Genetics of Type 2 Diabetes in East Asian Populations

Because type 2 diabetes (T2D) is highly familial, there has been a concentrated effort to uncover the genetic basis of T2D worldwide over the last decade. In East Asians, T2D is experiencing a rapidly rising prevalence that is characterized by a relatively lower body mass index, as compared with that in Europeans. To date, at least 15 convincing T2D loci have been identified from large-scale genome-wide association studies and meta-analyses in East Asians. Many of these are likely responsible for pancreatic ?? cell function, as indicated in studies from Europeans. Many T2D loci have been replicated across the ethnic groups. There are, however, substantial interethnic differences in frequency and effect size of these risk alleles. Despite accumulating genetic information on T2D, there are still limitations in our ability to explain the rapidly rising prevalence and lean phenotype of disease observed in East Asians, suggesting that more extensive work using diverse research strategies is needed in the future.     

Genetics of Type 2 Diabetes: the Power of Isolated Populations

Type 2 diabetes (T2D) affects millions of people worldwide. Improving the understanding of the underlying mechanisms and ultimately improving the treatment strategies are, thus, of great interest. To achieve this, identification of genetic variation predisposing to T2D is important. A large number of variants have been identified in large outbred populations, mainly from Europe and Asia. However, to elucidate additional variation, isolated populations have a number of advantageous properties, including increased amounts of linkage disequilibrium, and increased probability for presence of high frequency disease-associated variants due to genetic drift. Collectively, this increases the statistical power to detect association signals in isolated populations compared to large outbred populations. In this review, we elaborate on why isolated populations are a powerful resource for the identification of complex disease variants and describe their contributions to the understanding of the genetics of T2D.     

Personalized Medicine for Diabetes: Genetics Factors Contributing to Type 2 Diabetes across Ethnicities

Type 2 diabetes mellitus (T2DM) is among the many common diseases with a strong genetic component, but until recently, the variants causing this disease remained largely undiscovered. With the ability to interrogate most of the variation in the genome, the number of genetic variants has grown from 2 to 19 genes, many with multiple variants. An additional three genes are associated primarily with fasting glucose rather than T2DM. Despite the plethora of new markers, the individual effect is uniformly small, and the cumulative effect explains little of the genetic risk for T2DM. Furthermore, the success is largely restricted to European populations. Despite success in mapping genes in Asian populations, success in United States minorities, particularly African Americans, has been limited. The genetic findings highlight the role of the β cell in diabetes pathogenesis, but much remains to be discovered before genetic prediction and individualized medicine can become a reality for this disease.     

2型糖尿病认知功能障碍神经影像学研究进展

2型糖尿病(T2DM)认知功能障碍以记忆力下降为主要表现,是T2DM脑损伤的一种表现形式.目前通过神经影像学检查已可直接探测出T2DM患者脑损伤:脑部磁共振平扫发现T2DM患者记忆障碍与脑萎缩 (特别是海马萎缩)有关,通过弥散张量成像(DTI)可发现其存在广泛的脑白质连接异常; 功能性磁共振成像(fMRI)发现其海马和周围的脑区之间连接减少; 脑电图 (EEG)研究发现T2DM患者对刺激信号的反应时间延长、警觉性和注意力明显下降.这些神经影像学研究有助于进一步阐明糖尿病脑病机制.     

An Integrative Analysis of the Effect of Lifestyle and Pharmacological Interventions on Glucose Metabolism in the Prevention and Treatment of Youth-Onset Type 2 Diabetes

Preventing and managing youth-onset type 2 diabetes are a major challenge. This paper reviews the evidence of lifestyle and drug therapies in improving glucose, insulin, and insulin sensitivity. Forty-four interventions were analyzed, of which 11 were drug (mainly metformin) interventions combined with lifestyle while the remainder used lifestyle strategies only. Fewer than a dozen out of 44 interventions reported significant improvements in glucose-related outcomes. Metformin in addition to lifestyle therapy did not necessarily enhance intervention effects. The overall lack of findings can be partially attributed to the heterogeneity of study populations, the lack of intervention intensity, under-powered study design, and the challenging lives of at-risk populations. New treatment options in both drugs and lifestyle strategies are direly needed.     

