Current treatment of insulin resistance in type 2 diabetes mellitus

The two major metabolic perturbations resulting in hyperglycaemia in type 2 diabetes are insulin resistance and insulin deficiency. Insulin resistance occurs in peripheral organs (muscle and fat), leading to decreased glucose uptake and utilisation, and in liver, leading to increased hepatic glucose production. Thiazolidinediones, pharmacological ligands for PPAR gamma, can modulate the expression of genes influencing carbohydrate and lipid metabolism. Pioglitazone, a recently introduced thiazolidinedione, improves glycaemic control and lipid profiles in people with type 2 diabetes. Some of the possible mechanisms of improving glycaemic control include (a) increase in GLUT-1 and GLUT-4, (b) enhancement of insulin signalling, (c) decrease in tumour necrosis factor-alpha action, (d) reduction in plasma free fatty acid and (e) decrease in PEPCK. Together these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver. Possible mechanisms resulting in more desirable lipid profiles include an increase in phosphodiesterase-3B resulting in reduced intra-cellular lipolysis in adipocytes and an increase in lipoprotein lipase resulting in enhanced clearance of triglyceride-rich lipoproteins(TRLs). Pioglitazone, used as monotherapy or in combination with sulphonylurea, biguanide or insulin, improves glycaemic control, lowers serum triglycerides and raises high density lipoprotein (HDL)-cholesterol. It enhances hepatic and peripheral insulin sensitivity. In clinical trials, there has been no evidence of hepatotoxicity or increased incidence of elevated serum ALT in subjects taking pioglitazone compared with placebo.     

2型糖尿病患者高甘油三酯血症与胰岛素抵抗的关系

目的 探讨2型糖尿病患者高甘油三酯血症与胰岛素抵抗的关系.方法 将2008年6月至2010年6月我院收治的149例2型糖尿病患者按甘油三酯升高与否分为高甘油三酯血症组(88例)与甘油三酯正常组(61例).通过测定2型糖尿病患者腰围(WC)、腰围身高比值(WHtR)、空腹血糖(FPG)、糖化血红蛋白(HbAlc)、尿酸(UA)、总胆固醇(TC)、空腹胰岛素(FINS)、稳态模型胰岛素抵抗指数(HOMA-IR),比较两组上述指标间的差异.结果 高甘油三酯血症组患者的WC、WHtR、UA、TC、FINS、HOMA-IR与甘油三酯正常组比较有明显升高[高甘油三酯血症组:WC(89.51±10.31) cm,WHtR 0.55±0.06,UA(316.95±88.50) μmol/L,wC(5.74±1.72) mmol/L,FINS(8.63±4.91) μU/L,HOMA-IR 4.48±3.14;甘油三酯正常组WC:(86.31±7.98) cm,WHtR 0.53±0.05,UA(275.48±88.36)μmol/L,wC(5.15±1.13) mmol/L,FINS(6.20±3.89) μU/L,HOMA-IR 3.38±2.76;t值分别是2.133、2.315、2.815、2.349、2.364、2.221,P均＜0.05].HOMA-IR与WC(r=0.233,P＜ 0.01)、WHtR(r=0.268,P ＜0.01)、BMI(r =0.161,P ＜0.05)、FPG(r =0.442,P ＜0.01)、AST(r =0.169,P ＜0.05)、UA(r=0.907,P＜0.01)、TG(r=0.220,P＜0.01)、FINS(r=0.907,P＜0.01)呈正相关.结论 2型糖尿病伴甘油三酯增高者加重胰岛素抵抗.     

2型糖尿病合并胆石症与胰岛素抵抗相互关系的探讨

目的:探讨2型糖尿病合并胆石症与胰岛素抵抗之间关系.方法:测定35例2型糖尿病合并胆石症患者的空腹血糖、空腹胰岛素、三酰甘油,总胆固醇,高密度脂蛋白,低密度脂蛋白(LDL),并计算胰岛素敏感指数,观察其变化及相互关系,并与42例不伴胆石症的2型糖尿病患者相比较.结果:2型糖尿病并胆石症组与不伴胆石症组相比较,前者空腹胰岛素、三酰甘油、总胆固醇,低密度脂蛋白明显升高,胰岛素敏感指数明显下降.结论:胰岛素抵抗可能是2型糖尿病患者胆石形成的危险因素.     

Causes of insulin resistance in type 1 diabetes

Insulin resistance is a well-known phenomenon in diabetic patients. Its occurrence in Type 1 (insulin-dependent) diabetes is thought to be due both to metabolic and immunological disturbances. In this context, a key role is attributed to the augmented release of the 'diabetogenic' hormones, adrenaline, glucagon, cortisol and growth hormone, as well as to hypertonic dehydration and to the presence of insulin-binding antibodies. In this connection it is noteworthy that among the 'diabetogenic' hormones adrenaline exerts the strongest insulin-antagonistic effect and that hypertonic dehydration is associated with impairment of insulin action and of non-insulin-dependent hepatic glucose uptake (in vitro), while hypotonic rehydration reduces the elevated hepatic glucose production in dehydrated Type 1 diabetic patients. By contrast, the generally only slightly elevated serum insulin-binding capacity in insulin-treated diabetics is probably of least importance in the development of insulin resistance, unless excessively high insulin antibody titres prevail.     

