糖尿病，胰岛素和癌症风险

There is a consensus that both type 1 and type 2 diabetes are associated with a spectrum of cancers but the underlying mechanisms are largely unknown.On the other hand,there are ongoing debates about the risk association of insulin use with cancer.We have briefly reviewed recent related research on exploration of risk factors for cancer and pharmacoepidemiological investigations into drug use in diabetes on the risk of cancer,as well as the current understanding of metabolic pathways implicated in intermediary metabolism and cellular growth.Based on the novel findings from the Hong Kong Diabetes Registry and consistent experimental evidence,we argue that use of insulin to control hyperglycemia is unlikely to contribute to increased cancer risk and that dysregulations in the AMPactivated protein kinase pathway due to reduced insulin action and insulin resistance,the insulin-like growth factor-1(IGF-1)-cholesterol synthesis pathway and renin-angiotensin system,presumably due to reduced insulin secretion and hyperglycemia,may play causal roles in the increased risk of cancer in diabetes.Further exploration into the possible causal relationships between abnormalities of these pathways and the risk of cancer in diabetes is warranted.

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system(RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials(RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios(HR) regarding the treatment effects of these drugs for cardiovascular disease(CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Relationship between obesity and cardiovascular risk factors in elderly Chinese subjects

OBJECTIVE: To investigate the relative effects of degree and distribution of body fat with several cardiovascular disease (CVD) risk factors in elderly Chinese subjects. METHODS: One hundred and thirty-five elderly Chinese individuals (age range, 60-65 y) without any history of significant renal, hepatic or cardiac disease were recruited. Seated blood pressure, anthropometric and fasting plasma biochemical parameters were measured. Student's t-test was used to compare the differences in biochemical and anthropometric markers between cohorts. RESULTS: Males were heavier (64.6 +/- 8.6, 57.2 +/- 8.2kg, P

阿卡波糖心血管评估（ACE）试验依据与设计

心血管疾病（CVD）患者和糖耐量减低（IGT）者患2型糖尿病（T2DM）的风险较高。生活方式的调整或药物干预可以延缓T2DM的进展，但没有证据表明它们能够降低该人群的心血管风险。阿卡波糖是一种α-葡萄糖苷酶抑制剂，能够降低餐后血糖；其被证明能够使T2DM风险降低25％，并有可能降低无CVD的IGT受试者的心血管风险。阿卡波糖心血管评估（ACE）试验是一项随机、安慰剂对照、双盲、二级预防试验，受试者为7500例患有冠心病（定义为既往心肌梗死、不稳定型心绞痛或当前稳定的心绞痛）并伴有IGT且年龄I〉50岁的患者。以1：1的比例将患者随机分组，分别在标准CVD治疗药物基础上服用阿卡波糖50mg，每天3次或相匹配的安慰剂。排除标准包括糖尿病病史、过去3个月内发生过心血管事件、NYHAⅢ／Ⅳ级心力衰竭、重度肝病和重度肾功能损害。本研究在中国内地和中国香港的约150家医院内进行。主要复合心血管终点是至首次发生心血管死亡、非致死性心肌梗塞或非致死性卒中的时间。次要终点包括全因死亡和新发T2DM。ACE是一项对CVD进行二级预防的研究，用于评估冠心病患者和IGT者在标准心血管治疗的基础上加用阿卡波糖的效果。CVD的治疗与干预标准包括合理使用能降低心血管风险因素的药物，例如B肾上腺素能受体阻断剂、血管紧张素转换酶抑制剂、抗血小板药物和降血脂药物。在高血糖症患者中，血糖可能是另一个可调节的风险因素。流行病学证据表明，IGT会导致CVD发病率和死亡率上升，尽管其程度低于T2DM患者。餐后高血糖是餐后血糖代谢障碍的一个指标，它是心血管事件的一个独立的预测因子，因为负荷后血糖值与心血管事件的相关性比空腹血糖值更强，即使在非糖尿病受试者中也是这样。餐后代谢障碍影响动脉粥样硬化与CVD的机制包含多种因素。体内血糖的急性上升会诱导内皮功能障碍，可能是通过氧化应激引起。急性高血糖症也与血栓形成的激活以及炎性级联反应相关。用药物治疗来降低餐后高血糖会导致CVD的替代指标下降。在之前未用药物而被随机分配接受瑞格列奈（一种短效促泌剂，主要对餐后高血糖进行控制）或格列本脲（一种长效磺脲类药物）的患者中，使用瑞格列奈的患者C反应蛋白和白细胞介素-6的下降程度较大，颈动脉内一中膜厚度指标也是如此。阿卡波糖能够通过延缓碳水化合物的消化和吸收，降低餐后高血糖，改善内皮功能障碍，降低炎性指标（包括细胞核因子．xB活化及其核转位以及C反应蛋白），减少凝血因子（纤维蛋白原和凝血素），减少低密度脂蛋白氧化，降低颈动脉内一中膜厚度。相比那格列奈，阿卡波糖餐后血流量介导的血管扩张改善更显著。它也会放大二肽基肽酶4抑制剂阿格列汀的降血糖效应。IGT者中进行的降糖药物临床试验大都集中在预防T2DM上，而对心血管结局鲜有关注。STOP．NIDDM试验（1429名IGT受试者被随机分配阿卡波糖或安慰剂）显示，在平均3．3年的随访期后，阿卡波糖降低T2DM风险25％。后续分析也显示心肌梗死风险以及预先指定的任一心血管事件风险下降，但只有47名受试者发生了CVD。一项关于阿卡波糖的荟萃分析提示，阿卡波糖能显著降低T2DM患者的心肌梗死风险和心血管死亡、卒中、外周动脉疾病、心绞痛、心力衰竭和血管重建的风险。这些数据支持了该假设：使用阿卡波糖降低餐后高血糖能够消除IGT者的高CVD风险。目前为止唯一的有关降低餐后血糖药物的前瞻性CVD结局试验NAVIGATOR显示，那格列奈对心血管结局没有影响。ORIGIN试验（增大基础胰岛素用量以降低IGT者或早期T2DM患者的空腹血糖值）结果也显示对心血管结局没有影响。ACE试验的目的是确定阿卡波糖是否能够减少冠心病患者和IGT者中的心血管事件，其次要结局是T2DM的预防情况。

Evidence for DNA Damage as a Biological Link Between Diabetes and Cancer

Objective： This review examines the evidence that： Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage： DNA damage can cause mutations： and DNA mutation is linked to carcinogenesis. Data Sources： We retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis. Study Selection： We included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes. Results： There are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification （i.e., oxidation）. Emerging experimental data suggest that signal pathways （i.e., Akt/tuberin） link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk. Conclusions： This review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.