Epidemiology of microvascular complications of diabetes in South Asians and comparison with other ethnicities

Type 2 diabetes mellitus is widely prevalent in South Asians, and has a significant effect on health, as well as the economies of South Asian countries, particularly when the disease is associated with complications. There are certain characteristics associated with the South Asian phenotype that make South Asians especially prone to diabetes, as well as its complications. Microvascular complications cause considerable morbidity and mortality. There are significant differences in the epidemiology of microvascular complications between South Asians and people of other races. There is evidence of higher prevalence of nephropathy and retinopathy in South Asians compared with Caucasians; however, recent studies indicate that this trend seems to be leveling off. Importantly, diabetic neuropathy occurs less frequently in South Asians compared with Caucasians. These observations have important implications in managing South Asian patients with diabetes and microvascular complications.     

Genetic markers of type 2 diabetes: Progress in genome‐wide association studies and clinical application for risk prediction

Type 2 diabetes (T2D) has become a leading public health challenge worldwide. To date, a total of 83 susceptibility loci for T2D have been identified by genome‐wide association studies (GWAS). Application of meta‐analysis and modern genotype imputation approaches to GWAS data from diverse ethnic populations has been key in the effort to discover T2D loci. Genetic information is expected to play a vital role in the prediction of T2D, and many efforts have been made to develop T2D risk models that include both conventional and genetic risk factors. Yet, because most T2D genetic variants identified have small effect size individually (10%–20% increased risk of T2D per risk allele), their clinical utility remains unclear. Most studies report that a genetic risk score combining multiple T2D genetic variants does not substantially improve T2D risk prediction beyond conventional risk factors. In this article, we summarize the recent progress of T2D GWAS and further review the incremental predictive performance of genetic markers for T2D.     

Improving postprandial hyperglycemia in patients with type 2 diabetes already on basal insulin therapy: Review of current strategies

A large number of patients with type 2 diabetes (T2D) on basal insulin do not reach their HbA1c goals and require additional therapy to address postprandial hyperglycemia. Guidelines from expert bodies have outlined several approaches to accomplish postprandial glucose (PPG) control, and recent literature suggests several more. This article provides strategies for primary care physicians caring for patients with T2D who do not achieve glycemic control with basal insulin alone. Current treatment guidelines and strategies for improving PPG control are reviewed, including the efficacy, safety, and cost‐effectiveness of rapid‐acting insulin (RAI) analogs, premixed insulin, glucagon‐like peptide‐1 (GLP‐1) receptor agonists (RAs), dipeptidyl peptidase 4 inhibitors, sodium–glucose cotransporter 2 inhibitors, and α‐glucosidase inhibitors. Other approaches, such as combinations of newer basal insulin plus RAI and a fixed‐ratio combination of basal insulin and a GLP‐1 RA, are also described.     

Regional evidence and international recommendations to guide lipid management in Asian patients with type 2 diabetes with special reference to renal dysfunction

The anticipated increase in the prevalence and incidence of type 2 diabetes in Asia, and its associated cardiovascular–renal complications, will place a significant burden on patients, caregivers, and society. Despite the proven effectiveness of lipid management in reducing these complications, there are major treatment gaps, especially in Asian patients with young‐onset diabetes and chronic kidney disease (CKD). Recent international guidelines recommended the adoption of absolute risk estimation of atherosclerosis and cardiovascular disease to guide treatment intensity. These recommendations replaced the previous strategy of using low‐density lipoprotein cholesterol targets to guide initiation and intensification of lipid lowering, albeit still widely practiced in Asia. The latest guidelines also highlight the high risk of atherosclerosis and cardiovascular disease (ASCVD) for people with diabetes, who should be protected with statins, except for young patients without other risk factors, who will need yearly monitoring of blood lipid levels. Given the propensity of Asian patients with diabetes to develop CKD and the amplifying effect of CKD on ASCVD, the use of statins in Asian patients is particularly important. Due to interethnic differences in drug metabolism, rosuvastatin, which is largely cleared by the kidney, should be prescribed in low dosages (5–10 mg daily) in Asian populations. Conversely, epidemiological and experimental data confirm pleotropic and organ‐protective effects of atorvastatin, with proven safety in Asian populations within a daily dose range of 10–40 mg. Thus, there is a need for Asian countries to review and align their lipid‐lowering treatment guidelines to reduce the substantial burden of diabetes in the Asian region.     

