Molecular mechanisms of endothelial dysfunction in diabetes mellitus]

Diabetes is a strong risk factor for vascular diseases. Recent studies have shown that disruption of endothelial cell function results in vascular injury. One of causes underlying the endothelial dysfunction in diabetics is hyperglycemia. Many epidemiological studies demonstrated that hyperglycemia increased the incidence of macrovascular diseases. In contrast to the microvascular complications in diabetes, however, the macrovascular complication often develops even in patients with good glycemic control, suggesting that some factors other than hyperglycemia may contribute to it. Insulin resistance is one of possible candidates for that. In fact, it is shown that insulin resistance is an independent risk factor for atherosclerosis. In this article, we reviewed recent hypothesis explaining how hyperglycemia or insulin resistant state caused endothelial dysfunction.     

Screening, diagnosis and management of diabetes mellitus and diabetic complications

Diabetes mellitus comprises a group of metabolic disturbances that are characterized by hyperglycemia. In 1997 the American Diabetes Association (ADA) proposed new criteria for the diagnosis and classification of diabetes mellitus, which was also adopted by WHO. Although the criteria is the same, the ADA puts emphasis on the use of the fasting plasma glucose (FPG) for screening and diagnosis, whereas WHO maintains the use of the OGTT and recommends the FPG only if an OGTT can not be performed. Different pathogenetic processes are involved in the development of diabetes ranging from autoimmune destruction of beta-cells resulting in an absolute insulin deficiency to insulin with a defect on insulin secretion. The new classification is based on the etiology of the disease. Diabetes is classified into one of four categories: Type-1, type-2 Diabetes mellitus, specific forms of diabetes, and gestational diabetes. For screening and diagnosis FPG or the two hour value after the OGTT can be used. Glycosylated hemoglobin is not suitable for screening and diagnosis of diabetes despite some contradictory statements. For many decades clear evidence was missing that chronic hyperglycemia caused diabetic late complications; complications including dysfunction or failure of several organ systems, in particular eyes, kidneys, nerves, and the cardiovascular system. The results of two large prospective trials--the Diabetes Control and Complications Trial (DCCT; 1993) and the United Kingdom Prospective Study (UKPDS; 1998)--that were recently published provided the final proof that normoglycemia prevents or delays the progression of these late complications. Due to the insidious nature of these complications they are often not diagnosed and have to be looked for in each patients with diabetes and have to be controlled regularly. Based on the results of the UKPDS and other studies, evidence based therapeutic goals could be defined. Multifactorial interventions with increased physical activity, cessation of smoking, aspirin treatment, lowering of HbA1c, blood pressure, and lipids in patients with type 2 diabetes have been proven to drastically reduce the risk of developing diabetic nephropathy or cardiovascular complications drastically. We recommend the following treatment strategy for patients with type 2 diabetes in clinical practice: 1) Treatment should be individualized. 2) Treatment should be started step by step to document efficacy of treatment and compliance of patients. 3) Plasma glucose and blood pressure should be normalized in all patients with type 2 diabetes (up to an age of 70 years), since there are no threshold values for HbA1c and blood pressure. 4) Therapeutic goals should be checked every three to six months. 5) In the case that therapeutic goals can not be met, treatment should be intensified. Often a combination therapy with many different drugs is required. 6) A specialist for diabetes should be consulted, if the therapeutic goals can not be met over a period of six months.     

A Practical Guide for Aggressive Management of Type 2 Diabetes

The incidence of diabetes mellitus is increasing at alarming rates in the United States which presents a management challenge for primary care practitioners. Evidence from landmark trials such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study has shown that tight glycemic control markedly reduces long-term diabetic complications. However, practitioners are often hesitant to institute measures such as multiple drug regimens, insulin therapy, or both. This article offers practitioners an evidence-based guide for managing patients with diabetes while maintaining the clinical practice guidelines as outlined by the American Diabetes Association and the American Association of Clinical Endocrinologists.     

