Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology

The rapid rise in prevalence of type 2 diabetes mellitus (T2DM) has been driven by changes in environmental factors – primarily increased caloric intake and reduced energy expenditure – resulting in reduced whole body insulin sensitivity (often termed insulin resistance). Insulin resistance has been proposed to be a major driver of progression to T2DM. However, of 38 individual susceptibility loci for T2DM recently identified by genome wide association studies, by far the majority code for proteins involved in β-cell function. In this review, we discuss the possible reasons for the paucity of insulin resistance genes and ask whether the new genetic susceptibility data should focus attention on β-cell targets in the development of therapies for T2DM.     

胰岛素泵强化治疗对降糖药继发性失效的2型糖尿病患者炎性细胞因子及胰岛功能的影响

目的观察胰岛素泵强化治疗对降糖药继发性失效(SFS)的2型糖尿病患者炎性细胞因子及胰岛功能的影响。方法 50例SFS的2型糖尿病患者停用口服降糖药,改用胰岛素泵强化治疗2周,观察治疗前后的空腹血糖、餐后2-h血糖、胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)水平的变化。结果强化治疗后,患者空腹血糖、餐后2-h血糖、HOMA-IR、TNF-α、IL-6水平均较治疗前明显下降(P<0.05),HOMA-β较治疗前明显增高(P<0.05)。结论胰岛素泵强化治疗可减轻SFS的2型糖尿病患者胰岛素抵抗,改善胰岛β细胞功能,降低机体炎性因子水平。     

初诊2型糖尿病短期胰岛素泵强化治疗对血清炎症因子及胰岛功能的影响

目的：观察短期胰岛素泵强化治疗对初诊2型糖尿病患者（T2DM）血清C反应蛋白（CRP）、肿瘤坏死因子-α（TNF-α）、白介素-6（IL-6）水平及胰岛β细胞功能的影响。方法：初诊T2DM患者64例,应用胰岛素泵强化治疗14 d,比较治疗前后血清CRP、TNF-α、IL-6、胰岛素分泌指数（HOMA-IS）、胰岛素抵抗指数（HOMA-IR）的变化,并与38例健康对照组人群进行比较。结果：T2DM患者治疗前血清CRP、TNF-α、IL-6水平较正常对照组明显升高（P<0.01）;强化治疗后较治疗前血清CRP、TNF-α、IL-6水平明显降低（P<0.01）,HOMA-IS明显升高（P<0.01）,而HOMA-IR则明显降低（P<0.01）。结论：初诊T2DM患者存在慢性炎症反应,胰岛素具有抗炎作用,胰岛素强化治疗可改善患者糖代谢,减轻胰岛素抵抗,从而降低炎症因子的表达。     

Treatment of polycystic ovary syndrome with insulin-lowering agents

Early diagnosis and therapy of the underlying insulin resistance of heritable polycystic ovary syndrome (PCOS), often manifested at menarche, facilitate the reduction and/or reversal of the reproductive and metabolic morbidity of PCOS, as well as reduce the risk factors for cardiovascular disease. PCOS is characterised by oligoamenorrhoea, clinical and biochemical hyperandrogenism, infertility, recurrent miscarriage, insulin resistance, hyperinsulinaemia, gestational diabetes, impaired glucose tolerance, Type 2 diabetes, morbid obesity, hypertension, hypofibrinolysis, hypertriglyceridaemia, low levels of high density lipoprotein-cholesterol and a sevenfold risk increase in cardiovascular disease. Insulin sensitising-lowering agents reduce insulin resistance and hyperinsulinaemia, reverse PCOS endocrinopathy and ameliorate the reproductive, metabolic and cardiovascular morbidity of the disorder. The largest literature on the subject discusses metformin. Improved pregnancy outcomes in women with PCOS receiving metformin may be attributed to its ability to reduce insulin resistance, hyperinsulinaemia and hypofibrinolytic plasminogen activator inhibitor activity by the enhancement of folliculogenesis and improvement of oocyte quality.     

Ceftaroline fosamil for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infection

Early diagnosis and therapy of the underlying insulin resistance of heritable polycystic ovary syndrome (PCOS), often manifested at menarche, facilitate the reduction and/or reversal of the reproductive and metabolic morbidity of PCOS, as well as reduce the risk factors for cardiovascular disease. PCOS is characterised by oligoamenorrhoea, clinical and biochemical hyperandrogenism, infertility, recurrent miscarriage, insulin resistance, hyperinsulinaemia, gestational diabetes, impaired glucose tolerance, Type 2 diabetes, morbid obesity, hypertension, hypofibrinolysis, hypertriglyceridaemia, low levels of high density lipoprotein-cholesterol and a sevenfold risk increase in cardiovascular disease. Insulin sensitising-lowering agents reduce insulin resistance and hyperinsulinaemia, reverse PCOS endocrinopathy and ameliorate the reproductive, metabolic and cardiovascular morbidity of the disorder. The largest literature on the subject discusses metformin. Improved pregnancy outcomes in women with PCOS receiving metformin may be attributed to its ability to reduce insulin resistance, hyperinsulinaemia and hypofibrinolytic plasminogen activator inhibitor activity by the enhancement of folliculogenesis and improvement of oocyte quality.     

