The recent epidemic of type 2 diabetes in Asia differs from that reported in other regions of the world in several key areas: it has evolved over a much shorter time, in an earlier stage of life, and in people with lower body mass indices. These phenotypic characteristics of patients strongly suggest that insulin secretory defects may perform a more important function in the development and progression of diabetes. A genetic element clearly underlies β-cell dysfunction and insufficient β-cell mass; however, a number of modifiable factors are also linked to β-cell deterioration, most notably chronic hyperglycemia and elevated free fatty acid (FFA) levels. Neither glucose nor FFAs alone cause clinically meaningful β-cell toxicity, especially in patients with normal or impaired glucose tolerance. Thus the term "glucolipotoxicity" is perhaps more appropriate in describing the phenomenon. Several mechanisms have been proposed to explain glucolipotoxicity-induced β-cell dysfunction and death, but its major factors appear to be depression of key transcription factor gene expression by altered intracellular energy metabolism and oxidative stress. Therefore, stabilization of metabolic changes induced by glucolipotoxicity in β-cells represents a new avenue for the treatment of type 2 diabetes mellitus.
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Cardiovascular disease (CVD), a leading cause of death in patients with diabetes mellitus, has several pathogenic mechanisms that are well established. However, the traditional hypoglycemic agents do not have proven positive effects on macrovascular disease. Novel therapeutic agents target the incretin pathway including the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and the dipeptidyl peptidase-4 inhibitors. The glucose-regulatory actions of these agents function by increasing insulin secretion and suppressing glucagon. They also act to increase weight loss not only by inhibiting gastric emptying, but also by reducing appetite. Although GLP-1 and GLP-1R agonists have demonstrated beneficial effects on myocardium and vascular endothelium including coronary and peripheral mouse vessels, they also have anti-inflammatory and anti-atherogenic actions. These agents also have positive effects on the lipid profile and blood pressure. Although these cardioprotective actions seem to be beyond the effects of glucose control and weight loss, they are mediated through GLP-1R- or GLP-1R-independent actions of cleaved GLP-1 (9-36). Larger randomized controlled trials are necessary to elucidate the clinical promise of these beneficial CVD effects.
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As in other countries, type 2 diabetes is major health concern in Korea. A dramatic increase in the prevalence of type 2 diabetes and its chronic complications has led to an increase in health costs and economic burdens. Early detection of high risk individuals, hidden diabetic patients, and improvement in the quality of care for the disease are the first steps to mitigate the increase in prevalence. The Committee of Clinical Practice Guidelines of the Korean Diabetes Association revised and updated the '3rd Clinical Practice Guidelines' at the end of 2010. In the guidelines, the committee recommended active screening of high risk individuals for early detection and added the hemoglobin A1c level to the diagnostic criteria for type 2 diabetes based on clinical studies performed in Korea. Furthermore, the committee members emphasized that integrating patient education and self-management is an essential part of care. The drug treatment algorithm based on the degree of hyperglycemia and patient characteristics were also updated.
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With a developing worldwide epidemic of diabetes mellitus, the renal complications associated with diabetes have become a serious health concern. Primary therapy for treating diabetic nephropathy is a multifactorial process. Peroxisome proliferator-activated receptor alpha (PPARα) agonists have been used primarily in clinical practice for the treatment of dyslipidemia and insulin resistance. Given that PPARα expression and regulation of metabolic pathways are involved in oxidative stress, inflammation, blood pressure regulation, and the renin-angiotensin aldosterone system, PPARα likely influences the development and pathogenesis of diabetic nephropathy via indirect effects on glucose and lipid homeostasis and also by direct action on the kidneys. These findings suggest that PPARα may become an important therapeutic target for treating diabetic renal complications.
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Several polymers were used to delivery genes to diabetic animals. Polyaminobutyl glycolic acid was utilized to deliver IL-10 plasmid DNA to prevent autoimmune insulitis of non-obese diabetic (NOD) mouse. Polyethylene glycol grafted polylysine was combined with antisense glutamic acid decarboxylase (GAD) MRNA to represent GAD autoantigene expression. GLP1 and TSTA (SP-EX4) were delivered by bioreducible polymer to stop diabetic progression. Fas siRNA delivery was carried out to treat diabetic NOD mice animal.
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Glycosphingolipids (GSLs) are present in all mammalian cell plasma membranes and intracellular membrane structures. They are especially concentrated in plasma membrane lipid domains that are specialized for cell signaling. Plasma membranes have typical structures called rafts and caveola domain structures, with large amounts of sphingolipids, cholesterol, and sphingomyelin. GSLs are usually observed in many organs ubiquitously. However, GSLs, including over 400 derivatives, participate in diverse cellular functions. Several studies indicate that GSLs might have an effect on signal transduction related to insulin receptors and epidermal growth factor receptors. GSLs may modulate immune responses by transmitting signals from the exterior to the interior of the cell. Guillain-Barré syndrome is one of the autoimmune disorders characterized by symmetrical weakness in the muscles of the legs. The targets of the immune response are thought to be gangliosides, which are one group of GSLs. Other GSLs may serve as second messengers in several signaling pathways that are important to cell survival or programmed cell death. In the search for clear evidence that GSLs may play critical roles in various biological functions, many researchers have made genetically engineered mice. Before the era of gene manipulation, spontaneous animal models or chemical-induced disease models were used.