Management of diabetes during acute stroke and inpatient stroke rehabilitation

OBJECTIVES: To summarize evidence on the impact of hyperglycemia on stroke outcomes and to present therapy algorithms for inpatient management in diabetic stroke patients. DATA SOURCES: Guidelines for inpatient management of diabetes were reviewed and extracted from a technical review and recommendations from 2 national diabetes and endocrine organizations. MEDLINE database searches were conducted using key words: stroke, diabetes, hyperglycemia, hypoglycemia, inpatient, hospitalized, treatment, outcomes, disability, self-management, and education. STUDY SELECTION: Studies were selected that specifically addressed the impact of the following in stroke patients: hyperglycemia and diabetes on rehabilitation outcomes, management strategies for hyperglycemia and diabetes, and strategies for facilitating diabetes self-management. DATA EXTRACTION: Two authors independently extracted data and management practices from selected articles and published practice guidelines. DATA SYNTHESIS: Diabetes is prevalent in stroke patients and results in poorer inpatient hospital and rehabilitation outcomes. Management of diabetes in stroke patients is further complicated by impairments in mobility and vision, necessitating accommodation strategies and tools for self-management. Optimal management of hyperglycemia using insulin or oral hypoglycemic agents results in reduced morbidity and mortality among diabetic inpatients. CONCLUSIONS: To achieve inpatient glycemic management targets, use of clinical management algorithms, self-management tools, and systems approaches such as diabetes management teams are useful.     

Gycemic control, mealtime glucose excursions, and diabetic complications in type 2 diabetes mellitus

Type 2 diabetes mellitus is a heterogeneous disorder characterized by 2 pathogenic defects, impaired insulin secretion and insulin resistance. The resultant hyperglycemia causes microvascular and macrovascular complications that increase morbidity and mortality in patients with diabetes mellitus. Optimum glycemic control in patients with type 1 and type 2 diabetes mellitus prevents the development of microvascular disease and, to a lesser extent, macrovascular disease. Prandial hyperglycemia may be an independent risk factor for the development of diabetic complications. This article reviews the pathophysiologic mechanisms of glucose metabolism and describes the results of epidemiological and interventional studies that have demonstrated the association of acute and chronic hyperglycemia with the development of diabetic complications. The American Diabetes Association has defined diagnostic and treatment goals for diabetes mellitus, striving to achieve near-normal glycemic control to delay or prevent the development of diabetic complications. A number of oral antidiabetic agents and insulins are currently available for the treatment of type 2 diabetes mellitus in the United States. These agents target fasting and postmeal plasma glucose levels to improve glycemic control. Alone or in combination, these agents have enhanced the clinical approaches to treating diabetes mellitus.     

Managing atherosclerosis in patients with type 2 diabetes mellitus and metabolic syndrome

Diabetes mellitus with its increasing prevalence is a major global health problem in United States. Macrovascular complications, especially atherosclerosis, are the major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Metabolic syndrome is considered to be a metabolic precursor of type 2 diabetes mellitus and is an independent risk factor in the pathogenesis of atherosclerosis. It is a constellation of proatherogenic metabolic abnormalities, which include obesity, hypertension, characteristic dyslipidemia, hyperglycemia, insulin resistance, and compensatory hyperinsulinemia. Recent epidemiological data have demonstrated a strong causal association between insulin resistance and coronary vascular disease independent of hyperglycemia associated with type 2 diabetes mellitus. Given the high prevalence of metabolic syndrome in the general population and its role in the pathogenesis of atherosclerosis, every attempt should be made to recognize early the metabolic syndrome and to modify the associated proatherogenic metabolic abnormalities. Management of atherosclerosis in insulin-resistant states like metabolic syndrome and type 2 diabetes is a multifactorial process involving nonpharmacological interventions like exercise, diet control, and pharmacological therapy directed at hypertension, hyperglycemia, and dyslipidemia. Further research is warranted to demonstrate the effects of these interventions unequivocally in preventing the progression of metabolic syndrome to overt type 2 diabetes mellitus with its associated macrovascular complications.     

