Insulin strategies for type 2 diabetes mellitus

OBJECTIVE: To review the currently available insulin analogs and the benefits of insulin therapy in the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1990-March 2004) was conducted using insulin and type 2 diabetes mellitus as search terms to identify clinical trials and review articles. The bibliographies of identified articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and deemed relevant if they included and assessed clinical outcomes. DATA SYNTHESIS: Since its discovery in 1922, insulin therapy has been the only available pharmacologic treatment for type 1 diabetes and a mainstay therapy for patients with type 2 diabetes who fail to obtain glycemic control with oral antidiabetic agents. This article reviews the current insulin analogs available on the market and insulin regimens that are designed to mimic the pancreatic beta-cells' response to a glucose load. CONCLUSIONS: Insulin therapy is often withheld until late in the disease process for patients with type 2 diabetes mellitus. This results in an enormous burden of disease for patients. Insulin therapy is beneficial in obtaining glycemic control and may attenuate the complications associated with diabetes.     

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.     

The prevention of type 2 diabetes mellitus

There is a worldwide epidemic of type 2 diabetes, with numbers predicted to reach over 210 million by the year 2010. Important risk factors for type 2 diabetes are obesity, physical inactivity and dietary factors. Recent evidence shows that type 2 diabetes can certainly be delayed, and possibly prevented, by intensive lifestyle intervention, and therapies including acarbose, metformin, orlistat and the glitazones in selected populations. However, the UK has not had a successful record in trials which aim to prevent diabetes, and therefore implementation of effective and successful intensive lifestyle intervention to prevent diabetes may prove difficult in the UK. Other 'non-glucose lowering' agents, such as statins, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, may have a role to play in the prevention of diabetes.     

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。     

Strategies for the prevention of elderly-onset type 2 diabetes mellitus

The recent medical statistics have revealed that the incidence of type 2 diabetes increased more rapidly in elderly people than that of manhood. Several randomized clinical trials to evaluate the strategies for preventing type 2 diabetes such as Diabetes Prevention Program (DPP), The Finnish Diabetes Prevention Study, The STOP-NIDDM, have been conducted. These studies suggested that a lifestyle intervention and treatment with antihyperglycemic agent inhibit the onset of diabetes in elderly people as well as manhood. However, the evidence for elderly people is not sufficient. The social and physical features of elderly persons should also been taken into account for the strategies to prevent the elderly-onset type 2 diabetes.     

Insulin resistance and preeclampsia in gestational diabetes mellitus

OBJECTIVE: To compare the degree of insulin resistance in women with gestational diabetes mellitus (GDM) who do and do not develop preeclampsia. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of initially normotensive women with GDM who underwent oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and glucose clamp studies in the early third trimester (n = 150) and 15 months postpartum (n = 89). After delivery, the women were categorized as nonpreeclamptic or preeclamptic (systolic blood pressure [SBP] > or = 140 mmHg, diastolic blood pressure [DBP] > or = 90 mmHg, and at least >1+ proteinuria or >300 mg/24 h). Metabolic parameters between the groups were compared by chi2 or Fisher's exact tests and ANOVA with P < 0.05 as significant. RESULTS: A total of 29 women (19%) developed preeclampsia, which was mild in 21 and severe in 8 women. At entry, there were no differences in age, weight indexes, and glycemic measures between the nonpreeclamptic and preeclamptic groups. Those with preeclampsia were significantly taller (61.5 +/- 2.4 vs. 60.1 +/- 2.3 in, P = 0.003), were more often nulliparous (38 vs. 16%, P = 0.01), and had higher entry SBP (112 +/- 10 vs. 103 +/- 6.9 mmHg, P < 0.0001) and DBP (64 +/- 9 vs. 59 +/- 5 mmHg, P = 0.002). No significant differences between the groups were found in any measures of the OGTT glucose levels, insulin sensitivity index, glucose effectiveness, acute response to glucose, or disposition index, nor were there any differences found in the euglycemic clamp measures of basal or steady-state levels of glucose, insulin, free fatty acid, hepatic glucose output, peripheral glucose clearance, C-peptide, or glucagon. At 15 months postpartum, blood pressure levels remained significantly higher in the preeclamptic group (n = 19) compared with the nonpreeclamptic group (n = 70). No differences in any glycemic or insulin resistance measures were found. CONCLUSIONS: Women with GDM were uniformly insulin resistant. Those who developed preeclampsia, when compared with those who remained nonpreeclamptic, were not more insulin resistant in either the third trimester or 15 months postpartum. However, women who developed preeclampsia had blood pressure levels that were significantly higher, although still in the normal range, than those of women who remained nonpreeclamptic.     

