Type 2 diabetes. How new insights, new drugs are changing clinical practice.

In 1997, the American Diabetes Association recommended a normal fasting blood glucose of < 126 mg/dL as the criteria for diagnosis of type 2 diabetes. Since then, new data have suggested that post-prandial glucose may have a stronger correlation with cardiovascular disease than fasting blood glucose. Two trials, the DCCT and UKPDS, provided evidence of the relationship between hyperglycemia and long-term diabetic complications. Preventing short-term complications, such as cognitive decline, is a more immediate goal and less well-studied. Type 2 diabetes is understood to result most often from insulin resistance and insulin deficiency. New classes of drugs offer expanded therapeutic options for managing this dual metabolic defect. These drugs have invalidated the former therapeutic paradigm of diet, sulfonylureas, and then insulin therapy.     

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.     

Control of post-prandial hyperglycemia--an essential part of good diabetes treatment and prevention of cardiovascular complications

AIM: This article reviews the relationship between the control of post-prandial hyperglycemia and diabetes-related complications. DATA SYNTHESIS: Hyperglycemia is a modifiable risk factor that has a deleterious effect on the development and progression of microvascular and macrovascular complications in patients with type 2 diabetes. The UK Prospective Diabetes Study revealed how reductions in hemoglobin A1c (HbA1c) correlate with a significant reduction in all-cause mortality and the incidence of myocardial infarction. The Diabetes Intervention Study showed that poor control of fasting glycemia does not increase the risk of myocardial infarction or mortality, whereas poor control of post-prandial glucose is associated with a high all-cause mortality rate. HbA1c is the standard measure for metabolic control and therapeutic efficacy, but does not reflect fluctuations in glycemic control. Plasma glucose concentrations in healthy subjects remain within a narrow range, which suggests that the fluctuations in glucose levels caused by inappropriate treatment may have negative consequences. These fluctuations have been associated with acute adverse effects (particularly excessive post-prandial hyperglycemia, pre-meal hypoglycemia and weight gain) that counteract the positive effect of lowering fasting plasma glucose and HbA1c. Post-prandial hyperglycemia and spikes also have deleterious effects on insulin secretion and sensitivity. Prandial oral antidiabetic agents such as alpha-glucosidase inhibitors (acarbose, miglitol) and rapidly acting insulin secretagogues (nateglinide, repaglinide) have recently been introduced to improve the control of post-prandial hyperglycemia. CONCLUSION: Near-normal post-prandial glycemic control is associated with lower rates of cardiovascular and all-cause mortality than excessive post-challenge hyperglycemia. In addition to the aggressive control of HbA1c and fasting plasma glucose, the strict normalisation of postprandial hyperglycemia is an essential part of good diabetes treatment. There is growing evidence from epidemiological and clinical studies that this also reduces the risk of cardiovascular complications.     

高糖条件下高胰岛素水平对细胞内脂质平衡的影响

糖尿病是一种因体内胰岛素绝对不足(Ⅰ型糖尿病)或者相对不足(Ⅱ型糖尿病)而导致的代谢综合征,高血糖是其主要特征之一.现阶段糖尿病的最佳治疗方案仍是胰岛素治疗,但考虑到糖尿病常常并发动脉粥样硬化,且高胰岛素水平对动脉粥样硬化的作用仍然存在着争议,因此阐明高糖条件下,高胰岛素水平对细胞内脂质平衡的影响对糖尿病动脉粥样硬化的治疗有着重要的意义.     

Education of patients and use of insulin pumps in diabetic treatment

Diabetes Mellitus is a chronic disease well known for its fatal complications. Therefore, an international call for measures was declared to keep complications of diabetes to a minimum in order to reduce the costs of treating these complications (St. Vincent Declaration). The common international guidelines for treatment of patients with Type 1 Diabetes Mellitus are the Diabetes Control and Complications Trial (DCCT). The United Kingdom Prospective Diabetes Study (UKPDS) investigated the use of tight glycaemic control in those with Type 2 Diabetes Mellitus. This paper will explain the importance of intensive insulin treatment for diabetic patients, even when they are dialysing, to prevent diabetic complications. There's always a possibility of reducing diabetic complications to ensure a better quality of life. It will also discuss the different treatment options available including Continuous Subcutaneous Insulin Infusion, which has been demonstrated as the most effective mode of treatment.     