Type II diabetes mellitus update: diagnosis and management

Diabetes mellitus type II (currently known as non-insulin-dependent diabetes) is apparently the result of genetically imposed insulin resistance. Type II diabetes is far more common than insulin-dependent (type I) diabetes, which is probably an autoimmune disease resulting in inadequate insulin production. The decade of the '80s has seen several changes in the management of type II diabetes, including: more widespread use of glycosylated hemoglobin and home blood glucose monitoring as surveillance tools; modification of the dietary regimen by advocating increased amounts of complex carbohydrates; use in this country of the second-generation oral sulfonylureas; and therapeutic trials of tricyclic antidepressants for relief of painful diabetic neuropathy. Diabetes mellitus type II is potentially preventable through encouragement of weight loss and regular screening for those genetically at risk.     

Taurin in combined treatment of metabolic syndrome and diabetes mellitus

In addition to information on the prevalence, etiology and pathogenesis of metabolic syndrome and type 2 diabetes mellitus, the role of insulin resistance, lipotoxicity, hyperglycemia and glucose toxicity in development complications of metabolic syndrome and diabetes mellitus, the article presents evidence from multicenter clinical trials of taurin/dibicor efficacy in the treatment of metabolic syndrome, diabetes mellitus, cardiovascular complications, diabetic retinopathy. It is demonstrated that taurin/ dibicor has a positive effect on insulin resistance and body mass in obesity, on carbohydrate and lipid metabolism, on cell membranes, blood pressure, acuity of vision. Taurin/dibicor protects against macro- and microvascular diabetic complications, improves vision, cardiovascular system condition, quality and duration of life.     

The effect of a genetic variant for obesity and Type 2 Diabetes on the therapeutic potential of exercise and calorie restrictive diets in Zucker rats

Obesity and Type 2 Diabetes are modern pandemics caused by unique genetic-environmental interactions and distinguished by almost universal treatment failures. Relative influences of genome and lifestyle changes on an adult onset Obesity-Type 2 diabetes phenotype were explored. Zucker rats, a recessive model of genetic obesity-Type 2 Diabetes (117 fa/fa and 98 Fa/fa) were used. Dietary induced obesity (DIO) was imposed via a high fat diet on one-half; and one-half were forced to swim daily (EX). After 6 weeks, 78 animals were placed on a calorie (Kcal) restrictive diet for 6 more weeks. Genotype accounted for > 20% additional insulin resistance and obesity and modulated the effects of DIO and EX in adult animals exhibiting obesity-Type 2 diabetes. Only DIO gains were responsive to Kcal restriction. EX effects on insulin resistance were mediated by both Kcal restriction and genotype. Kcal restriction directly reduced hyperglycemia. Genetic variation was the major determinant of obesity and Type 2 Diabetes in Zucker rats. Genetically induced obesity and insulin sensitivity were resistant to EX and Kcal restriction; DIO and hyperglycemia were responsive to both. Successful treatment of Type 2 Diabetes requires understanding of how genotype may continue to modify adult responses to lifestyle change.     

Dealing with diabetic nephropathy

Nephropathy may develop in patients with type 1 diabetes because poor glycemic control produces effects that eventually lead to glomerular scarring and renal failure. The worse and more prolonged the hyperglycemia, the greater the risk of diabetic nephropathy. In patients with type 2 diabetes, hyperglycemia, as well as insulin resistance and generalized vascular disease, is involved in the pathogenesis of nephropathy. The glomerular changes of early diabetic nephropathy can be identified only by renal biopsy or by testing for microalbuminuria. Once macroalbuminuria occurs (albumin excretion rate, > 300 mg/day), usually after type 1 diabetes has been present for 10 to 15 postpubertal years, end-stage renal disease is almost inevitable. However, aggressive control of hypertension in diabetic patients without microalbuminuria helps avoid nephropathy, and tight glycemic control in those with microalbuminuria can avoid or delay its onset. Even when macroalbuminuria is present, treatment can prolong renal function. Aggressive antihypertensive therapy, especially with ACE inhibitors, can reduce renal decline by half. Avoiding circumstances that may damage the kidneys (e.g., use of radiocontrast materials or nephrotoxic drugs, dehydration, hyperlipidemia, urinary tract infection, buildup of AGEs) is critical. Some treatment methods are controversial (dietary protein restriction) or still under investigation (use of injected or oral heparin) but may help delay renal transplantation or dialysis.     