Clinical efficacy of metformin against insulin resistance parameters: sinking the iceberg

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.     

IS INSULIN RESISTANCE LINKED TO HYPERTENSION?

1. The volume of work reporting insulin resistance in multiple forms of chronic hypertension has generated tremendous interest in whether this abnormality is an important factor in causing hypertension. Insulin resistance, however, is an imprecise term used interchangeably to describe widely disparate types of impairment in insulin action throughout the body and the type of insulin resistance has major ramifications regarding its potential for inducing long-term increases in blood pressure (BP). 2. Hepatic insulin resistance (impaired insulin-mediated suppression of hepatic glucose output) is the primary cause of fasting hyperinsulinaemia and is a cardinal feature of obesity hypertension. Evidence from chronic insulin infusion studies in rats suggests hyperinsulinaemia can increase BP under some conditions; however, conflicting evidence in humans and dogs leaves in question whether hyperinsulinaemia is a factor in hypertension induced by obesity. 3. Peripheral insulin resistance (impaired insulin-mediated glucose uptake, primarily of an acute glucose load in skeletal muscle) also present in obesity hypertension, but now reported in lean essential hypertension as well, is linked most notably to impaired insulin-mediated skeletal muscle vasodilation. This derangement has also been proposed as a mechanism through which insulin resistance can cause hypertension. 4. The present review will discuss the lack of experimental or theoretical support for that hypothesis and will suggest that a direct link between insulin resistance and BP control may not be the best way to envision a role for insulin resistance in cardiovascular morbidity and mortality.     

Insulin sensitiser drugs

Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease.     

Insulin sensitiser drugs

Insulin resistance is the predominant early pathological defect in Type 2 diabetes. As well as being a risk factor for the development of Type 2 diabetes, insulin resistance is also associated with increased cardiovascular risk and other metabolic disturbances including visceral adiposity, hyperinsulinaemia, impaired glucose tolerance, hypertension and dyslipidaemia [1-4]. The newest approach to oral antidiabetic therapy is to target improvements in insulin sensitivity at muscle, adipose tissue and hepatic level. This results in improvements in glycaemic control and other features of the insulin resistance syndrome, with potential long-term benefits in preventing/delaying the onset of diabetic complications and macrovascular disease.     

丹皮多糖-2b对2型糖尿病大鼠模型的作用及其降糖作用机制

目的　观察丹皮多糖 2b(PSM 2b)对 2型糖尿病(T2DM)大鼠模型的作用 ,并探讨其降血糖作用的机制。方法　链脲霉素和高热量喂饲复制大鼠T2DM。灌胃给药 5wk。用葡萄糖氧化酶法、放射免疫分析法及受体放射配体结合分析法分别测定血清葡萄糖、胰岛素及肝细胞膜的胰岛素受体。结果　PSM 2b能明显降低空腹血糖 ,改善糖耐量异常及血脂异常 ,提高肝细胞低亲和力胰岛素受体 (InsR)最大结合容量 (RT2 ) ,使胰岛素敏感性指数 (ISI)增加 (P <0 0 5 )。结论　PSM 2b对T2DM大鼠模型有明显的治疗作用 ,其降糖机制与提高胰岛素受体数目、改善受体环节的胰岛素抵抗有关     

The antihyperglycemic effect of curcumin in high fat diet fed rats. Role of TNF-α and free fatty acids

This study was conducted to investigate the effect of curcumin, obtained from Curcuma longa, in comparison with rosiglitazone on the progression of insulin resistance and type 2 diabetes mellitus (T2DM) and the mechanisms underlying this effect. Insulin resistance and T2DM was induced in male Sprague Dawley rats by high fat diet (HFD) feeding for 60 and for 75 days representing two regimens of the study, protection and treatment. Prophylactic oral administration of curcumin (80 mg/kg), rosiglitazone (1 mg/kg), their combination, or vehicle (in control groups) was started along with HFD feeding in different groups. Treatment is achieved by oral administration of the previously mentioned agents in the last 15 days of HFD feeding after induction of insulin resistance and T2DM in rats.Curcumin showed an anti-hyperglycemic effect and improved insulin sensitivity, and this action may be attributed at least in part to its anti-inflammatory properties as evident by attenuating TNF-α levels in HFD fed rats, and its anti-lipolytic effect as evident by attenuating plasma free fatty acids. The curcumin effects are comparable to those of rosiglitazone, which indicate that they may act similarly. Finally we can say that, curcumin could be a beneficial adjuvant therapy in patients with T2DM.     