Islet transplantation: a realistic alternative for the treatment of insulin deficient diabetes mellitus

Diabetes mellitus is a devastating disease and the WHO [World Health Report, World Health Organization, 2002] (World Health Organization) expects that the number of diabetic patients will increase to 300 million by the year 2025. Type 1 diabetes results from an autoimmune-mediated destruction of the insulin-secreting beta-cells in the islets of Langerhans of the pancreas, whereas Type 2 diabetes is a disease of the older population which is due to systemic insulin resistance and reduced insulin secretion by the pancreatic beta-cells. Surgical resection of the pancreas may also cause insulin-dependent diabetes depending on the size of the remaining pancreas. The long-term complications of diabetes are a direct result of the constantly elevated levels of blood glucose in the absence of an effective insulin treatment. Recent prospective studies such as the diabetes control and complication trial (DCCT) [N. Engl. J. Med. 329 (1993) 977] and the UK prospective diabetes study [Lancet 352 (1998) 837] have convincingly demonstrated that improved blood glucose control in all type diabetes reduces the risk of the development of the secondary complications of diabetes. Despite intensive insulin therapy, most individuals with insulin deficient diabetes are unable to maintain a blood glucose level in the normal range at all times. Therefore, the only way to ensure the long-term health of patients with diabetes is find a way of maintaining constant normoglycemia. It seems logical that the replacement of the islet tissue itself, either by transplanting a vascularized pancreatic allograft or by transplanting purified pancreatic islet cells, offers a better approach than simply replacing insulin that has been lost. In this article, we outline the major achievements made recently in the development of therapeutic islet transplantation applications and offer an explanation as to why islet transplantation seems to be an ideal solution for absolute insulin deficient diabetes.     

Insulin resistance is a cardiovascular risk factor in humans

Diabetes is a common metabolic disorder associated to elevated cardiovascular morbidity and mortality that is not explained by hyperglycemia or traditional cardiovascular risk factors such as smoking or hypercholesterolemia. Intensive glycemic control with insulin that achieves near-normal glycemia does not reduce significantly macrovascular complications compared with conventional glycemic control. Cardiovascular disease continues to develop in patients with diabetes despite adequate glycemic control. In contrast, intensive control with metformin (leading to insulin resistance improvement) reduces diabetes complications, including cardiovascular events, suggesting that enhancement of insulin sensitivity rather than plasma glucose level has a major role improving diabetes outcomes. Accordingly, insulin resistance estimated by glucose tolerance tests is better predictor of future cardiovascular events than fasting glucose level in nondiabetic individuals. Insulin resistance precedes for decades the clinical onset of type 2 diabetes and deteriorates metabolic control of type 1 diabetes. Numerous investigations including cross-sectional and prospective studies, meta-analyses, and systematic reviews provide compelling evidence that insulin resistance by itself is a cardiovascular risk factor in a variety of population groups, including the general population and patients with diabetes. Several estimations of insulin resistance have been consistently associated with elevated rate of cardiovascular events independently of other cardiovascular risk factors and diabetes status. The clinical expression of insulin resistance (the metabolic syndrome or any of its components including obesity, hyperinsulinemia, hypertension, and dyslipemia) has been related to cardiovascular disease as well. An estimation conducted by the Archimedes model confirms that insulin resistance is the most important single cause of coronary artery disease.     

Pharmacologic therapy for type 2 diabetes mellitus.

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.     

