.     

A critical evaluation of the NICE guidelines for post-myocardial infarction prophylaxis

The UK National Institute for Clinical Excellence (NICE) has recently published guidelines on prophylaxis for patients who have experienced a myocardial infarction (MI). Based on a previously commissioned extensive review of the literature, the recommendations are antiplatelet therapy, β-blockers and angiotensin converting enzyme inhibitors (ACEIs) for all patients; statins for those with hypercholesterolaemia; spironolactone for those with moderate-to-severe heart failure (HF); and insulin for those with diabetes. While there may be concerns about some of the details (eg., the possible adverse interaction between aspirin and ACEIs), comments on the use of statins for those with HF, the lack of advice on the choice of lipid-lowering therapy for those intolerent of statins, the dangers of spironolactone therapy and the practicality of intensive insulin treatment, the guidelines are firmly based on sound evidence of efficacy and cost effectiveness. The NICE guidelines should therefore stimulate the provision of resources to address the gap between current practice and these recommendations.     

Phosphatidylinositide 3-kinase inhibition: A new potential target for the treatment of polycystic ovarian syndrome

Context: Quercetin, a flavonoid, has been tried in traditional medicine for treating many disorders and reported to have inhibitory action on PI3 kinase.

Objective: This study investigates the effect of quercetin on testosterone propionate induced polycystic ovary syndrome (PCOS) model, which shows both metabolic and endocrine features of PCOS.

Materials and methods: Female pre-pubertal Sprague–Dawley rats were randomly divided into four groups: normal control, PCOS control, quercetin, and metformin treated. PCOS was induced by testosterone propionate (10?mg/kg, s.c.) and treatments were carried out orally at the dose of 150?mg/kg from the 6th week. At the 6th and 10th week, blood was collected to investigate metabolic indices, and reproductive biochemical parameters including morphology of ovary, uterus, and estrous cyclicity were assessed. The ovaries were processed to determine CYP17A1 gene expression.

Results: The treatment with quercetin did not modify body weight gain but uterine (296.7?±?5.11 versus 263.0?±?8.60?mg) and ovary weights (49.5?±?1.93 versus 37.8?±?3.43?mg) were found to be decreased significantly (p <0.05) as compared with the PCOS control group. The PCOS control group showed hyperinsulinemia, hyperandrogenemia, and dyslipidemia. Treatment with quercetin showed statistically significant (p?<0.01) improvement in insulin (12.46?±?0.3 versus 10.0?±?0.28 μU/ml), testosterone (0.65?±?0.02 versus 0.29?±?0.02 μU/ml), luteinising hormone (20.6?±?0.28 versus 15.1?±?0.36 U/ml), and lipid profile. Histological examination of ovary and uterus confirmed the disease occurrence and remission state in the diseased and treated groups, respectively. Quercetin also demonstrated PI3 kinase inhibition in a docking study and decreased CYP17A1 gene expression.

Discussion and conclusion: Thus, we can conclude that quercetin may have beneficial effect in PCOS by virtue of inhibition of PI3K which attributes to a decrease in the expression of CYP17A1 gene, having a key role in steroidogenesis.     

甘精胰岛素联合格列美脲治疗2型糖尿病80例

目的 探讨甘精胰岛素联合格列美脲治疗2型糖尿病的疗效和安全性.方法 选择医院2008年10月至2011年9月收治的80例2型糖尿病患者[空腹血糖(FBG)不低于10 mmol/L],给予睡前皮下注射甘精胰岛素联合口服格列美脲治疗12周,根据FBG水平调整胰岛素用量,治疗目标为5.5 mmol/L0.05).结论 甘精胰岛素联合格列美脲治疗2型糖尿病的疗效好,低血糖发生率低,安全性好,是治疗2型糖尿病的理想方案.     

胰岛素和亚硒酸钠最佳配比组方研究

目的 确定普通胰岛素与亚硒酸钠降血糖作用的最佳组方配比.方法 采用小剂量链脲佐菌素腹腔注射联合高糖高脂饲养的大鼠模型,以血糖降低百分率为考察指标,根据权重配方法设不同配比组方6组,分析结果得出最佳理论配比,并进一步做确证性试验考察二者的相互关系.结果 胰岛素与亚硒酸钠对血糖的控制为协同作用,二者比例为1 U:5μg时可显著降低血糖.结论 胰岛素和亚硒酸钠的最佳配比为1 U:5μg.     

