Cardiovascular disease in recent onset diabetes mellitus

Diabetes is associated with a marked increased risk of atherosclerotic vascular disorders, including coronary, cerebrovascular, and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. Conventional risk factors, including hyperlipidemia, hypertension, smoking, obesity, lack of exercise, and a positive family history, contribute similarly to macrovascular complications in type 2 diabetic patients and non-diabetic subjects. The levels of these factors in diabetic patients are certainly increased, but not enough to explain the exaggerated risk for macrovascular complications in the diabetic population. Furthermore, recently, macrovascular complications of diabetes have been shown to start before the onset of diabetes. Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT). Since insulin resistance-related postprandial metabolic derangements are thought to play a central role in the development and progression of CVD in patients with IGT, amelioration of postprandial metabolic disturbance is a therapeutic target for the prevention of CVD in these high-risk patients. Therefore, in this paper, we review the molecular mechanisms for the increased risk of CVD in recent onset diabetes mellitus, especially focusing on postprandial dysmetabolism. We also discuss here the potential therapeutic strategies that specially target the mechanisms responsible for vascular alterations in diabetes.     

Hyperglycemia and atherosclerosis. Causal relation or association?

Hyperglycemia may lead to atherosclerosis by different pathogenic mechanisms. Nonenzymatic glycation and oxidation of LDL may increase its atherogenicity. Glycation may modify some arterial wall structural proteins. Increased blood glucose leads to hypertriglyceridemia which results in decrease of HDL-cholesterol level and in increase of atherogenic dense LDL particles. Hyperglycemia also adversely affects processes of platelet aggregation, hemocoagulation and fibrinolysis. It accelerates the development of diabetic nephropathy--a condition with a high prevalence of macrovascular diseases. Prospective epidemiologic studies have shown that diabetic patients in worse metabolic control had an increased cardiovascular morbidity and mortality. Therapeutic randomized studies in type 1 (DCCT) and type 2 (UKPDS) diabetic patients have shown that better diabetes control had a preventive effect against development of microvascular complications. The incidence of macrovascular complications both in type 1 diabetic patients on intensive insulin or sulfonylurea treatment has been decreased on the level of borderline statistical significance. Metformin lead to a significant decrease in myocardial infarction incidence in the subgroup of obese type 2 diabetic patients. In conclusion, maximal possible metabolic control of diabetes prevents the development of microvascular complication, but more impressive decrease in macrovascular disease incidence probably requires to affect another important risk factors for atherosclerosis, such as dyslipidemia and hypertension.     

Non-insulin-dependent diabetes in older patients. Complications and risk factors

Non-insulin-dependent diabetes mellitus is predominantly a disease of aging, with more than 70 percent of non-insulin-dependent (type II) diabetic patients older than 55 years of age. The prevalence of macrovascular, microvascular, and neurologic complications in outpatients with type II diabetes between the ages of 55 and 74 was compared with that in a similarly aged nondiabetic group of patients. The association between duration of diabetes, hypertension, age, and other putative risk factors that are prevalent in this elderly diabetic population and the occurrence of complications was explored. This cross-sectional survey confirmed a significant increase in retinopathy, neuropathy, impotence, and macrovascular complications in patients with type II diabetes. Within the diabetic population, duration of disease was associated with the occurrence of retinopathy and neuropathy, but not associated with such macrovascular complications as coronary artery disease. Gender, type of therapy, and previously identified risk factors for vascular disease such as hypertension had little impact on the prevalence of complications in this population. The notion that type II diabetes in the elderly represents "mild" diabetes with regard to complications must be discarded. Further identification of risk factors within this diabetic population may suggest therapeutic approaches that will prevent or ameliorate the development of complications.     

Intensive insulin regimens: evidence for benefit

It is now well established that the risk of experiencing diabetic complications is dependent on the degree of glycaemic control in patients with diabetes. Clinical trials such as the Diabetes Control and Complications Trial (DCCT) and Kumamoto study have demonstrated that tight glycaemic control achieved with intensive insulin regimens can reduce the risk of developing or progressing retinopathy, nephropathy or neuropathy in patients with type I or II diabetes. The EDIC trial, a follow-up to the DCCT, has shown that the previous degree and duration of glycaemic exposure are also important determinants of risk of developing microvascular diabetic complications. It appears that beneficial outcomes with regard to microvascular risk can be achieved with the improved metabolic control associated with intensive insulin regimens; however, data examining the effect of intensive insulin regimens on macrovascular risk is inconclusive. Epidemiological data highlight the role of postprandial blood glucose in cardiovascular disease and mortality, especially in patients with type II diabetes. Consequently, it is logical to suppose that insulin regimens that control both fasting plasma glucose and postprandial glucose excursions should also achieve the best macrovascular risk outcomes and there are some data that suggest this. Intensive insulin treatment can also improve prognosis in acute clinical situations such as myocardial infarction in patients with or without diabetes. In summary, intensive insulin regimens achieve strict metabolic control in patients with diabetes and could offer the best possible outcomes with regard to microvascular and macrovascular complications.     

Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus

Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The plasma levels of lipoprotein cholesterol and triglycerides are largely influenced by the degree of glycaemic control. With poor metabolic control, plasma cholesterol and triglycerides are frequently elevated. In contrast, in well-regulated patients without micro- and macrovascular complications lipid levels are generally normal or even favourable, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. With the development of diabetic nephropathy the cardiovascular risk increases markedly and this complication is associated with increased concentrations of cholesterol and of the atherogenic lipoprotein species, lipoprotein(a), and low levels of high-density lipoprotein cholesterol. The rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in non-diabetic populations. It is hoped that with increased recognition of dyslipidaemia and aggressive therapeutic measures the overkill in diabetes mellitus from macrovascular diseases will be reduced.     

Coronary heart disease in diabetes mellitus: risk factors and epidemiology.

Cardiovascular complications in diabetic patients, especially type 2, can be classified as microvascular (renal, ophthalmologic and neurologic) and macrovascular (coronary, cerebrovascular and peripheral vascular). Type 1 and 2 diabetic patients have increased cardiovascular risk, especially for coronary artery disease. This has been well established through high-quality studies, as have interventions to ameliorate the major risk factors. The main risk factors for increased incidence of coronary artery disease in diabetic patients include hyperlipidemia, hypertension, smoking, microalbuminuria and hyperglycemia. The therapeutic approach to the type 2 diabetic patient should include--if there is no individual contraindication--diet control, physical exercise, smoking cessation and, particularly, pharmacologic interventions with antiplatelets (mainly aspirin and clopidogrel) and/or anticoagulants (warfarin), angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers and anti-dyslipidemics (mainly statins), as well as oral antidiabetics (or insulin). In this paper we present and discuss the results of lowering cardiovascular risk in these patients, which should lead to a marked decrease in the incidence of coronary artery, cerebrovascular and peripheral vascular disease, with consequent improvement in prognosis.     

Treatment of lipids and type 2 diabetes

The development of type 2 diabetes is increasing in epidemic proportions. There is a significant risk for cardiovascular disease, which is the most prevalent and detrimental complication for the diabetic population. Serum lipid abnormalities are common in patients with diabetes, and due to this increased vascular risk, it is recommended to aggressively treat the hyperlipidemia. Therefore, intensive lipid-lowering therapy should be used for primary and secondary prevention against macrovascular complications for patients with type 2 diabetes. In this article some of the key studies justifying the need for lipid reduction in patients with type 2 diabetes are reviewed and practical guidelines for management of the dyslipidemia are suggested.     

The Effectiveness of Intensive Glycemic Control for the Prevention of Vascular Complications in Diabetes Mellitus

Obesity and type 2 diabetes mellitus have reached epidemic proportions in the US, and indeed, globally. While microvascular complications contribute to considerable morbidity, much of the excess mortality (around 70%) is due to macrovascular disease. Hyperglycemia has predictable toxic effects on multiple organs ('glucotoxicity') including the pancreas, where it impairs insulin secretion and insulin gene expression through mechanisms that lead to glucose densensitization and beta-cell exhaustion, eventually resulting in irreversible beta-cell failure. There is robust evidence to suggest that strict glycemic control reduces diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) in both primary- and secondary-prevention settings. While unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease is lacking, meta-analytic data and controlled clinical trial data suggest there may still be clinically significant lowering of the risk for macrovascular endpoints through strict glycemic control. Cardiovascular disease in a diabetic patient is a collusion of several factors besides hyperglycemia, such as hypertension, dyslipidemia, diffuse endothelial dysfunction, hypercoagulability, and inflammation. It is important to address lifestyle issues such as maintenance of ideal bodyweight, good dietary practice, smoking cessation, and regular exercise in the comprehensive risk management of a diabetic patient, in order to reduce the vascular complications. Large, ongoing clinical trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) are likely to establish the potential benefits of glycemic control in preventing or postponing macrovascular complications of diabetes.     