Cardiometabolic risk management in type 2 diabetes and obesity

Type 2 diabetes has become an epidemic in the United States, mainly due to an increase in obesity and sedentary lifestyle. Diabetes is considered a cardiovascular risk equivalent, and cardiovascular death remains the most common cause of death in this population. The cardiovascular complications of diabetes, beginning as early as 10 years before the development of frank hyperglycemia, are strongly linked to the development of insulin resistance and the ensuing metabolic disarray often referred to as the metabolic syndrome. To provide proper therapy for cardiovascular prevention, the down-stream effects of insulin resistance must be understood. The most important aspect of treating patients with the metabolic syndrome is the realization that treatment must begin before the development of frank hyperglycemia, particularly if cardiovascular events are to be avoided. Thus, in addition to managing the hyperglycemia that develops with the onset of diabetes, insulin resistance, dyslipidemia, and hypertension must also be properly addressed.     

Potential Adjunctive Therapies in Adolescents with Type 1 Diabetes Mellitus

Appropriate insulin therapy is central to the management of all individuals with type 1 diabetes mellitus. The potential role of adjunctive therapy in type 1 diabetes is to improve insulin action, and facilitate the ability of all individuals with type 1 diabetes to achieve and maintain 'better' metabolic control. The landmark clinical trial in type 1 diabetes is the Diabetes Control and Complications Trial (DCCT). The DCCT showed that there is no threshold below which a reduction in glycemia would not provide further benefit against diabetes-related microvascular complications. This study in particular provides the rationale for attempting to achieve as near normoglycemia as possible. We review the use of recognized pharmacologic agents as potential insulin adjunctives in children and adolescents with type 1 diabetes. Adjunctive therapies can be grouped into the following categories based on their putative mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin), and other targets of action (e.g. pirenzepine and insulin-like growth factor-1 [IGF-1], which reduce growth hormone secretion, and glucagon-like peptide-1, which acts to stimulate insulin secretion). Many of these agents have been found to be effective in short-term studies with decreases in glycosylated hemoglobin of 0.5-1.0%, lowered postprandial blood glucose levels, and decreased daily insulin doses. Adverse effects such as poor gastrointestinal tolerability (metformin, acarbose) or potential acceleration of retinopathy (IGF-1) indicates the need for further studies of efficacy, safety, and patient selection before these adjunctive therapies can be widely recommended in type 1 diabetes.     

Insulin therapy in Europe

The prevalence of type 1 diabetes is rising in all European countries, particularly in Scandinavia and the UK. Insulin therapy in Europe is strongly influenced by the results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS), both of which showed the importance of tight metabolic control in patients with diabetes. The importance of tight glycemic control is also emphasized in the Saint Vincent Declaration, which established 5-year goals for antidiabetic therapy in Europe. Insulin therapy in Europe has been significantly improved over the past 10 years, owing to a number of developments. These include increased use of intensive insulin therapy in patients with type 1 diabetes; the development of new insulin analogs, including insulin glargine for injection therapy and short-acting agents that are particularly suitable for use in pumps and the establishment of comprehensive and standardized treatment goals and guidelines. Nevertheless, important obstacles must still be overcome to optimize therapy for patients with diabetes and reduce the long-term complications of this disease. These obstacles include low public awareness of diabetes and its symptoms, training of physicians as well as patients that is often insufficient to ensure adherence to professional guidelines for diabetes care, and limitations in communication among professional care providers.     

如何评估和实现糖尿病缓解

长期以来，人们一直认为2型糖尿病是进展性终身性疾病，需长期药物治疗。然而，近年来研究表明，部分糖尿病患者经生活方式干预、药物或代谢手术治疗后可免于药物治疗，血糖仍可处于达标或正常状态，即实现糖尿病缓解。根据2021年美国糖尿病学会(ADA)和欧洲糖尿病学会(EASD)联合发布的《糖尿病缓解专家共识》及《缓解2型糖尿病中国专家共识》将停用降糖药物至少3个月后糖化血红蛋白<6.5%定义为糖尿病缓解。目前实现糖尿病缓解的方法包括生活方式干预、药物及代谢手术。糖尿病缓解对患者、家庭及整个社会意义重大，然而并非所有患者均可实现糖尿病缓解。充分评估糖尿病缓解的条件，将有助于更好地实现和维持糖尿病缓解。临床上应加强对已实现糖尿病缓解患者的管理，定期随访，长期监测，以及时发现复发，改善预后。     

Weight Effect of Current and Experimental Drugs for Diabetes Mellitus

Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.     