Socioeconomic factors relating to diabetes and its management in India

Diabetes is an escalating problem in India and has major socioeconomic dimensions. Rapid dietary changes coupled with decreased levels of physical activity have resulted in increases in obesity and diabetes in rural and semi‐urban areas, as well as in urban‐based people living in resettlement colonies. Increasing risk has also been recorded in those who suffered from poor childhood nutrition and in rural‐to‐urban migrants. Social inequity manifests in disparities in socioeconomic status (SES), place of residence, education, gender, and level of awareness and affects prevention, care, and management. All these population subsets have major socioeconomic challenges: low levels of awareness regarding diabetes and prevention, inadequate resources, insufficient allotment of healthcare budgets, and lack of medical reimbursement. Unawareness and delays in seeking medical help lead to complications, resulting in many‐fold increased costs in diabetes care. These costs plunge individuals and households into a vicious cycle of further economic hardship, inadequate management, and premature mortality, resulting in more economic losses. At the societal level, these are massive losses to national productivity and the exchequer. Overall, there is an immediate need to strengthen the healthcare delivery system to generate awareness and for the prevention, early detection, cost‐effective management, and rehabilitation of patients with diabetes, with a focus on people belonging to the lower SES and women (with a particular focus on nutrition before and during pregnancy). Because of an enhanced awareness campaign spearheaded through the National Program on Prevention of Cardiovascular Disease, Cancer, Diabetes and Stroke (NCPCDS) initiated by Government of India, it is likely that the level of awareness and early detection of diabetes may increase.     

Current understanding of the role of gut dysbiosis in type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disorder that results from destruction of the insulin‐producing pancreatic β‐cells. The disease mainly affects juveniles. Changes in the composition of the gut microbiota (dysbiosis) and changes in the properties of the gut barrier have been documented in T1D subjects. Because these factors affect immune system functions, they are likely to play a role in disease pathogenesis. However, their exact role is currently not fully understood and is under intensive investigation. In this article we discuss recent advancements depicting the role of intestinal dysbiosis on immunity and autoimmunity in T1D. We also discuss therapies aimed at maintaining a healthy gut barrier as prevention strategies for T1D.     

Monogenic diabetes: Implementation of translational genomic research towards precision medicine

Various forms of early onset non‐autoimmune diabetes are recognized as monogenic diseases, each subtype being caused by a single highly penetrant gene defect at the individual level. Monogenic diabetes (MD) is clinically and genetically heterogeneous, including maturity onset diabetes of the young and infancy‐onset and neonatal diabetes mellitus, which are characterized by functional defects of insulin‐producing pancreatic β‐cells and hyperglycemia early in life. Depending on the genetic cause, MD differs in the age at diabetes onset, the severity of hyperglycemia, long‐term diabetic complications, and extrapancreatic manifestations. In this review we discuss the many challenges of molecular genetic diagnosis of MD in the face of a substantial genetic heterogeneity, as well as the clinical benefit and cost‐effectiveness of an early genetic diagnosis, as demonstrated by simulation models based on lifetime complications and treatment costs. We also discuss striking examples of proof‐of‐concept of genomic medicine, which have enabled marked improvement in patient care and long‐term clinical management. Recent advances in genome editing and pluripotent stem cell reprogramming technologies provide new opportunities for in vitro diabetes modeling and the discovery of novel drug targets and cell‐based diabetes therapies. A review of these future directions makes the case for exciting translational research to further our understanding of the pathophysiology of early onset diabetes.     

Emerging trends and the clinical impact of food insecurity in patients with diabetes

Food insecurity is a major public health concern in the United States affecting 15 million households according to data in 2017 from the US Department of Agriculture. Food insecurity, or the inability to consistently obtain nutritious food, disproportionately affects socioeconomically disadvantaged households, as well as those with chronic diseases including diabetes mellitus (DM). This review article explores the literature over the past 10 years pertaining to the complex relationship between food insecurity, social determinants of health, and chronic disease with an emphasis on diabetes and glycemic control. Those with diabetes and food insecurity together have been shown to have worse glycemic control compared to those who are food secure, but it remains unclear exactly how food insecurity affects glycemic control. Prior interventional studies have targeted aspects of food insecurity in patients with diabetes but have reported variable outcomes with respect to improvement in glycemic control despite effectively reducing rates of food insecurity. Additionally, few data exist regarding long‐term outcomes and diabetes‐related complications in this population. It is likely that many factors at both the community and individual levels impact glycemic control outcomes in the setting of food insecurity. Further studies are needed to better understand these factors and to create multifaceted targets for future interventional studies aimed at improving glycemic control in this population.     