肿瘤坏死因子-α、白细胞介素-6和脂联素与2型糖尿病胰岛素抵抗的关系

目的 研究2型糖尿病（T2DM）患者肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和脂联素与胰岛素抵抗的关系.方法 选择80例T2DM患者（T2DM组）和40例健康体检者（对照组）,测定各组空腹血清TNF-α,IL-6和脂联素水平,同时分别测定各组患者体质量指数（BMI）、空腹血糖、血清胰岛素水平,计算胰岛素抵抗指数（HOMA-IR）.结果 T2DM组TNF-α、IL-6水平均明显高于对照组,脂联素水平明显低于对照组（均P＜0.05）.在T2DM组中,TNF-α和IL-6均与HOMA-IR呈正相关（P＜0.01,P＜0.05）,脂联素与HOMA-IR呈负相关（P＜0.01）.结论 IL-6、TNF-α及脂联素参与了2型糖尿病的发病过程,与胰岛素抵抗密切相关.     

A risk-benefit assessment of metformin in type 2 diabetes mellitus.

Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care. Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus. The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced. The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.     

2型糖尿病伴发肾结石的危险因素

目的 分析2型糖尿病伴发肾结石患者的临床特征,探讨2型糖尿病伴发肾结石的相关危险因素.方法 采用回顾性分析方法,测定2型糖尿病伴肾结石组患者（60例）与2型糖尿病不伴肾结石组患者（60例）的空腹血糖（FPG）、糖化血红蛋白（HbA1c）、血清胰岛素、c肽、尿酸（UA）、甘油三脂（TC）、总胆固醇（TC）、低密度胆固醇（LDL-C）水平,计算胰岛素抵抗指数（Homa-IR）,统计分析两组患者上述指标结果差异性.结果 2型糖尿病伴肾结石组患者FPG（11.4±5.4） mmol/L、HbA1c％（9.5±2.7）、空腹血清胰岛素（10.5±6.2）mIU/L、空腹c肽（3.5±2.3） nmol/L、UA（377.1±119.3） mmol/L、TC（5.6±2.1） mmol/L、LDL-C（5.5±3.9）mmol/L、Homa-IR（5.1±3.7）,上述指标水平较2型糖尿病不伴肾结石组显著性升高（P值分别为0.035,0.026,0.017,0.004,0.048,0.037,0.022,0.029,均小于0.05）.结论 胰岛素抵抗、高血糖、高尿酸、脂代谢紊乱可能是2型糖尿病伴发肾结石的危险因素.     

Optimisation of glycaemic control during episodes of severe/acute hyperglycaemia in patients with type 2 diabetes mellitus

Background Patients with type 2 diabetes mellitus (T2DM) are frequently admitted to the hospital with severe or acute hyperglycaemia secondary to an acute illness or disease. Uncontrolled glycaemia is a significant problem during severe or acute hyperglycaemia. Objective This study sought to identify demographic, clinical, and genetic factors that may contribute to increased insulin resistance or worsening of glycaemic control in patients with T2DM. Setting This prospective cohort study included 156 patients with T2DM and severe or acute hyperglycaemia who were treated with insulin at any medical ward of the National University of Malaysia Medical Centre. Method Insulin resistance was determined using the homeostatic model assessment?Cinsulin resistance index. Glycaemic control during the episode of hyperglycaemia was assessed as the degree to which the patient achieved the target glucose levels. The polymerase chain reaction?Crestriction fragment length polymorphism method was used to identify polymorphisms in insulin receptor substrate (IRS) genes. Main outcome measure Identification of possible predictors (demographic, clinical, or genetic) for insulin resistance and glycaemic control during severe/acute hyperglycaemia. Results A polymorphism in IRS1, r.2963 G>A (p.Gly972Arg), was a significant predictor of both insulin resistance [odds ratios (OR) 4.48; 95?% confidence interval (CI) 1.2?C16.7; P?=?0.03) and worsening of glycaemic control (OR 6.04; 95?% CI 0.6?C64.6; P?=?0.02). The use of loop diuretics (P?<?0.05) and antibiotics (P?<?0.05) may indirectly predict worsening of insulin resistance or glycaemic control in patients with severe/acute hyperglycaemia. Conclusion Clinical and genetic factors contribute to worsening of insulin resistance and glycaemic control during severe/acute hyperglycaemia in patients with T2DM. Early identification of factors that may influence insulin resistance and glycaemic control may help to achieve optimal glycaemic control during severe/acute hyperglycaemia.     