Pharmacologic prevention or delay of type 2 diabetes mellitus

OBJECTIVE: To evaluate the current data on pharmacologic interventions intended to prevent or delay the onset of type 2 diabetes mellitus. DATA SOURCES: Searches of MEDLINE (1966-July 2002) and an extensive manual review of journals were performed using the key search terms diabetes mellitus, metformin, acarbose, troglitazone, orlistat, nateglinide, risk reduction, and prevention. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and all information deemed relevant was included for this review. Randomized controlled trials and meta-analyses were included if the primary outcome measure was prevention of diabetes and/or change in the rate of progression to diabetes. DATA SYNTHESIS: Type 2 diabetes mellitus is a growing epidemic. Major risk factors include obesity, impaired glucose tolerance, and impaired fasting glucose. Complications of diabetes result in significant morbidity and mortality and are a substantial public health issue. Four randomized, blinded, controlled trials have assessed the efficacy of different medications, including metformin, troglitazone, acarbose, and orlistat, at decreasing the risk of progression to diabetes in patients at risk for developing diabetes. All of these agents decreased the risk of progression to diabetes. CONCLUSIONS: Metformin, troglitazone, acarbose, and orlistat have been shown to decrease the risk of progression to diabetes in patients at risk for developing diabetes. Other questions that address issues such as identifying target populations, cost-effectiveness, and screening strategies must be answered to more fully define the place of pharmacologic therapy to prevent or delay diabetes.     

Costs associated with the primary prevention of type 2 diabetes mellitus in the diabetes prevention program

OBJECTIVE: To describe the costs of the Diabetes Prevention Program (DPP) interventions to prevent or delay type 2 diabetes. RESEARCH DESIGN AND METHODS: We describe the direct medical costs, direct nonmedical costs, and indirect costs of the placebo, metformin, and intensive lifestyle interventions over the 3-year study period of the DPP. Resource use and cost are summarized from the perspective of a large health system and society. Research costs are excluded. RESULTS: The direct medical cost of laboratory tests to identify one subject with impaired glucose tolerance (IGT) was $139. Over 3 years, the direct medical costs of the interventions were $79 per participant in the placebo group, $2,542 in the metformin group, and $2,780 in the lifestyle group. The direct medical costs of care outside the DPP were $272 less per participant in the metformin group and $432 less in the lifestyle group compared with the placebo group. Direct nonmedical costs were $9 less per participant in the metformin group and $1,445 greater in the lifestyle group compared with the placebo group. Indirect costs were $230 greater per participant in the metformin group and $174 less in the lifestyle group compared with the placebo group. From the perspective of a health system, the cost of the metformin intervention relative to the placebo intervention was $2,191 per participant and the cost of the lifestyle intervention was $2,269 per participant over 3 years. From the perspective of society, the cost of the metformin intervention relative to the placebo intervention was $2,412 per participant and the cost of the lifestyle intervention was $3,540 per participant over 3 years. CONCLUSIONS: The metformin and lifestyle interventions are associated with modest incremental costs compared with the placebo intervention. The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society.     

Insulin resistance, glucose intolerance and diabetes mellitus in HIV-infected patients

An increased prevalence of insulin resistance, glucose intolerance and diabetes has been reported in HIV infection in the highly active antiretroviral therapy (HAART) era. This development might be clinically significant because of its association with cardiovascular morbidity and mortality as well as the therapeutic challenges of managing polypharmacy. The development of insulin resistance, glucose intolerance and diabetes could be related to the underlying HIV infection, the contribution of different antiretroviral agents, treatment-associated weight gain, immune restoration, as well as the non-HIV related factors. Dissecting these factors in clinical practice might be difficult. Clinical studies include short-term treatments in healthy, non-HIV-infected individuals; randomized, controlled trials; comparative studies of different HAART regimens; and randomized studies of switching regimens in patients with viral suppression and stable immune function. This article reviews the latest knowledge regarding the epidemiology, pathogenesis, prevention and treatment of insulin resistance, glucose intolerance and diabetes mellitus in HIV-infected individuals.     

The prevention of type 2 diabetes mellitus: recent advances

Diabetes is a major public health problem that is approaching epidemic proportions globally. There is an urgent need for strategies to curb the rising prevalence of this disease, and prevention appears a logical approach. Lifestyle modifications with weight loss and moderate exercise can reduce the incidence of diabetes by >50% in patients with impaired glucose tolerance (IGT). The use of metformin, acarbose and other agents have been shown in randomized prospective trials to prevent type 2 diabetes in high-risk subjects with IGT. Other pharmacological interventions are currently being examined in large prospective studies. It is likely that one or a combination of these approaches could make diabetes prevention a reality in the near future.     

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.     

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     

Insulin resistance and its impact on the approach to therapy of type 2 diabetes

Insulin resistance is a core defect in Type 2 diabetes, occurring in peripheral organs (skeletal muscle and adipose tissue) leading to decreased glucose uptake and utilisation and in liver leading to increased hepatic glucose production. As long as the beta-cell can compensate for this by producing more insulin, glucose tolerance remains normal. However, as insulin resistance worsens, the beta-cell starts to fail to compensate leading to impaired glucose tolerance and then frank diabetes. The exact pathophysiology of insulin resistance is not clear but it probably involves a combination of genetic and environmental factors. These factors may result in changes in the number of insulin receptors, their affinity for insulin or a defect in post-receptor signalling or a combination of these. Insulin resistance also affects lipid metabolism such that there is increased production of triglycerides from the liver, which in turn both amplifies insulin resistance and exacerbates atherogenesis. The promotion of atherosclerosis by insulin resistance means that patients with Type 2 diabetes are at particularly high risk of cardiovascular disease. Therefore, treatment of insulin resistance with thiazolidinediones has the potential to offer improvements both in glycaemic control and in cardiovascular events.