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short‐acting, prandial, and long‐acting GLP‐1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short‐acting prandial GLP‐1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.     

Vitamin D and Type 2 diabetes mellitus (维生素D与2型糖尿病)

Based on increasing evidence from animal and human studies, vitamin D deficiency is now regarded as a potential risk factor for Type 2 diabetes mellitus (T2DM). Vitamin D is involved in the pathogenesis of pancreatic β‐cell dysfunction, insulin resistance, and systemic inflammation, conditions that contribute to the development of T2DM. Vitamin D can affect the progress of this disease directly through the activation of its own receptor, and indirectly via the regulation of calcium homeostasis. Observational studies have revealed the association between vitamin D deficiency and incident T2DM. More double‐blind randomized control studies that investigate the effects of vitamin D supplementation on insulin sensitivity, insulin secretion, and the occurrence of T2DM are needed.     

Continuous spectrum of glucose dysmetabolism due to the KCNJ11 gene mutation—Case reports and review of the literature

The KCNJ11 gene encodes the Kir6.2 subunit of the adenosine triphosphate‐sensitive potassium (K_ATP) channel, which plays a key role in insulin secretion. Monogenic diseases caused by KCNJ11 gene mutation are rare and easily misdiagnosed. It has been shown that mutations in the KCNJ11 gene are associated with neonatal diabetes mellitus (NDM), maturity‐onset diabetes of the young 13 (MODY13), type 2 diabetes mellitus (T2DM), and hyperinsulinemic hypoglycemia. We report four patients with KCNJ11 gene mutations and provide a systematic review of the literature. A boy with diabetes onset at the age of 1 month was misdiagnosed as type 1 diabetes mellitus (T1DM) for 12 years and received insulin therapy continuously, resulting in poor glycemic control. He was diagnosed as NDM with KCNJ11 E322K gene mutation, and glibenclamide was given to replace exogenous insulin. The successful transfer time was 4 months, much longer than the previous unsuccessful standard of 4 weeks. The other three patients were two sisters and their mother; the younger sister was misdiagnosed with T1DM at 13 years old, while the elder sister was diagnosed with diabetes (type undefined) at 16 years old. They were treated with insulin for 3 years, with poor glycemic control. Their mother was diagnosed with T2DM and achieved good glycemia control with glimepiride. They were diagnosed as MODY13 because of the autosomal dominant inheritance of two generations, early onset of diabetes before 25 years of age in the two sisters, and the presence of the KCNJ11 N48D gene mutation. All patients successfully transferred to sulfonylureas with excellent glycemic control. Therefore, the wide spectrum of clinical phenotypes of glucose dysmetabolism caused by KCNJ11 should be recognized to reduce misdiagnosis and implement appropriate treatment.     

Revisiting multiple models of progression of β‐cell loss of function in type 1 diabetes: Significance for prevention and cure

Type 1 diabetes (T1D) results from a chronic autoimmune process that leads to β‐cell destruction and exogenous insulin dependence. The natural history of T1D proposed by Eisenbarth suggested six relatively independent stages over the course of the entire disease process, which was considered to be linear and chronic. Based on this classical theory, immunotherapies aim to prevent or reverse all these periods of β‐cell loss. Over the past 30 years, much novel information about the pathogenesis of T1D proved that there are complex metabolic changes occurring throughout the entire disease process. Therefore, new possible models for the natural history of the disease have been proposed; these models, in turn, may help facilitate fresh avenues for the prevention and cure of T1D. Herein, we briefly review recent findings in this field of research, with the aim of providing a better theoretical basis for clinical practice.     