Die diabetische Nephropathie

Diabetic nephropathy represents the most important microvascular complication in long-term diabetes mellitus because chronic renal insufficiency is further aggravated by increased cardiovascular morbidity and mortality in diabetic patients. Although early intensive insulin therapy has led to a significant reduction of incidence and prevalence of end-stage renal failure over the last decades in juvenile type 1 diabetes mellitus, the total number of type 2 diabetic patients with chronic renal insufficiency is dramatically increasing due to the improved life expectancy of the general population and the more effective medical treatment of macrovascular complications such as arterial hypertension, coronary artery disease, and peripheral arterial occlusive disease. Apart from the personal burden for each individual the frightening epidemiologic dimension of diabetic nephropathy represents an outstanding challenge for our social systems.     

Clinical Advances in Hemoglobin A1c Measurement: Arguments for and against the Role of Glucose Variability in the Development of Diabetes Complications

There is now unequivocal evidence that improving glycemic control in both type 1 and type 2 diabetes reduces the likelihood of developing the micro- and macrovascular complications of the disease. However, it is still unclear whether a patient with very variable glucose is at any different a risk of these problems than someone who has the same mean glucose but much more stable glycemia. This article reviews the evidence that exists to both support and refute the claim that increased glucose variability should be regarded as an independent risk factor for the development of diabetic vascular disease.     

Anti-Inflammatory Properties of C-Peptide

C-peptide, historically considered a biologically inactive peptide, has been shown to exert insulin-independent biological effects on a number of cells proving itself as a bioactive peptide with anti-inflammatory properties. Type 1 diabetic patients typically lack C-peptide, and are at increased risk of developing both micro- and macrovascular complications, which account for significant morbidity and mortality in this population. Inflammatory mechanisms play a pivotal role in vascular disease. Inflammation and hyperglycemia are major components in the development of vascular dysfunction in type 1 diabetes. The anti-inflammatory properties of C-peptide discovered to date are at the level of the vascular endothelium, and vascular smooth muscle cells exposed to a variety of insults. Additionally, C-peptide has shown anti-inflammatory properties in models of endotoxic shock and type 1 diabetes-associated encephalopathy. Given the anti-inflammatory properties of C-peptide, one may speculate dual hormone replacement therapy with both insulin and C-peptide in patients with type 1 diabetes may be warranted in the future to decrease morbidity and mortality in this population.     

The Role of Toll-Like Receptors in Diabetes-Induced Inflammation: Implications for Vascular Complications

Diabetes confers an increased risk for both microvascular and macrovascular complications. Numerous studies have reported increased levels of biomarkers of inflammation that could predispose to vascular complications. The pattern recognition receptors of the innate immune response, such as Toll-like receptors (TLRs), especially TLR2 and TLR4, have been incriminated in both atherosclerosis and insulin resistance. Studies have reported increased expression and activity of these receptors in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus. Most recently, knockout of TLR2 has been shown to attenuate the proinflammatory state of T1DM and the progression of diabetic nephropathy. The increased activity of TLRs in diabetes could be the result of a conspiracy of both endogenous and exogenous ligands. Biomediators of increased TLR2 and TLR4 activity include tumor necrosis factor-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and type 1 interferons. Modulating these TLRs could be beneficial in forestalling diabetic complications given the pivotal role of inflammation in both microvascular and macrovascular complications.     

成人隐匿性自身免疫性糖尿病胰岛素抵抗与β细胞功能的研究

目的 探讨成人隐匿性自身免疫性糖尿病（LADA）患者的胰岛素抵抗（IR）与胰岛β细胞功能的关系。方法 对40例LADA、40例速发性1型糖尿病（T1DM）、50例2型糖尿病（T2DM）患者和30例正常健康者（对照组）进行了身高、体重、空腹和餐后2h血糖、空腹胰岛素、糖化血红蛋白（HbA1c）、血脂、24h尿蛋白检测,并做眼科检查、周围神经电生理检查、下肢血管彩超,计算体重指数（BMI）、腰臀围比（WHR）、胰岛素抵抗指数（HOMA-IR）和胰岛素释放指数（HOMA-IS）。结果 LADA患者HOMA-IR和HOMA-IS高于T1DM,低于T2DM（P均〈0．01）。LADA患者病程5a内下肢血管病变及其病变危险因素低于T2DM（P〈0．05）,与T1DM相似;微血管病变三组问比较无差异。结论 LADA患者既存在IR,又有胰岛β细胞分泌功能不足。     

