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.     

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.     

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.     

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.     

A comparative analysis of current blood pressure management guidelines in people with and without diabetes

Hypertension is the leading global risk factor for cardiovascular disease and premature death. Recommendations from current guidelines of blood pressure (BP) management differ in many ways; therefore, we did an overview and comparative analysis of major clinical guidelines of BP management in people with and without diabetes, including the definition and classification of hypertension, initiation of antihypertensive drug therapy, BP control targets, and antihypertensive treatment strategies. BP management in patients with diabetes was discussed in great detail using both hypertension and diabetes guidelines. We conclude that high‐level evidence from high‐quality clinical studies is urgently needed to settle uncertainties on BP management recommendations.     

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.     

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.     

Diabetes in developing countries

There has been a rapid escalation of type 2 diabetes (T2D) in developing countries, with varied prevalence according to rural vs urban habitat and degree of urbanization. Some ethnic groups (eg, South Asians, other Asians, and Africans), develop diabetes a decade earlier and at a lower body mass index than Whites, have prominent abdominal obesity, and accelerated the conversion from prediabetes to diabetes. The burden of complications, both macro‐ and microvascular, is substantial, but also varies according to populations. The syndemics of diabetes with HIV or tuberculosis are prevalent in many developing countries and predispose to each other. Screening for diabetes in large populations living in diverse habitats may not be cost‐effective, but targeted high‐risk screening may have a place. The cost of diagnostic tests and scarcity of health manpower pose substantial hurdles in the diagnosis and monitoring of patients. Efforts for prevention remain rudimentary in most developing countries. The quality of care is largely poor; hence, a substantial number of patients do not achieve treatment goals. This is further amplified by a delay in seeking treatment, “fatalistic attitudes”, high cost and non‐availability of drugs and insulins. To counter these numerous challenges, a renewed political commitment and mandate for health promotion and disease prevention are urgently needed. Several low‐cost innovative approaches have been trialed with encouraging outcomes, including training and deployment of non‐medical allied health professionals and the use of mobile phones and telemedicine to deliver simple health messages for the prevention and management of T2D.     

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).     

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.     

Current role of short‐term intensive insulin strategies in newly diagnosed type 2 diabetes (短期胰岛素强化治疗策略对初诊2型糖尿病患者的作用)

Type 2 diabetes mellitus (T2DM) is a progressive disease characterized by worsening insulin resistance and a decline in β‐cell function. Achieving good glycemic control becomes more challenging as β‐cell function continues to deteriorate throughout the disease process. The traditional management paradigm emphasizes a stepwise approach, and insulin has generally been reserved as a final armament. However, mounting evidence indicates that short‐term intensive insulin therapy used in the early stages of type 2 diabetes could improve β‐cell function, resulting in better glucose control and more extended glycemic remission than oral antidiabetic agents. Improvements in insulin sensitivity and lipid profile were also seen after the early initiation of short‐term intensive insulin therapy. Thus, administering short‐term intensive insulin therapy to patients with newly diagnosed T2DM has the potential to delay the natural process of this disease, and should be considered when clinicians initiate treatment. Although the early use of insulin is advocated by some guidelines, the optimal time to initiate insulin therapy is not clearly defined or easily recognized, and a pragmatic approach is lacking. Herein we summarize the current understanding of early intensive insulin therapy in patients with newly diagnosed T2DM, focusing on its clinical benefit and problems, as well as possible biological mechanisms of action, and discuss our perspective.     

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.     

Going beyond HbA1c to understand the benefits of advanced diabetes therapies

The gold standard for monitoring overall glycemia is HbA1c. However, HbA1c has several important limitations, giving more weight to the prior 2 to 3 months rather than short‐term glycemic control. In addition, the level of the HbA1c does not reflect the important interpersonal differences in its relationship with mean glucose, and HbA1c is affected by many common clinical conditions (anemia, uremia) that can interfere with the accuracy of its measurement in the laboratory. The development and refinement of continuous glucose monitoring (CGM), a glucose‐ and patient‐centric technology, over the past two decades have permitted the creation of new single and composite metrics, such as the percentage of time in range and the glucose pentagon, respectively, which provide clinically relevant insights into short‐term glycemic control. In addition, CGM creates new outcome metrics for clinical management and investigational studies (percentage of time in hypoglycemia, percentage of time in target range) that can accurately and meaningfully report the effects of an intervention, whether that is a drug, a device, or a psychosocial program, and CGM provides the key input to drive algorithm‐based insulin delivery. Finally, CGM linked with artificial intelligence permits real‐time feedback to patients about modifiable patterns of glycemic excursions.     

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.     

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.     

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.     

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal‐protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.     

Therapeutic approaches for latent autoimmune diabetes in adults: One size does not fit all

Recent advances in the understanding of latent autoimmune diabetes in adults (LADA) pathophysiology make it increasingly evident that people with LADA comprise a heterogenous group of patients. This makes the establishment of a standard treatment algorithm challenging. On top of its glucose‐lowering action, insulin may exert anti‐inflammatory effects, rendering it an attractive therapeutic choice for a type of diabetes in which autoinflammation and beta cell insufficiency play major pathogenetic roles. However, there is growing evidence that other antidiabetic drugs, such as metformin, dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists, and thiazolidinediones, might have a role in optimizing glycemic control and preserving beta cell function in individuals with LADA, either alone or in combination with insulin. Although most of these drugs have been routinely used in the daily clinical setting for years, large prospective randomized trials are needed to assess whether they are capable of delaying progression to insulin dependence as well as their effects on diabetic complications. The aim of the present review is to discuss the current state and future perspectives of LADA therapy, emphasizing the need for individualized and patient‐centered therapeutic approaches.     

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.     

Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

Reactive oxygen and nitrogen species (ROS and RNS, respectively) are byproducts of cellular physiological processes of the metabolism of intermediary nutrients. Although physiological defense mechanisms readily convert these species into water or urea, an improper balance between their production and removal leads to oxidative stress (OS), which is harmful to cellular components. This OS may result in uncontrolled growth or, ultimately, cell death. In addition, ROS and RNS are closely related to the development of diabetes and its complications. Therefore, numerous researchers have proposed the development of strategies for the removal of ROS/RNS to prevent or treat diabetes and its complications. Some molecules that are synthesized in the body or obtained from food participate in the removal and neutralization of ROS and RNS. Metallothionein, a cysteine‐rich protein, is a metal‐binding protein that has a wide range of functions in cellular homeostasis and immunity. Metallothionein can be induced by a variety of conditions, including zinc supplementation, and plays a crucial role in mediating anti‐OS, anti‐apoptotic, detoxification, and anti‐inflammatory effects. Metallothionein can modulate various stress‐induced signaling pathways (mitogen‐activated protein kinase, Wnt, nuclear factor‐κB, phosphatidylinositol 3‐kinase, sirtuin 1/AMP‐activated protein kinase and fibroblast growth factor 21) to alleviate diabetes and diabetic complications. However, a deeper understanding of the functional, biochemical, and molecular characteristics of metallothionein is needed to bring about new opportunities for OS therapy. This review focuses on newly proposed functions of a metallothionein and their implications relevant to diabetes and its complications.