Disordered eating behaviors in youth with type 1 diabetes

Eating disorders are a significant health problem for many adolescents and are described as occurring along a spectrum of symptoms including disordered eating behaviors and clinical eating disorders. Poor self-esteem and body image, intense fear of gaining weight or refusal to maintain weight, and purging unwanted calories are clinical features of some eating disorders. Type 1 diabetes is a chronic illness with marked insulin deficiency. Chronic hyperglycemia creates a state of glucosuria with subsequent weight loss. Diabetes treatment focuses on intensive daily management of blood glucose by balancing insulin, food intake, and physical activity. Insulin omission offers an easy method for the purging of unwanted calories. The combination of these 2 illnesses is potentially deadly and also leads to an increased risk of poor diabetes outcomes. This includes poor metabolic control (measured by elevated hemoglobin A1C), increased risk of diabetic ketoacidosis, and microvascular complications such as retinopathy and nephropathy. Diabetes clinicians should be aware of the potential warning signs in an adolescent with diabetes as well as assessment and treatment options for eating disorders with concomitant type 1 diabetes. This article reviews the available data on the prevalence, screening tools, assessment guidelines, and treatment options for eating disorders in youth with type 1 diabetes.     

Hypoglycemia as a barrier to glycemic control

Diabetes mellitus is associated with significant morbidity and mortality derived from long-term microvascular and macrovascular complications of chronic hyperglycemia. The Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) have clearly shown the benefits of intensive glycemic control for preventing or delaying the development and progression of long-term complications. However, intensive glycemic control, particularly with insulin therapy, is associated with an increased incidence of hypoglycemia, which is the major barrier to the implementation of intensive treatment from the physician's and patient's perspective. Avoiding the use of intensive treatment most often precludes optimal glycemic control. Some of the many underlying causes of hypoglycemia are defective and deficient counterregulatory responses, relative hyperinsulinization owing to a missed meal, excessive or unplanned exercise, erroneous insulin dosages, excessive insulinotropic effects of some oral secretagogues, and the failure of traditional insulin preparations to simulate the physiologic patterns of endogenous basal insulin secretion found in nondiabetic individuals. Additionally, patient involvement is critical to intensive glycemic control and should involve frequent self-monitoring of blood glucose (SMBG), adherence to treatment regimens, and knowledge of the interrelationship among physical activity, diet, and insulin. This review summarizes the current knowledge on hypoglycemia with a focus on the improvements in insulin therapy (i.e., the mealtime and basal insulin analogs) that may produce more normal physiologic insulin profiles with an attendant lower risk of hypoglycemia than that currently seen in clinical practice.     

Clinical experience with insulin glargine in type 1 diabetes

The Diabetes Control and Complications Trial (DCCT) demonstrated the importance of optimal glycemic control achieved through intensive insulin therapy in reducing the microvascular complications associated with type 1 diabetes. However, the DCCT, which was conducted prior to the availability of insulin analogs, also reported a significant increase in severe hypoglycemia with intensive versus conventional therapy. Insulin analogs were developed to aid patients in achieving better diabetes control by providing insulins with optimized pharmacokinetic and pharmacodynamic characteristics. Insulin glargine was the first long-acting insulin analog with a 24-h duration of action, offering once-daily injection, and has now been in clinical use for over 10 years. The authors performed a systematic search of EMBASE, MEDLINE, and Web of Science (Science Citation Index) to determine the efficacy of insulin glargine in type 1 diabetes in basal-bolus insulin regimens. Randomized controlled trials have demonstrated that glycemic control with insulin glargine is at least comparable to that with neutral protamine Hagedorn (NPH) insulin in adults and in children and adolescents, and with continuous subcutaneous insulin infusion in adults. However, these same trials show a significantly lower risk for hypoglycemia with insulin glargine compared with NPH insulin in adults.     