Genetics of the HLA Region in the Prediction of Type 1 Diabetes

Type 1 diabetes (T1D) is one of the most widely studied complex genetic disorders, and the genes in HLA are reported to account for approximately 40–50% of the familial aggregation of T1D. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The DR-DQ haplotypes conferring the highest risk are DRB1*03:01-DQA1*05:01-DQB1*02:01 (abbreviated “DR3”) and DRB1*04:01/02/04/05/08-DQA1*03:01-DQB1*03:02/04 (or DQB1*02; abbreviated “DR4”). The risk is much higher for the heterozygote formed by these two haplotypes (OR = 16.59; 95% CI, 13.7–20.1) than for either of the homozygotes (DR3/DR3, OR = 6.32; 95% CI, 5.12–7.80; DR4/DR4, OR = 5.68; 95% CI, 3.91). In addition, some haplotypes confer strong protection from disease, such as DRB1*15:01-DQA1*01:02-DQB1*06:02 (abbreviated “DR2”; OR = 0.03; 95% CI, 0.01–0.07). After adjusting for the genetic correlation with DR and DQ, significant associations can be seen for HLA class II DPB1 alleles, in particular, DPB1*04:02, DPB1*03:01, and DPB1*02:02. Outside of the class II region, the strongest susceptibility is conferred by class I allele B*39:06 (OR =10.31; 95% CI, 4.21–25.1) and other HLA-B alleles. In addition, several loci in the class III region are reported to be associated with T1D, as are some loci telomeric to class I. Not surprisingly, current approaches for the prediction of T1D in screening studies take advantage of genotyping HLA-DR and HLA-DQ loci, which is then combined with family history and screening for autoantibodies directed against islet-cell antigens. Inclusion of additional moderate HLA risk haplotypes may help identify the majority of children with T1D before the onset of the disease.     

Type 2 Diabetes and Genetics, 2010: Translating Knowledge into Understanding

Type 2 diabetes (T2D) is epidemic, but much has been learned about its molecular etiology in recent years. In this review, we present the substantial evidence for the contribution of genetic variation to the development of T2D that has accumulated over the past decade, emphasizing the respective contribution of candidate gene, linkage analysis, and genome-wide association approaches. We then discuss how this emerging knowledge is informing and reshaping the understanding of T2D biology and how, in the near term, genetics may be used clinically to identify individuals who are at risk of disease or who may derive benefit from specific treatment modalities. In the final section, we address common questions posed to T2D geneticists and highlight the future approaches that will continue to improve our understanding of T2D genetics.     

Recent Advances in In-Vitro Assays for Type 2 Diabetes Mellitus: An Overview

BACKGROUNDA higher rate of attenuation of molecules in drug discovery has enabled pharmaceutical companies to enhance the efficiency of their hit identification and lead optimization. Selection and development of appropriate invitro and in-vivo strategies may improve this process as primary and secondary screening utilize both strategies. In-vivo approaches are too relentless and expensive for assessing hits. Therefore, it has become indispensable to develop and implement suitable in-vitro screening methods to execute the required activities and meet the respective targets. However, the selection of an appropriate in-vitro assay for specific evaluation of cellular activity is no trivial task. It requires thorough investigation of the various parameters involved.AIMIn this review, we aim to discuss in-vitro assays for type 2 diabetes (T2D), which have been utilized extensively by researchers over the last five years, including target-based, non-target based, low-throughput, and high-throughput screening assays.METHODSThe literature search was conducted using databases including Scifinder, PubMed, ScienceDirect, and Google Scholar to find the significant published articles.DISCUSSION and CONCLUSIONThe accuracy and relevance of in-vitro assays have a significant impact on the drug discovery process for T2D, especially in assessing the antidiabetic activity of compounds and identifying the site of effect in high-throughput screening. The report reviews the advantages, limitations, quality parameters, and applications of the probed invitro assays, and compares them with one another to enable the selection of the optimal method for any purpose. The information on these assays will accelerate numerous procedures in the drug development process with consistent quality and accuracy.     