Early detection of undiagnosed diabetes mellitus: a US perspective

Undiagnosed Type 2 diabetes has become a common condition in the US, comprising one-third of all cases of the disease. We believe that screening for and detection of undiagnosed Type 2 diabetes is an important endeavor. In this review we provide evidence that diabetes is a condition that is appropriate for population screening and detection. This includes evidence that: 1. Type 2 diabetes is a significant health problem. It affects more than 16 million adults in the US and places these individuals at high risk for serious complications of the eyes, nerves, kidneys, and cardiovascular system. 2. There is a latent phase before diagnosis of Type 2 diabetes. During this period of undiagnosed disease, risk factors for diabetic micro- and macrovascular complications are markedly elevated and diabetic complications are developing. 3. Diagnostic criteria for diabetes have been established and are based on plasma glucose values. These criteria define a group of individuals with significant hyperglycemia who also have a high frequency of risk factors for micro- and macrovascular disease. 4. The natural history of Type 2 diabetes is understood. In most patients, diabetes proceeds inexorably from genetic predisposition, through the stage of insulin resistance and hyperinsulinemia, to beta cell failure and overt clinical disease. 5. There are effective and acceptable therapies available for Type 2 diabetes and its complications. Treating hyperglycemia to prevent complications is more effective than treating these complications after they have developed. Furthermore, guidelines for treatment to prevent cardiovascular disease in people known to have diabetes are more stringent than in those individuals who are not known to have diabetes. 6. There is a suitable test for screening for undiagnosed Type 2 diabetes that has high sensitivity and specificity - measurement of fasting plasma glucose. Guidelines for identifying persons at high risk for diabetes have been established.     

Peripheral arterial disease in diabetes mellitus type 1 and type 2: are there different risk factors?

BACKGROUND: Diabetic patients have increased prevalence of peripheral arterial disease (PAD). It is not clearly shown whether the prognostic factors are identical in relation to the type of diabetes. This study was done to compare the associations of PAD with risk factors and with micro- and macrovascular complications of inpatients with type 1 and type 2 diabetes. METHODS: In a retrospective cross-sectional study 1087 patients with type 1 diabetes and 1060 patients with type 2 diabetes were examined. PAD was diagnosed when ankle-brachial-pressure-index (ABI) was < 1.0. In cases with incompressible arteries (mediasclerosis) pulse wave forms were analyzed. Multivariate logistic regression analysis was applied to evaluate the impact of different variables on PAD risk, after adjusting for different variables separately. RESULTS: In both types of diabetes (type 1 vs. type 2) PAD risk (odds ratio; OR) was increased in the presence of coronary heart disease (OR 9.3 vs. 3.5), diabetic nephropathy (OR 3.0 vs. 2.8), neuropathy (OR 7.9 vs. 1.8), foot ulceration (OR 8.9 vs. 5.5), increased daily insulin requirement > 0.6 mu/kg b.w. (OR 5.2 vs. 2.9), diabetes duration of 20-29 years (OR 28.9) and > 30 years (OR 51.1) in type 1 diabetes, and diabetes duration of 10-19 years (OR 3.8) and > 20 years (OR 4.3) in type 2 diabetes. In type 2 diabetes, PAD risk was associated with microalbuminuria (OR 2.1), macroalbuminuria (OR 3.3), background retinopathy (OR 1.9), proliferative retinopathy (OR 2.8), increased triglycerides (TG) (OR 1.7) and decreased HDL-cholesterol (HDL-C > 0.90 mmol/l: OR 0.49). CONCLUSIONS: PAD risk factors and micro- and macrovascular comorbidity are very similar in type 1 and type 2 diabetes.     

绝经后2型糖尿病患者性激素结合球蛋白与动脉粥样硬化危险因子的相关性

目的研究绝经后2型糖尿病（T2DM）患者的性激素结合球蛋白（SHBG）与动脉粥样硬化（AS）危险因子的相关性。方法绝经后T2DM患者45例（20例合并大血管并发症,25例无大血管并发症）,测定SHBG、FPG、Fins、FC—P、TC、TG、HDL—C、LDL-C、纤维蛋白原（FIB）。以ISI=-Ln（FPG·Fins）作为胰岛素敏感性指标。对SHBG与BMI、WHR、FPG、Fins、FC—P、ISI、脂代谢指标、FIB的相关性进行分析。结果有大血管并发症组SHBG、ISI显著低于无大血管并发症组,而WHR、FPG、Fins、FC-P、TC、LDLC、FIB显著高于无大血管并发症组。在简单相关分析中,SHBG与ISI呈显著正相关（R=0．731,P〈0．01）。在逐步叫归分析中,FC-P为预测SHBG最强的指标。结论低水平的SHBG是绝经后2型糖尿病患者动脉粥样硬化的危险因素之一。     

Treatment of diabetic dyslipoproteinemia.

