Insulin signaling and pathophysiology of type 2 diabetes mellitus

The pathophysiology of type 2 diabetes is characterized by defects in insulin action and in insulin secretion. Metabolic actions of insulin are mediated by the insulin receptor/IRS/PI 3-kinase signaling pathway in insulin's target organs including the liver, skeletal muscle and adipose tissue. Recent evidence suggests that insulin action in the brain also plays an important role in the regulation of glucose metabolism in the liver. Insulin signaling in pancreatic beta cells appears to regulate glucose-induced insulin secretion. Although the mechanism how insulin resistance develops is not fully understood, dysregulation of fatty acid metabolism, abnormalities of the function and the secretion of adipokines, as well as the increase in stress signaling might contribute to the development of insulin resistance.     

New strategies for basal insulin treatment in type 2 diabetes mellitus

BACKGROUND: The clinical progression of type 2 diabetes mellitus (DM) is well understood. Glycemic control gradually deteriorates, and progression of DM eventually leads to an increased risk for microvascular and macrovascular complications. Reassessment of current insulin treatment strategies leading to restoration of glycemic control is essential to prevent or stop the progression of type 2 DM and its complications. OBJECTIVE: The purpose of this article was to review the importance of instituting a strategy of basal insulin therapy in patients with type 2 DM. METHODS: Relevant articles were obtained through an online search of PubMed and MEDLINE for literature published from 1990 to 2003. The search terms used were insulin therapy, combination oral therapy, treatment failure, glycemic control, insulin analogues, insulin glargine, basal insulin, and microvascular complications. RESULTS: Large-scale intervention trials, such as the United Kingdom Prospective Diabetes Study (UKPDS), have reported that patients with type 2 DM treated with oral combination therapy are unable to maintain glycemic control. These observations have led to a reassessment of the role of insulin therapy in type 2 DM. The importance of tight glycemic control through the aggressive use of insulin early in the course of the disease is apparent from the UKPDS, Diabetes Control and Complications Trial, and other, smaller studies. Considerable evidence indicates that initiating a basal insulin-replacement strategy with an existing oral regimen can result in regaining glycemic control. Evidence emerging from recent studies indicates that use of intensive insulin therapy early in the course of the disease may have a positive clinical impact on outcome and slow the progression of complications. The availability of basal insulin analogues has expanded treatment options and improved the efficacy of therapeutic regimens for type 2 DM. CONCLUSIONS: The available data suggest using an earlier transition from monotherapy to combination therapy to minimize disease-associated morbidity. The availability of new insulin analogues has expanded therapeutic options and offers the potential to enhance the efficacy of therapeutic regimens for type 2 DM as well as improve the ease and safety of treatment when glycosylated hemoglobin cannot be maintained <7% on > or =1 oral antidiabetic agent.     

2型糖尿病的胰岛素和胰岛素类似物治疗

根据2型糖尿病(T2DM)患者的病情及β细胞功能,及时合理地使用胰岛素是使血糖正常化的必然选择。本文主要介绍了T2DM胰岛素治疗的适应证、治疗方案、停药指征、注意事项等内容。     

Liraglutide for type 2 diabetes mellitus

Introduction: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain.

Areas covered: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM.

Expert opinion: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.     

Liraglutide for type 2 diabetes mellitus

INTRODUCTION: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain. AREAS COVERED: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM. EXPERT OPINION: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.     

Incretin therapy for type 2 diabetes mellitus

In addition to progressive pancreatic β-cell failure resulting in impaired insulin secretion, and increased insulin resistance in muscle and liver, incretin hormone-related abnormalities have been identified as key underlying defects in patients with type 2 diabetes mellitus. Treatment goals for patients with type 2 diabetes should be aligned with the basic defects of the disease. Many of the available antidiabetes agents correct hyperglycemia but do not impact other cardiovascular risk factors, and may actually aggravate some. This paper reviews the role of defects in the incretin system in the pathophysiology of type 2 diabetes, and discusses recent advances in the use of incretinbased agents that target the fundamental disease mechanisms of type 2 diabetes. The incretinbased agents reduce hyperglycemia and provide beneficial effects on surrogate markers of cardiovascular risk, including weight gain, elevated blood pressure, and dyslipidemia.     

Insulin therapy in type 2 diabetes

Unlike type 1 diabetic patients, who have no significant insulin secretion and require insulin therapy from the disease onset, a prominent feature in the early stages of type 2 diabetes is insulin resistance with hyperinsulinemia. Therefore, improving insulin sensitivity by diet, exercise, and weight management will benefit type 2 diabetic patients. When these measures fail, glycemic goals may be achieved with oral agents. However, at the late stage of disease,most patients require exogenous insulin therapy to achieve optimal glucose control. The American Diabetes Association recommends that the objective of normalizing glycemia and glycosylated hemoglobin concentrations for patients with type 2 diabetes should be similar to that for type 1 diabetes.     