胰岛素抵抗在2型糖尿病发病机制中的作用

胰岛素抵抗(insulin resistance,IR)又称胰岛素敏感性下降,通常指胰岛素介导的葡萄糖利用率降低。IR是糖尿病的主要发病机制之一,并伴随着糖尿病发生、发展的全过程,其在肥胖、高血压和血脂     

Impact of insulin resistance and nephropathy on homocysteine in type 2 diabetes

OBJECTIVE: To assess the impacts of insulin resistance and renal function on plasma total homocysteine (tHcy) levels in patients with type 2 diabetes with a wide range of nephropathy. RESEARCH DESIGN AND METHODS: Plasma tHcy levels were measured using the enzyme immunoassay method in 75 patients with type 2 diabetes and compared with those in 54 healthy control subjects. Insulin sensitivity indexes were assessed in patients with type 2 diabetes by hyperinsulinemic-euglycemic clamp using artificial pancreas. RESULTS: Plasma tHcy levels and their log-translormed values (log tHcy) were significantly higher in all patients with diabetes than in control subjects (tHcy, 12.0 +/- 0.7 [SE] vs. 8.7 +/- 0.3 micromol/l, P < 0.0001; log tHcy, 1.040 +/- 0.021 vs. 0.920 +/- 0.016 micromol/l, P < 0.0001). Plasma tHcy levels in patients with diabetes were significantly increased according to degree of nephropathy (P < 0.0001). On simple regression analyses, log tHcy correlated with insulin sensitivity indexes (r = -0.319, P = 0.005) as well as creatinine clearance (r = 0.634, P < 0.0001) in all patients with diabetes. Multiple regression analyses showed that insulin sensitivity indexes (beta = -0.245) as well as creatinine clearance were independent contributors to log tHcy in all patients with diabetes (R2 = 0.750, P < 0.0001). For the 59 patients with diabetes with creatinine clearance >60 ml/min, insulin sensitivity indexes were also shown to be a significant contributor to log tHcy (beta = -0.438, R2 = 0.561, P < 0.001). CONCLUSION: Insulin resistance and renal function are independent determinants of tHcy levels in patients with type 2 diabetes.     

The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes

Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials.     

2型糖尿病胰岛素抵抗的中医治疗

胰岛素抵抗不仅是2型糖尿病的重要病理基础,还与并发症的危险因素密切相关。它参与了糖尿病的发生、发展、结局的全过程。针对胰岛素抵抗是2型糖尿病干预的关键方法之一,中药改善胰岛素抵抗可以用复方治疗、单味中药及其提取物治疗等。近年来的一些研究显示,中医中药具有整体性、多层次、多靶点调节的特点,在改善胰岛素抵抗方面有一定的应用前景。     

Atherosclerosis in type 2 diabetes mellitus: the role of insulin resistance

Type 2 diabetes mellitus is associated with a marked increase in the risk of atherosclerotic diseases, including coronary heart disease, peripheral arterial disease, and cerebrovascular disease. Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus. Insulin resistance and its attendant metabolic abnormalities may cause much of the increased cardiovascular risk of type 2 diabetes mellitus. Among the abnormalities associated with insulin resistance are dyslipidemia, hypertension, systemic inflammation, and a prothrombotic state. This review discusses the role that each of these disorders plays in the cardiovascular risk of type 2 diabetes mellitus.     

Tissue-specific insulin resistance in type 2 diabetes: lessons from gene-targeted mice

Type 2 diabetes is caused by genetic and environmental factors that affect the ability of the organism to respond to insulin. This impairment results from decreased insulin action in target tissues and insulin production in (3 cells. Genetic factors play a key role in the development of type 2 diabetes. However, the inheritance of diabetes is non-Mendelian in nature because of genetic heterogeneity, polygenic pathogenesis, and incomplete Perretrance. Novel insight into this complex process has been obtained from ‘designer’ mice bearing targeted mutations in genes of the insulin action and insulin secretion pathways. These mutant mice are beginning to challenge established paradigms in the pathogenesis of type 2 diabetes and to shed light on the genetic interactions underlying its complex inheritance. Here we review recent progress in the field and assess its relevance to the pathogenesis of diabetes in humans.     