Diabetes mellitus, specifically type 2, is often associated with disorders in lipid metabolism. Elevated levels of plasma free fatty acids play a pivotal role by contributing significantly to insulin resistance. In addition free fatty acids promote diabetic dyslipidemia through increasing VLDL synthesis in the liver, and by virtue of cholesterylester transfer protein, modifying LDL to increase small-dense LDL subfractions and to decrease HDL cholesterol. This atherogenic lipoprotein profile (elevated triglycerides, increased small-dense low-density lipoproteins, and decreased high-density lipoproteins), contributes to the development of atherosclerosis and increases the risk of experiencing cardiovascular events, the most common cause of death in type 2 diabetes. To decrease the risk of cardiovascular disease events in diabetics, dyslipidemia needs to be treated, as evidenced from epidemiology, from intervention trials, and from subgroup analyses of large intervention trials initiated to evaluate effects of lipid lowering treatment that also included patients with type 2 diabetes. Most measures used to counteract hyperglycemia, are also prone to ameliorate dyslipidemia: dietary intervention (medical nutrition) including omega-3 fatty acids as part of lifestyle changes that also comprise cessation of smoking, increases in physical activity and reduction in body weight. In addition insulin, biguanides, acarbose and glitazones applied for glycemic control also improve diabetic dyslipidemia. Additional pharmacological treatment of dyslipidemia if persisting after glycemic control relies on different drug classes. Fibrates effectively reduce free fatty acids, fasting and postprandial lipemia, shift the distribution of LDL particles towards less dense subfractions and increase HDL cholesterol, thus particularly addressing key components of diabetic dyslipidemia. For LDL cholesterol lowering statins are mainly used that decrease LDL cholesterol levels by competitive inhibition of the HMG-CoA reductase. As type 2 diabetes is found to be associated with a two- to fourfold increase in coronary heart disease risk and as the degree of glycemia is more related to microvascular complications, correcting dyslipidemia appears to be a major task in order to reduce macrovascular events in patients with type 2 diabetes.     

C反应蛋白与2型糖尿病大血管病变危险因素的相关性研究

2型糖尿病(DM)合并大血管病变者血清C反应蛋白(CRP)水平明显高于2型DM无大血管病变组及正常对照组(P<0.01),2型DM无大血管病变组高于正常对照组(P<0.01)。提示CRP可能是2型DM和2型DM大血管病变的危险因子,炎症可能参与了2型DM及2型DM大血管病变的发生和发展。     

Approach to the management of diabetic patients with heart failure: role of thiazolidinediones

Diabetes mellitus is a chronic, progressive disease that results in microvascular and macrovascular complications. Patients with diabetes are at high risk for developing heart failure, and the prevalence of diabetes in patients with heart failure ranges from 24% to 44%, with an estimated 1 to 2 million individuals in the United States having both diabetes and heart failure. Patients with diabetes and heart failure are at increased risk for mortality. Primary treatment goals in diabetes include restoration and maintenance of normoglycemia, avoidance of diabetic complications, and prevention of cardiovascular events. The range of therapeutic options for glycemic control has been extended with the introduction of thiazolidinediones (TZDs) used as monotherapy or in combination with other oral antidiabetic medications or insulin. TZDs decrease plasma insulin levels, improve endothelial function, decrease vascular inflammation, and decrease C-reactive protein levels, effects that are potentially beneficial in patients with heart failure. Weight gain and peripheral edema are recognized side effects of these drugs, particularly when used in combination with insulin. Although health care providers should be aware of the potential risk of worsened heart failure when TZDs are used in patients with diabetes and heart failure, these agents may be considered for use in patients with New York Heart Association class I and II heart failure when appropriate monitoring can be provided. Prospective clinical trials are currently under way to further define the cardiovascular safety and efficacy of TZDs in diabetic patients with heart failure.     

Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context

Type 2 diabetes mellitus is the consequence of both insulin resistance and impaired insulin secretion. In the progression from normal glucose tolerance to diabetes, postprandial glucose (PPG) levels often rise before fasting plasma glucose (FPG) levels increase above 126 mg/dL (7.0 mmol/L). Numerous epidemiologic studies have shown that impaired glucose tolerance is associated with increased risk for macrovascular disease and that isolated postchallenge hyperglycemia is an independent factor for increased mortality. Reducing the risk for microvascular complications by improving glycosylated hemoglobin (HbA(1c)) levels is well documented. Emerging data now support the relationship between glycemic control and macrovascular disease. Epidemiologic studies documenting postprandial hyperglycemia and the risk for increased mortality suggest that lowering PPG levels might be beneficial. Optimizing both FPG and PPG is important in achieving normal/near-normal glucose levels. Many patients with type 2 diabetes have difficulty attaining the recommended HbA(1c) goal despite normal/near-normal FPG levels; thus, pharmacologic treatment targeting PPG levels may prove beneficial.