Insulin treatment increases skeletal muscle fibre area in patients with diabetes mellitus type 2

The effects of insulin treatment on skeletal muscle characteristics were studied in 18 patients (62 ± 11 years) with poorly controlled diabetes mellitus type 2 (mean duration 7·5 ± 6 years). Skeletal muscle biopsy samples were taken from the lateral portion of the quadriceps muscle before and after a period of insulin treatment of 40 ± 14 days. Enzyme activities (phosphofructokinase, 3‐hydroxyacyl‐CoA dehydrogenase, citrate synthase, lactate dehydrogenase and creatine kinase) and myoglobin content were assessed. In a subgroup of 11 patients (60 ± 11 years), skeletal muscle fibre type composition (type I, IIA, IIB and IIC) and fibre type cross‐sectional area were also analysed. Following insulin treatment there were 32 and 38% increases, respectively, in the cross‐sectional areas of type IIA and IIB fast‐twitch fibres (P<0·02). The fibre type distribution did not change. The myoglobin content in muscle decreased by 20% (P<0·01). Of the enzymes tested, the 3‐hydroxyacyl‐CoA dehydrogenase activity decreased by 10% (P<0·04). Serum glucose, HbA1_C and serum triglyceride levels decreased (P<0·001) and body weight and arm muscle circumference increased (P<0·02). In conclusion, insulin treatment of patients with poorly controlled non‐insulin‐dependent diabetes mellitus increased the fast‐twitch fibre area, reduced myoglobin levels and decreased muscle enzyme activity related to fatty acid oxidation.     

38例2型糖尿病并胆石症患者的胰岛素、血脂水平及其相关关系

目的：探讨2型糖尿病并胆石症患者的胰岛素、血脂水平及其相关关系。方法：测定38例2型糖尿病并胆石症患者的空腹胰岛素、血清脂质及载脂蛋白水平,计算胰岛素敏感指数（ISI）,分析其相互关系,并与38例不伴胆石症的2例糖尿病患者相比较。结果：2型糖尿病并胆石症组与不伴胆石症组相比较,前者的ISI明显降低（P＜0．01）,空腹胰岛素,甘油三酯,总胆固醇和载脂蛋白A1（ApoA1),明显升高（P＜0．01,P＜0．05）,高密度脂蛋白－胆固醇（HDL－C）,载脂蛋白AⅡ（ApoAⅡ)则无显著变化（P＞0．05）,ISI与甘油三酯,总胆固醇呈负相关,与HDL－C呈正相关,多元回归分析显示胆石症与ISI呈负相关。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。     

Insulin resistance syndrome, pre-diabetes, and the prevention of type 2 diabetes mellitus

Insulin resistance syndrome (IRS), also known as the metabolic syndrome, is now well recognized as a distinct pathological and clinical entity, with multiple significant ramifications for both the high-risk individual as well as the public health system. The primary contributory cause is obesity. Common manifestations associated with IRS may include atherosclerotic heart disease, hypertension, impaired glucose tolerance, dyslipidemia, polycystic ovary syndrome, and hypercoagulability. This review will present the features associated with the disorder, the accepted clinical diagnosis, available and potential treatment modalities, and ongoing or completed trials which suggest that progression from IRS to type 2 diabetes mellitus and early coronary heart disease may be prevented in adolescents and adults.     

Nateglinide therapy for type 2 diabetes mellitus.

OBJECTIVE: To review the pharmacology, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy of nateglinide. DATA SOURCES: Primary and review articles regarding nateglinide were identified by MEDLINE search (from 1966 to January 2001); abstracts were identified through the Institute for Scientific Information Web of Science (from 1995 to January 2001) and the American Diabetes Association; additional information was obtained from the nateglinide product information. STUDY SELECTION/DATA EXTRACTION: All articles and meeting abstracts identified from the data sources were evaluated and all information deemed relevant was included in this review. Much of the information was from abstracts or the product labeling, since few clinical studies have been published in the medical literature. DATA SYNTHESIS: Nateglinide is a novel nonsulfonylurea oral antidiabetic agent that stimulates insulin secretion from the pancreas. It has a rapid onset and short duration of action, allowing administration before a meal to reduce postprandial hyperglycemia. Improvement in glycemic control with nateglinide monotherapy has been demonstrated in patients not previously treated with antidiabetic medications. Greater improvement in glycemic control was observed when nateglinide was administered in combination with metformin. CONCLUSIONS: Nateglinide is similar to repaglinide, but has a quicker onset of action, quicker reversal, and does not usually require dosage titration. Based on the pharmacodynamics of nateglinide and repaglinide, nateglinide produces a more rapid postprandial increase in insulin secretion, and its duration of response is shorter than that of repaglinide. The risk of postabsorptive hypoglycemia should be lower than with either sulfonylureas or repaglinide.     

Pathogenesis of type 2 diabetes mellitus

This article provides an overview of the pathogenesis of type 2 diabetes mellitus. Discussion begins by describing normal glucose homeostasis and ingestion of a typical meal and then discusses glucose homeostasis in diabetes. Topics covered include insulin secretion in type 2 diabetes mellitus and insulin resistance, the site of insulin resistance, the interaction between insulin sensitivity and secretion, the role of adipocytes in the pathogenesis of type 2 diabetes, cellular mechanisms of insulin resistance including glucose transport and phosphorylation, glycogen and synthesis,glucose and oxidation, glycolysis, and insulin signaling.