胰岛素及胰岛素抵抗与糖尿病认知功能障碍

糖尿病导致的学习记忆功能障碍日益受到人们的重视。糖尿病明显增加痴呆的发生风险,包括血管性痴呆和阿尔茨海默病;糖尿病本身也可以导致患者轻、中度认知功能的下降。胰岛素水平不足和胰岛素抵抗可明显导致糖尿病认知功能障碍的发生并加速了认知功能下降的进展。     

Life-threatening hyperglycemia and acidosis related to olanzapine: a case report and review of the literature

The authors report a case with life-threatening hyperglycemia and acidosis in a patient with no previous diabetic history following treatment with olanzapine. A 35-year-old woman with a history of bipolar affective disorder treated with olanzapine presented with severe diabetic ketoacidosis. She had no prior history of diabetes or risk factors for diabetes. Glycosylated hemoglobin (HbA1c) on admission blood sample suggested that long-term glycemic control had been poor. The authors postulate that treatment with olanzapine precipitated hyperglycemia, an elevated creatine kinase level, and a high amylase level. A concurrent urinary tract infection precipitated an episode of sepsis, which combined to precipitate life-threatening diabetic ketoacidosis. During her stay in the intensive treatment unit and subsequently in the medical ward, her blood glucose concentration was intensively monitored. She remains on insulin therapy, and her antipsychotic medication was changed to risperidone. Newer atypical antipsychotic drugs such as olanzapine have been introduced with the benefit of fewer extrapyramidal side effects. A number of these have reported metabolic side effects of uncertain etiology such as diabetic ketoacidosis and elevated creatine kinase. The authors believe that the diabetic ketoacidosis occurred in this patient, who had no previous history of diabetes mellitus. Blood glucose should be monitored in patients taking olanzapine, especially in those patients with risk factors for diabetes mellitus.     

Primary prevention of diabetes mellitus

Diabetes mellitus is one of the chronic noncommunicable diseases that have increased markedly in this century. The discovery of insulin and other drugs for lowering hyperglycemia have certainly reduced mortality from acute complications of diabetes and improved the quality of life of many diabetic patients. Recent advances in research into the etiology and natural history of diabetes have increased our knowledge about different types of diabetes to such an extent that primary prevention of diabetes mellitus is becoming a reality. Until now, few studies have attempted to test measures for primary prevention of diabetes. Therefore, the data supporting the possibility for primary prevention are largely indirect and need to be tested in preventive trials or in community-based prevention programs. We believe, however, that the time is right to start action in populations in which the prevalence of diabetes is known to have clearly increased recently. We summarize the evidence that can be used as the scientific basis of primary prevention of diabetes mellitus.     

Screening and diagnosing gestational diabetes mellitus revisited: implications from HAPO

Screening and diagnosis of gestational diabetes has lacked uniform criteria both nationally and internationally. In addition, the relationship between the degree of hyperglycemia or glucose intolerance and the risk of maternal, fetal, and neonatal adverse outcomes has not been clearly established. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently published their recommendation for diagnosing and classifying gestational hyperglycemia in pregnancy after evaluation of the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) observational study. Their recommendations have recently been accepted by the American Diabetes Association and are currently under review by the American College of Obstetricians and Gynecologist (ACOG) in the United States. If accepted in the United States and internationally, the world would have consistent thresholds for evaluating hyperglycemia in pregnancy, which would not only include the diagnosis of gestational diabetes mellitus but also overt diabetes, which has not been encompassed by previously accepted definitions.     

Pharmacological treatment of hyperglycemia in type 2 diabetes

Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA’s recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.