Challenges in optimal metabolic control of diabetes

The results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) showed that tight glycemic control with any of several therapeutic regiments has the potential to significantly reduce the risks for long-term microvascular complications of type 1 or type 2 diabetes. The results of these large-scale long-term studies also demonstrated that there is no threshold for the relationship between blood glucose [i.e. glycosylated hemoglobin (HbA(1c))] and reduced risk. This means that 'optimal' glycemic control in a patient with type 1 or type 2 diabetes is a blood glucose level as close as possible to the level in an individual without diabetes. Limitations of most available therapies for type 1 and 2 diabetes have hampered achievement of this goal. Most available insulin preparations used to treat patients with type 1 disease can achieve approximately normal basal insulin levels only when used with a pump or a complex treatment regimen requiring a large number of daily injections. Pumps are limited by high expense, and complex injection protocols increase the potential for patient errors and non-compliance. The development of new insulins such as aspart insulin and lispro insulin, both short-acting, and insulin glargine, a long-acting insulin analogue suitable for once-daily administration, may help overcome these challenges. In patients with type 2 diabetes, achieving optimal glycemic control is complicated by the progressive nature of the disease and the loss of efficacy of oral agents (e.g. sulfonylureas, metformin, and thiazolidinediones) over time. Moreover, neither oral therapy nor insulin alone is likely to achieve optimal glycemic control in most of these patients in the long term. The availability of new insulin preparations that mimic the normal mealtime bursts of insulin, and another that provides a sustained insulin supply similar to basal insulin secretion in an individual without diabetes has the potential to significantly improve long-term control over blood glucose in patients with type 2 diabetes.     

Cardiovascular prevention in type 2 diabetes mellitus patients: the role of oral glucose-lowering agents

Diabetes mellitus (DM) is a metabolic disorder that requires medical diagnosis and treatment. Type 2 DM is due to a combination of defective secretion of and responsiveness to insulin. In early stages, the predominant abnormality is reduced insulin sensitivity, and hyperglycemia can be reversed by a variety of measures and medications. In this stage, the cornerstone of glucose-lowering therapy is lifestyle modification, but when counseling does not adequately achieve the recommended glycemic targets, at least five classes of oral drugs are available. In general, alpha-glucosidase inhibitors delay carbohydrate absorption, metiglinides and sulfonylureas increase insulin supply, and biguanides and thiazolidinediones enhance insulin action. Given the high cardiovascular morbidity and mortality in type 2 DM patients, the attempt to reduce cardiovascular complications, beyond the glucose lowering itself, is an extremely relevant task. Indeed, the role of oral glucose-lowering agents concerning hyperglycemia reduction is defined; however, they have not clearly demonstrated to reduce micro- and macrovascular disease, and hitherto, no firm evidence favors one pharmacological treatment over another. The aim of this update is to describe the existing experiences with oral glucose-lowering agents for type 2 DM treatment with respect to cardiovascular prevention.     

Diabetes - the Role of Metabolomics in the Discovery of New Mechanisms and Novel Biomarkers

Diabetes is a noncommunicable disease associated with ineffective production or utilization of insulin, which causes hyperglycemia and both short- and long-term effects on health including diabetic complications (nephropathy, neuropathy, and retinopathy) and an increased risk of developing cardiovascular diseases. Globally, there were 346 million people diagnosed with diabetes in 2011. The majority of deaths due to diabetes are observed in the developing world and an estimated 12 % of all healthcare costs are attributed to its treatment. Diabetes is a metabolic disorder and in recent decades it has been shown that metabolites other than glucose play important roles in insulin resistance and development of diabetes. To this end the holistic study of metabolites (termed metabolomics) is an important research tool to apply in diabetes research. Here, the importance of metabolomics in discovering novel mechanisms and biomarkers is highlighted through studies published in the period January 2011 to August 2012. Particular focus is placed on the study of branched chain amino acid metabolism, insulin secretion from ß-cells, diabetes complications and interventions, as well as showing how studies in cell and animal models can complement or validate observations in the human population.