Linking of metabolomic biomarkers with cardiometabolic health in Chinese population

Due to rapid nutrition transitions, the prevalence of cardiometabolic diseases, such as metabolic syndrome, type 2 diabetes, and cardiovascular diseases, has been increasing at an alarming rate in the Chinese population. Moreover, Asians, including Chinese, have been hypothesized to have a higher susceptibility to cardiometabolic diseases than Caucasians. Early prediction and prevention are key to controlling this epidemic trend; to this end, the identification of novel biomarkers is critical to reflect environmental exposure, as well as to reveal endogenous metabolic and pathophysiologic mechanisms. The emerging “omics” technologies, especially metabolomics, offer a unique opportunity to provide novel signatures or fingerprints to understand the effects of genetic and non‐genetic factors on cardiometabolic health. During the past two decades, metabolomic approaches have been increasingly used in various epidemiological studies, primarily in Western populations. Although the field is still in its early stages, some studies have tried to identify novel compounds or confirm their metabolites and associations with cardiometabolic diseases in Chinese populations, including amino acids, fatty acids, acylcarnitines and other metabolites. Despite major efforts to discover novel biomarkers for disease prediction or intervention, the limits in current study design, analytical platforms, and data processing approaches are challenges in metabolomic research worldwide. Therefore, future research with more advanced technologies, rigorous study designs, standardized detection and analytic approaches, and integrated data from multiomics approaches are essential to evaluate the feasibility of using metabolomics in clinical settings. Finally, the functional roles and underlying biological mechanisms of metabolomic biomarkers should be elucidated by future mechanistic research.     

Hemoglobin A1c and diagnosis of diabetes

The prevalence of diabetes is increasing markedly worldwide, especially in China. Hemoglobin A1c is an indicator of mean blood glucose concentrations and plays an important role in the assessment of glucose control and cardiovascular risk. In 2010, the American Diabetes Association included HbA1c ≥6.5% into the revised criteria for the diagnosis of diabetes. However, the debate as to whether HbA1c should be used to diagnose diabetes is far from being settled and there are still unanswered questions regarding the cut‐off value of HbA1c for diabetes diagnosis in different populations and ethnicities. This review briefly introduces the history of HbA1c from discovery to diabetes diagnosis, key steps towards using HbA1c to diagnose diabetes, such as standardization of HbA1c measurements and controversies regarding HbA1c cut‐off points, and the performance of HbA1c compared with glucose measurements in the diagnosis of diabetes.     

Sweet fish: Fish models for the study of hyperglycemia and diabetes

Fish are good for your health in more ways than you may expect. For one, eating fish is a common dietary recommendation for a healthy diet. However, fish have much more to provide than omega‐3 fatty acids to your circulatory system. Some fish species now serve as important and innovative model systems for diabetes research, providing novel and unique advantages compared with classical research models. Not surprisingly, the largest share of diabetes research in fish occurs in the laboratory workhorse among fish, the zebrafish (Danio rerio). Established as a genetic model system to study development, these small cyprinid fish have eventually conquered almost every scientific discipline and, over the past decade, have emerged as an important model system for metabolic diseases, including diabetes mellitus. In this review we highlight the practicability of using zebrafish to study diabetes and hyperglycemia, and summarize some of the recent research and breakthroughs made using this model. Equally exciting is the appearance of another emerging discipline, one that is taking advantage of evolution by studying cases of naturally occurring insulin resistance in fish species. We briefly discuss two such models in this review, namely the rainbow trout (Oncorhynchus mykiss) and the cavefish (Astyanax mexicanus).     

FoxO6 in glucose metabolism (FoxO6在葡萄糖代谢中的作用)

The forkhead box O (FoxO) subfamily has four members, namely FoxO1, FoxO3, FoxO4, and FoxO6. Unlike the other three members of the FoxO family, FoxO6 has garnered considerably less attention because of earlier reports that FoxO6 expression was limited to the brain. Recent data indicate that FoxO6 is produced in the liver of both rodents and humans. Hepatic FoxO6 activity, which remains at low basal levels in fed states, is markedly induced in fasted mice. FoxO6 activity becomes abnormally higher in the liver of mice with dietary obesity or type 2 diabetes (T2D). Genetically engineered mice with elevated FoxO6 activity in the liver exhibit prediabetes, culminating in the development of glucose intolerance, fasting hyperglycemia, and hyperinsulinemia. Conversely, inhibition of FoxO6 activity in the insulin‐resistant liver results in a reduction in fasting hyperglycemia, contributing to the amelioration of hyperinsulinemia in T2D mice. These new data suggest that FoxO6 is an important regulator of hepatic glucose metabolism in response to insulin or physiological cues. Insulin inhibits FoxO6 activity by promoting its phosphorylation and disabling its activity in the nucleus without altering its subcellular distribution via a mechanism that is distinct from other members of the FoxO subfamily. In this article, we comprehensively review the role of FoxO6 in glucose metabolism in health and disease. We also address whether FoxO6 dysregulation is a contributing factor for the pathogenesis of fasting hyperglycemia and discuss whether FoxO6 is a potential therapeutic target for improving fasting hyperglycemia in T2D.     