2型糖尿病胰岛素抵抗与肾素-血管紧张素-醛固酮系统的研究进展

2型糖尿病(T2DM)是与过度消费高热量食物,缺乏运动和肥胖有关的疾病。胰岛素抵抗就是组织或细胞对胰岛素的反应能力减低。研究发现肾素-血管紧张素-醛固酮系统(RAAS)参与T2DM的发生发展,血管紧张素转化酶抑制剂(ACEI)或血管紧张素Ⅱ受体拮抗剂(ARB)类药物可延缓胰岛素抵抗的进展。然而目前对其机制研究仍不明确,本文针对这一问题进行总结。     

Tissue-specific insulin resistance in type 2 diabetes: lessons from gene-targeted mice

Type 2 diabetes is caused by genetic and environmental factors that affect the ability of the organism to respond to insulin. This impairment results from decreased insulin action in target tissues and insulin production in beta cells. Genetic factors play a key role in the development of type 2 diabetes. However, the inheritance of diabetes is non-Mendelian in nature because of genetic heterogeneity, polygenic pathogenesis, and incomplete penetrance. Novel insight into this complex process has been obtained from 'designer' mice bearing targeted mutations in genes of the insulin action and insulin secretion pathways. These mutant mice are beginning to challenge established paradigms in the pathogenesis of type 2 diabetes and to shed light on the genetic interactions underlying its complex inheritance. Here we review recent progress in the field and assess its relevance to the pathogenesis of diabetes in humans.     

Renal injury, abnormal vitamin D metabolism and bone homeostasis in aged rats with insulin resistance or type 2 diabetes mellitus

OBJECTIVE: The study aimed to explore the relationship among renal injury, abnormal vitamin D metabolism, and bone homeostasis in insulin resistance (IR) or type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: The animal models of IR, T2DM, and T2DM treated with 1-alpha hydroxyvitamin D (1-alphaOHD) were established on 18-month-old male Wistar rats. Glucose infusion rates (GIR) and levels of urinary albumin (UA), serum 25-hydroxyvitamin D (25-(OH)D), serum 1,25-dihydroxyvitamin D (1,25-OH2D), and bone mineral density (BMD) in lumbar vertebrae and femoral bone were measured. RESULTS: Urinary albumin level in the rats with T2DM significantly increased, and there existed a significant and negative correlation between GIR and UA level in the rats with T2DM or IR. The levels of serum 25-OHD in all models were similar. The levels of serum 1,25-OH2D and BMD in the rats with IR were significantly higher than those in the rats with T2DM and were lower than those in normal control rats. In the aged rats with T2DM, administration of 1-alphaOHD had no effect on serum 25-OHD level although significantly increased the levels of serum 1,25-O2D and BMD. There existed a negative correlation between the levels of serum 1,25-(OH)2D and UA in the rats with T2DM or IR. CONCLUSIONS: In IR or T2DM, abnormal vitamin D metabolism is characterized by 1,25-OH2D deficiency and is related to renal injury, and there also existed bone loss. In T2DM, both 1,25-(OH)2D deficiency and bone loss can be reversed by 1-alphaOHD.     

Avandamet: combined metformin-rosiglitazone treatment for insulin resistance in type 2 diabetes

Insulin resistance is a major endocrinopathy underlying the development of hyperglycaemia and cardiovascular disease in type 2 diabetes. Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) counter insulin resistance, acting by different cellular mechanisms. The two agents can be used in combination to achieve additive glucose-lowering efficacy in the treatment of type 2 diabetes, without stimulating insulin secretion and without causing hypoglycaemia. Both agents also reduce a range of atherothrombotic factors and markers, indicating a lower cardiovascular risk. Early intervention with metformin is already known to reduce myocardial infarction and increase survival in overweight type 2 patients. Recently, a single-tablet combination of metformin and rosiglitazone, Avandamet, has become available. Avandamet is suitable for type 2 diabetic patients who are inadequately controlled by monotherapy with metformin or rosiglitazone. Patients already receiving separate tablets of metformin and rosiglitazone may switch to the single-tablet combination for convenience. Also, early introduction of the combination before maximal titration of one agent can reduce side effects. Use of Avandamet requires attention to the precautions for both metformin and rosiglitazone, especially renal, cardiac and hepatic competence. In summary, Avandamet is a single-tablet metformin-rosiglitazone combination that doubly targets insulin resistance as therapy for hyperglycaemia and vascular risk in type 2 diabetes.     

Role of impaired insulin secretion and insulin resistance in the pathogenesis of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a heterogenous disorder caused by a combination of genetic and acquired abnormalities that affect insulin sensitivity and insulin secretion. Currently available data suggest that insulin resistance is the acquired defect largely secondary to unhealthy lifestyles and that the major genetic factor is impaired insulin secretion. The latter is the result of both reduced β-cell mass and functional abnormalities makes the β-cell unable to compensate for increased insulin requirements caused by insulin resistance. Targeting both insulin resistance and impaired insulin secretion is therefore appropriate to prevent T2DM and to improve glycemic control in those with the disorder. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article. The authors also do not discuss the use of off-label products, which includes unlabeled, unapproved, or investigative products or devices.