Genetics of Diabetes

Reviews in Endocrine and Metabolic Disorders -     

Advances in Medical Therapy for Weight Loss and the Weight-Centric Management of Type 2 Diabetes Mellitus

Overweight and obesity are now recognized as leading causes of diseases such as type 2 diabetes, hypertension, hyperlipidemia, and ultimately, cardiovascular disease. Despite the serious consequences, roughly two thirds of Americans are presently classified as overweight, and about one third are classified as obese. Weight loss via lifestyle modification and pharmacotherapy can promote improvement in many of these obesity-related conditions. This review addresses recent advances in pharmacotherapy for the management of obesity and obesity-related co-morbidities, with a focus on the management of obesity specifically in individuals with type 2 diabetes. Emphasis is also placed on a proposed paradigm shift from the glucose-centric to the weight-centric management of type 2 diabetes mellitus.     

The Molecular Genetics of Sulfonylurea Receptors in the Pathogenesis and Treatment of Insulin Secretory Disorders and Type 2 Diabetes

Sulfonylurea receptors (SURs) form an integral part of the ATP-sensitive potassium (K_ATP) channel complex that is present in most excitable cell types. K_ATP channels couple cellular metabolism to electrical activity and provide a wide range of cellular functions including stimulus secretion coupling in pancreatic β cells. K_ATP channels are composed of SURs and inward rectifier potassium channel (Kir6.x) subunits encoded by the ABCC8/9 and KCNJ8/11 genes, respectively. Recent advances in the genetics, molecular biology, and pharmacology of SURs have led to an increased understanding of these channels in the etiology and treatment of rare genetic insulin secretory disorders. Furthermore, common genetic variants in these genes are associated with an increased risk for type 2 diabetes. In this review we summarize the molecular biology, pharmacology, and physiology of SURs and K_ATP channels, highlighting recent advances in their genetics and understanding of rare insulin secretory disorders and susceptibility to type 2 diabetes.     

Cardiomyopathy in Type 2 Diabetes

Type 2 diabetes mellitus (DM) is associated with increased risk for developing heart failure (HF) and worse outcomes once HF is present. While the exact mechanisms underpinning these observations remain poorly understood, several metabolic perturbations associated with DM have been implicated as contributors to the HF risk, including alterations of cardiomyocyte metabolic substrate switching between free fatty acid (FFA) and glucose metabolism; increased FFA exposure and cellular accumulation; and alterations in peroxisome proliferator-activated receptor-(PPAR-)alpha activity, among others. The commonly coincident conditions of left ventricular hypertrophy and ischemic heart disease likely confound the metabolic derangements further increasing HF risk. Continued investigation into these mechanistic connections is necessary to better understand the pathophysiology and ideally inform the pursuit of novel therapeutic targets and strategies to intervene on the HF associated with DM.     

Genetics of Type 2 diabetes.

Type 2 diabetes (T2D) has become a health-care problem worldwide, with the rise in disease prevalence being all the more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, as young adults and children are also being diagnosed with T2D. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. In this review, I highlight the main genes known to cause uncommon monogenic forms of diabetes (e.g. maturity-onset diabetes of the young--MODY--and insulin resistance syndromes), as well as describe some of the main approaches used to identify genes involved in the more common forms of T2D that result from the interaction between environmental risk factors and predisposing genotypes. Linkage and candidate gene studies have been highly successful in the identification of genes that cause the monogenic variants of diabetes and, although progress in the more common forms of T2D has been slow, a number of genes have now been reproducibly associated with T2D risk in multiple studies. These are discussed, as well as the main implications that the diabetes gene discoveries will have in diabetes treatment and prevention.     

Genetics of Diabetes Complications

A large body of evidence indicates that the risk for developing chronic diabetic complications is under the control of genetic factors. Previous studies using a candidate gene approach have uncovered a number of genetic loci that may shape this risk, such as the VEGF gene for retinopathy, the ELMO1 gene for nephropathy, and the ADIPOQ gene for coronary artery disease. Recently, a new window has opened on identifying these genes through genome-wide association studies. Such systematic approach has already led to the identification of a major locus for coronary artery disease on 9p21 as well three potential genes for nephropathy on 7p, 11p, and 13q. Further insights are expected from a broader application of this strategy. It is anticipated that the identification of these genes will provide novel insights on the etiology of diabetic complications, with crucial implications for the development of new drugs to prevent the adverse effects of diabetes.