Diabetes mellitus is a major public health problem, affecting about 10% of the population (1). Chronic complications of diabetes cause enormous human suffering, including blindness, kidney failure, amputations, myocardial infarction, and stroke. Inspired by the desire to develop better therapies, many researchers have investigated the pathophysiology of type 2 diabetes (T2D). While type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-secreting β cells of the pancreas, T2D is often associated with obesity and is characterized by both impaired insulin secretion and insulin resistance (2). T2D is a progressive disease. Insulin resistance manifests early in the natural history prior to occurrence of overt hyperglycemia. So long as pancreatic β cells secrete sufficient insulin to compensate for insulin resistance, glucose levels are maintained at relatively normal levels (3). Overt diabetes occurs when β cells no longer secrete sufficient insulin to maintain normoglycemia. Fasting hyperglycemia is driven by increased hepatic glucose production due to relatively low insulin levels combined with hepatic insulin resistance. Severity of metabolic defects increases over time, primarily because of increasingly severe impairment in insulin secretion.This Review will discuss the state of the art in pharmacotherapy of T2D. Treatment aims to prevent or delay occurrence of microvascular and macrovascular complications — the main causes of morbidity and mortality in T2D. We focus specifically on hemoglobin A_1c–lowering (HbA1c-lowering) drugs, although antihypertensives, lipid-lowering drugs, optimal nutrition, and physical exercise also contribute to a holistic approach to treatment.     

Guidelines for the management of atherosclerotic diseases in diabetes mellitus

Diabetes mellitus is associated with a greater risk of developing atherosclerosis and its complications: myocardial infarction, stroke and peripheral vascular disease. In patients with diabetes, atherosclerosis represents a complex multifactorial disease with increased lesion progression and severity compared to the nondiabetic population. Several risk factors have been proposed to explain the increased risk of cardiovascular disease with diabetes. They include: hyperglycemia, hypertension, dyslipidemia, obesity and other factors. It is difficult to precisely establish the elements leading to diabetes-accelerated atherosclerosis by means of epidemiological studies because all these factors coexist in diabetic patients. Then, management of atherosclerosis in diabetes is a multifactorial process involving nonpharmacological interventions like exercise, diet control, and pharmacological therapy directed at hypertension, hyperglycemia, and dyslipidemia.     

Insulin treatment in elder patients with diabetes

Diabetes is a highly expanding health problem in Japan, especially for older people. The prevalence of glucose intolerance and diabetes increases with age. A postprandial hyperglycemia is the primary clinical manifestation. In older diabetic patients, atherosclerotic complications (macroangiopathies), as well as microangiopathies, are significant problems, threatening their quality of life. Though insulin therapy requires some special considerations, insulin is indicated for any patients with a poor glycemic control with oral agents. Single or multiple dose (s) of insulin injection therapy is selected for each patient to prevent symptomatic hyperglycemia, or to achieve near-normal glycemic control. Also, to maintain the quality of life for these older patients, hypoglycemia, as well as hyperglycemia, should be avoided. Newly developed insulin analogue (s) may be more appropriate for preventing hypoglycemia. Another method of prevention and treatment of hypoglycemia are discussed in this article.     

Metabolic risk during antipsychotic treatment

BACKGROUND: Compared with the general population, individuals with schizophrenia demonstrate an increased prevalence of obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). Increased adiposity is associated with decreases in insulin sensitivity, leading to an increased risk of hyperglycemia and hyperlipidemia. Antipsychotic medications can increase adiposity, and a range of evidence from case reports, observational studies, retrospective database analyses, and controlled experimental studies (including randomized clinical trials) suggests that treatment with antipsychotic medications may be associated with an increased risk for insulin resistance, hyperglycemia, dyslipidemia, and T2DM. OBJECTIVE: This article reviews current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and T2DM, and examines the relationship of adiposity to medical risk. METHODS: Relevant publications were identified through a search of MEDLINE from 1975 to the present using the primary search parameters "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles concerning antipsychotic-associated weight gain and metabolic disturbance were also reviewed. Key studies in this emerging literature were summarized, including case reports, observational studies, retrospective database analyses, and controlled experimental studies. RESULTS: Individual antipsychotic medications are associated with different degrees of treatment-induced increases in body weight and adiposity, ranging from modest effects (<2 kg) with amisulpride, ziprasidone, and aripiprazole to clinically significant increases with olanzapine (4-10 kg). In addition to strong evidence concerning the effect of adiposity on insulin sensitivity in nonpsychiatric populations, increased adiposity in patients with schizophrenia has been associated with decreases in insulin sensitivity; this and other effects may contribute to increases in plasma glucose concentrations and lipid levels. CONCLUSION: Metabolic changes in psychiatric patients who receive antipsychotic agents can contribute to the development of the metabolic syndrome and increase the risk for T2DM and CVD.