细胞因子与2型糖尿病胰岛素抵抗的相关性研究

目的研究2型糖尿病及胰岛素抵抗患者白细胞介素6（IL-6）、IL-8、肿瘤坏死因子仪（TNF—α）及C反应蛋白（CRP）的变化,分析细胞因子与糖尿病及胰岛素抵抗的相关性。方法125例2型糖尿病患者其中胰岛素抵抗者80例为胰岛素抵抗组,非胰岛素抵抗者45例为非胰岛素抵抗组,40例健康体检者为对照组,采用酶联免疫吸附法测定3组的IL-6、IL-8、TNF-α,并同时测定空腹血糖、糖化血红蛋白、空腹胰岛素及空腹C肽水平,分析各指标与细胞因子的相关性。结果与正常对照组比较;2型糖尿病组血清细胞因子的含量均明显增高（P〈0．05）;胰岛素抵抗组的IL-6、TNF-α、CRP分别为（91．09±22．25）ng／L、（69．51±32．37）ng／L、（0．75±0．11）ng／L与非胰岛素抵抗组[分别为（77．09±22．20）ng/L、（54．87±13．23）ng/L、（0．43±0．09）ng／L]比较差异有统计学意义（P〈0．05）。结论2型糖尿病患者存在着细胞因子的过度激活,并与胰岛素抵抗密切相关,细胞因子在2型糖尿病及胰岛素抵抗的发生发展中起着重要的作用。     

Obesity and insulin resistance: Pathophysiology and treatment

The prevalence of obesity is a major cause of many chronic metabolic disorders, including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and cancer. Insulin resistance is often associated with metabolic unhealthy obesity (MUO). Therapeutic approaches aiming to improve insulin sensitivity are believed to be central for the prevention and treatment of MUO. However, current antiobesity drugs are reported as multitargeted and their insulin-sensitizing effects remain unclear. In this review, we discuss current understanding of the mechanisms of insulin resistance from the aspects of endocrine disturbance, inflammation, oxidative, and endoplasmic reticulum stress (ERS). We then summarize the antiobesity drugs, focusing on their effects on insulin sensitivity. Finally, we discuss strategies for obesity treatment.     

Novel approaches to drug discovery for the treatment of type 2 diabetes

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, which has become a serious global health problem. The side effects of known drugs and the deficiency of long-term safety data, in addition to the already determined adverse effects for the current preclinical drugs against T2DM, have largely called upon the urgent exploration of novel therapeutic and preventative strategies against this disease.

Areas covered: The authors highlight the potential approaches for anti-T2DM drug discovery by focusing on: the restoration of pancreatic β-cell mass, the promotion of insulin secretion, the regulation of oxidative stress and endoplasmic reticulum (ER) stress and the modulation of autophagy.

Expert opinion: T2DM is based on the gradual development of insulin resistance and β-cell dysfunction. Thus, the restoration of β-cell function is considered as one of the promising therapeutic strategies against T2DM. The stress factors, such as oxidative stress, ER stress and autophagy, play potent roles in the regulation of β-cell apoptosis, insulin secretion and sensitivity in the development of T2DM involving complicated cross-talks. Based on multiplex stress-involved regulatory networks, more and more novel potential targets have been discovered and the multi-targeted drug leads are expected to help develop more effective clinical agents for the treatment of T2DM.     

Insulin glargine and its role in glycaemic management of Type 2 diabetes

BACKGROUND: Insulin glargine (Lantus) was the first recombinant-DNA long-acting insulin analogue to be licensed for use in the treatment of diabetes mellitus. OBJECTIVE: This review considers the use of insulin glargine in the treatment of type 2 diabetes (T2DM). METHODS: Medline, Cochrane and Embase databases were searched for relevant papers from the year 2000 onwards. RESULTS/CONCLUSION: Overall glargine provides at least equivalent glycaemic control and is associated with less hypoglycaemia, especially nocturnal hypoglycaemia owing to its 24 h peakless profile, which allows more aggressive titration to achieve glycaemic targets. Glargine has been shown to be safely initiated both individually and within a group setting and titration algorithms self-managed by patients are effective in achieving diabetes control. Despite these advantages, caution is needed as clinical guidelines do not advocate its use in all people with T2DM until clinical efficacy and cost effectiveness have been proved. However, insulin glargine is a welcome addition to the plethora of treatment options available for T2DM.