Brain atrophy in middle‐aged subjects with Type 2 diabetes mellitus,with and without microvascular complications

Background: The rapid rise in Type 2 diabetes mellitus (T2DM) among young adults makes it important to understand structural changes in the brain at a presenile stage. This study examined global and regional brain atrophy in middle‐aged adults with T2DM, with a focus on those without clinical evidence of microvascular complications. Methods: The study recruited 66 dementia‐free middle‐aged subjects (40 with T2DM, 26 healthy volunteers [HVs]). Patients were grouped according to the presence (T2DM‐C; n = 20) or absence (T2DM‐NC; n = 20) of diabetic microvascular complications. Global brain volume (including gray matter [GM] and white matter) was calculated based on voxel‐based morphometry analysis. Regional GM volumes were further extracted using the anatomical automatic labeling template. Results: There was a significant difference in global brain volume among groups (P = 0.003, anova ). Global brain volume was lower in T2DM‐C patients than in both T2DM‐NC patients and HVs (mean [±SD] 0.720 ± 0.024 vs 0.736 ± 0.021 and 0.743 ± 0.019, respectively; P = 0.032 and P = 0.001, respectively). Regional analysis showed significant GM atrophy in the right Rolandic operculum (t = 3.42, P = 0.001) and right superior temporal gyrus (t = 2.803, P = 0.007) in T2DM‐NC patients compared with age‐ and sex‐matched HVs. Conclusions: Brain atrophy is present in dementia‐free middle‐aged adults with T2DM. Regional brain atrophy appears to be developing even in those with no clinical evidence of microvascular disturbances. The brain seems to be particularly vulnerable to metabolic disorders prior to peripheral microvascular pathologies associated with other target organs.     

Digital health technology and diabetes management

Diabetes care is largely dependent on patient self‐management and empowerment, given that patients with diabetes must make numerous daily decisions as to what to eat, when to exercise, and determine their insulin dose and timing if required. In addition, patients and providers are generating vast amounts of data from many sources, including electronic medical records, insulin pumps, sensors, glucometers, and other wearables, as well as evolving genomic, proteomic, metabolomics, and microbiomic data. Multiple digital tools and apps have been developed to assist patients to choose wisely, and to enhance their compliance by using motivational tools and incorporating incentives from social media and gaming techniques. Healthcare teams (HCTs) and health administrators benefit from digital developments that sift through the enormous amounts of patient‐generated data. Data are acquired, integrated, analyzed, and presented in a self‐explanatory manner, highlighting important trends and items that require attention. The use of decision support systems may propose data‐driven actions that, for the most, require final approval by the patient or physician before execution and, once implemented, may improve patient outcomes. The digital diabetes clinic aims to incorporate all digital patient data and provide individually tailored virtual or face‐to‐face visits to those persons who need them most. Digital diabetes care has demonstrated only modest HbA1c reduction in multiple studies and borderline cost‐effectiveness, although patient satisfaction appears to be increased. Better understanding of the barriers to digital diabetes care and identification of unmet needs may yield improved utilization of this evolving technology in a safe, effective, and cost‐saving manner.     

Diabetes and cancer relationships (糖尿病与肿瘤的关联性)

Diabetes and cancer are both heterogeneous and multifactorial diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that certain malignancies may be associated with diabetes, as well as with diabetes risk factors and, perhaps, with certain diabetes treatments. Numerous biological mechanisms could account for these relationships. Insulin‐like growth factor (IGF)‐1, IGF‐2, IGF‐1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. Although evidence from randomized controlled trials does not support or refute associations of diabetes and its treatments with either increased or reduced risk of cancer incidence or prognosis, consideration of malignancy incidence rates and the magnitude of the trials that would be required to address these issues explains why such studies may not be readily undertaken.     

Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus: A narrative review (预混胰岛素类似物在2型糖尿病治疗中的作用：叙述性综述)

Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in patients with T2DM. The present review focuses on relevant clinical evidence supporting the use of premixed insulin analogues in T2DM when intensifying therapy, and as starter insulins in insulin‐naïve patients. Our aim is to provide relevant facts and clinical evidence useful in the decision‐making process of treatment selection and individualized treatment goal setting to obtain sustained blood glucose control.