聚乙二醇化重组人胰岛素注射液Beagle犬毒动学研究

目的 研究毒性剂量暴露下聚乙二醇化重组人胰岛素注射液（PEG-Det）的毒动学（TK）,以评价系统暴露与剂量、时间及毒性结果之间的关系,通过重复给药分析药物在体内是否存在蓄积及代谢方式是否改变等特性。方法 32只健康Beagle犬随机分为4组,每组8只,雌雄各半,分别sc低、中、高剂量（37.5、75.0、150.0 μg/kg）PEG-Det及溶媒,每周给药2次,重复给药9个月。分别于首次（d1）、中期（d89）和末期（d260）给药后采用放射免疫分析（RIA）法检测不同时间血药浓度,采用罗氏血糖仪同步测定动物血糖水平。试验数据采用DAS 3.0药动程序拟合分析并计算TK参数。结果 各剂量组动物sc给药后,随血药浓度升高伴随血糖降低,且与给药剂量呈正相关;随给药频率增加,血糖降低幅度减小;单次和多次给药后,PEG-Det的C_max和AUC与剂量均呈正相关;随给药频率增加,各剂量组的C_max和AUC_ss降低,且给药末期（9个月）的蓄积指数（R_Cmax和R_AUC）均小于1;各剂量组在给药不同阶段的消除半衰期t_1/2z为20~30 h;达峰时间T_max和清除率CL_z/F均在一定范围内波动,不与剂量相关。结论 Beagle犬重复sc给予PEG-Det 37.5、75.0、150.0 μg/kg,随给药剂量增加,药物暴露量增大;经多次给药后,血浆中胰岛素浓度趋于平稳,体内无药物蓄积;且血糖降低幅度减少,在维持有效浓度和药效的基础上,降低了由低血糖带来的安全性风险。     

Pharmacodynamic and pharmacokinetic evaluation of insulin glargine U300 for the treatment of type 1 diabetes

Introduction: Glargine 300 units/ml (Gla-300) is a novel basal insulin formulation approved in 2015 for the treatment of diabetes. This more concentrated form of glargine causes delayed redissolution from the subcutaneous depot after injection and thus altered action profile.

Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of Gla-300 in patients with type 1 diabetes mellitus (T1DM) will be reviewed.

Expert opinion: Gla-300 has a flatter and more prolonged pharmacokinetic profile compared to glargine 100 units/ml (Gla-100), but is less potent on a unit per unit basis. The prolonged duration of Gla-300 should provide 24h coverage with a single daily dose in all patients. Two phase III trials comparing Gla-300 and Gla-100 were conducted in patients with T1DM. A1C reduction and other measures of glycemic control were similar between groups. Hypoglycemia rates were similar among groups in one trial, but favored Gla-300 in the other. Evidence for improvement in hypoglycemia with Gla-300 is more convincing in the type 2 diabetes population. Gla-300 is available in an insulin pen to mitigate potential dosing errors with different glargine concentrations; the maximum dose per injection is 80 units. Future research should include direct comparison with degludec and use in insulin-resistant populations.     

甘精胰岛素联合阿卡波糖治疗2型糖尿病疗效观察

目的 探讨甘精胰岛素联合阿卡波糖治疗2型糖尿病临床疗效.方法 选择确诊为2型糖尿病患者80例,随机分为对照组和治疗组,对照组38例,采用预混胰岛素(诺和灵30R)治疗,治疗组42例,采用甘精胰岛素联合阿卡波糖治疗,治疗12周,观察空腹血糖(FBG)、餐后2h血糖(2 hBG)、糖化血红蛋白(HbA1c)、体重指数(BMI)、血糖达标时间、低血糖事件发生率、胰岛素每天用量等指标.结果 2组经过12周治疗后,FBG、2 hBG、HbA1c指标均较治疗前有显著改善(P＜0.05),FBG、2 hBG、HbA1c各指标组间比较,差异无统计学意义(P＞0.05);BMI指标治疗前后比较,差异无统计学意义(P＞0.05);2组患者血糖达标时间比较,差异无统计学意义(P＞0.05);2组患者胰岛素每天用量、低血糖发生率比较,差异有统计学意义(P＜0.05).结论 甘精胰岛素联合阿卡波糖治疗2型糖尿病可显著改善血糖,降低血糖发生率低,且可减少胰岛素用量,临床效果显著,值得推广和借鉴.