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Diabetes is an increasing global health problem worldwide. Diabetes and its complications have become a major cause of morbidity and mortality in Korea. The prevalence of diabetes in Korea has increased six- to seven-fold from 1.5% to 9.9% in the past 40 years. The prevalence of impaired fasting glucose also increased to about 20% in 2009. The International Diabetes Federation has estimated that the prevalence of diabetes will rise to 11.4% in 2030. Possible risk factors for diabetes in Korea are age, male gender, obesity, prediabetes, gestational diabetes, smoking, decreased physical activity, and short sleep duration. With increasing obesity, especially in childhood, and improved longevity, the prevalence of diabetes is expected to dramatically increase more than previously estimated. Therefore, public efforts to introduce healthy lifestyle changes and diabetic prevention programs are necessary to reduce the global epidemic of diabetes.
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Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities.
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Diabetes mellitus is a serious and growing health problem worldwide and is associated with severe acute and chronic complications. Moreover, epidemiologic evidence suggests that people with diabetes are at significantly higher risk for many forms of cancer. Several studies indicate an association between diabetes and the risk of liver, pancreas, endometrium, colon/rectum, breast, and bladder cancer. Mortality is also moderately increased in subjects with diabetes. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in diabetic patients. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic as well as mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. The effect of diabetes treatment drugs, aside from metformin, on cancer is not conclusive. In order to fight the perfect storm of diabetes and cancer, strategies to promote primary prevention and early detection of these conditions are urgently needed.
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Genome wide association analyses have revealed large numbers of common variants influencing predisposition to type 2 diabetes and related phenotypes. These studies have predominantly featured European populations, but are now being extended to samples from a wider range of ethnic groups. The transethnic analysis of association data is already providing insights into the genetic, molecular and biological causes of diabetes, and the relevance of such studies will increase as human discovery genetics increasingly moves towards sequencing-based approaches and a focus on low frequency and rare variants.
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Hyperglycemia that does not satisfy the diagnostic criteria for diabetes mellitus (DM) is generally called prediabetes (preDM). The global prevalence of preDM has been increasing progressively in the past few decades, and it has been established that preDM status is a strong risk factor for DM and cardiovascular disease. Currently, preDM status is classified into two subtypes: impaired fasting glucose and impaired glucose tolerance. Currently, preDM is not regarded as an independent clinical entity, but only as a risk factor for others. In this article, we review various clinical aspects of preDM in terms of the working definition, changes in criteria over the years, epidemiology, and pathophysiological characteristics, and its clinical significance in current medicine.
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Type 2 diabetes is commonly accompanied by a low level of high density lipoprotein cholesterol (HDL-C) that contributes to the increased cardiovascular risk associated with this condition. Given that HDLs have the ability to improve increase the uptake of glucose by skeletal muscle and to stimulate the secretion of insulin from pancreatic beta cells the possibility arises that a low HDL concentration in type 2 diabetes may also contribute to a worsening of diabetic control. Thus, there is a double case for raising the level of HDL-C in patients with type 2 diabetes: to reduce cardiovascular risk and to improve glycemic control. Approaches to raising HDL-C include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. Of currently available drugs, the most effective is niacin. Newer formulations of niacin are reasonably well tolerated and have the ability to increase HDL-C by up to 30%. The effect of niacin on cardiovascular events in type 2 diabetes is currently being tested in a large-scale clinical outcome trial.
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Diabetic vascular complications are among the leading causes of morbidity and mortality in diabetic patients. In the past, many studies have focused on the mechanisms of hyperglycemia-induced chronic vascular complications via the formation of toxic metabolites such as oxidative stress, advanced glycosylated end products, persistent activation of protein kinase C, and increased sorbitol concentrations. However, vascular complications result from imbalances caused by increases in systemic toxic metabolites, such as those that occur under conditions of hyperglycemia and dyslipidemia, and by reductions in endogenous protective factors such as insulin, vascular endothelial growth factor, and platelet derived growth factor. This review outlines some of the evidence supporting the importance of enhancing endogenous regenerative factors.
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Korean women with a history of gestational diabetes mellitus (GDM) have a 3.5 times greater risk of developing postpartum diabetes than the general population. The incidence of type 2 diabetes mellitus in early postpartum is reported as 10-15% in Korean women. A prospective follow-up study on Korean women with GDM showed that approximately 40% of women with previous GDM were expected to develop diabetes within 5 years postpartum. Independent risk factors for the development of diabetes in Korean women with previous GDM are pre-pregnancy body weight, gestational age at diagnosis, antepartum hyperglycemia on oral glucose tolerance test, low insulin response to oral glucose load, and family history of diabetes. Women with postpartum diabetes have greater body mass indexes, body weight, and waist circumferences than women with normal glucose tolerance. Multiple logistic regression analysis has revealed that waist circumference is the strongest obesity index along with systolic blood pressure and that triglyceride levels are a major independent risk factor for developing diabetes. These results in Korean women with previous GDM underline the importance of postpartum testing in Korean women diagnosed with GDM, and demonstrate that impaired B-cell function, obesity, and especially visceral obesity, are associated with the development of diabetes.
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Although there is no HbA1c threshold for cardiovascular risk, the American Diabetic Association-recommended goal of HbA1c < 7.0% appears to be unacceptably high. To achieve an optimal HbA1c level goal of 6.0% or less, a high dosage of sulfonylureas and insulin would be required; the trade-off would be the common adverse effects of hypoglycemia and weight gain. In contrast, hypoglycemia is uncommon with insulin sensitizers and GLP-1 analogs, allowing the physician to titrate these drugs to maximum dosage to reduce HbA1c levels below 6.0% and they have been shown to preserve β-cell function. Lastly, weight gain is common with sulfonylurea and insulin therapy, whereas GLP-1 analogs induce weight loss and offset the weight gain associated with TZDs. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which has antiatherogenic effects and improves hepatic insulin sensitivity), a TZD (which improves insulin sensitivity and preserves β-cell function with proven durability), and a GLP-1 analog (which improves β, α-cell function and promotes weight loss) or a dipeptidyl peptidase IV inhibitor in patients with type 2 diabetes mellitus.
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