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India is one of the epicentres of the global diabetes mellitus pandemic. Rapid socioeconomic development and demographic changes, along with increased susceptibility for Indian individuals, have led to the explosive increase in the prevalence of diabetes mellitus in India over the past four decades. Type 2 diabetes mellitus in Asian Indian people is characterized by a young age of onset and occurrence at low levels of BMI. Available data also suggest that the susceptibility of Asian Indian people to the complications of diabetes mellitus differs from that of white populations. Management of this disease in India faces multiple challenges, such as low levels of awareness, paucity of trained medical and paramedical staff and unaffordability of medications and services. Novel interventions using readily available resources and technology promise to revolutionise the care of patients with diabetes mellitus in India. As many of these challenges are common to most developing countries of the world, the lessons learnt from India's experience with diabetes mellitus are likely to be of immense global relevance. In this Review, we discuss the epidemiology of diabetes mellitus and its complications in India and outline the advances made in the country to ensure adequate care. We make specific references to novel, cost-effective interventions, which might be of relevance to other low-income and middle-income countries of the world.

Hypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed. Graphical abstract

Globally, the number of people with diabetes mellitus has quadrupled in the past three decades, and diabetes mellitus is the ninth major cause of death. About 1 in 11 adults worldwide now have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Asia is a major area of the rapidly emerging T2DM global epidemic, with China and India the top two epicentres. Although genetic predisposition partly determines individual susceptibility to T2DM, an unhealthy diet and a sedentary lifestyle are important drivers of the current global epidemic; early developmental factors (such as intrauterine exposures) also have a role in susceptibility to T2DM later in life. Many cases of T2DM could be prevented with lifestyle changes, including maintaining a healthy body weight, consuming a healthy diet, staying physically active, not smoking and drinking alcohol in moderation. Most patients with T2DM have at least one complication, and cardiovascular complications are the leading cause of morbidity and mortality in these patients. This Review provides an updated view of the global epidemiology of T2DM, as well as dietary, lifestyle and other risk factors for T2DM and its complications.

Diabetes mellitus is a complex metabolic disorder associated with an increased risk of microvascular and macrovascular disease; its main clinical characteristic is hyperglycaemia. The last century has been characterised by remarkable advances in our understanding of the mechanisms leading to hyperglycaemia. The central role of insulin in glucose metabolism regulation was clearly demonstrated during the early 1920s, when Banting, Best, Collip and Macleod successfully reduced blood glucose levels and glycosuria in a patient treated with a substance purified from bovine pancreata. Later, during the mid-1930s, clinical observations suggested a possible distinction between ‘insulin-sensitive’ and ‘insulin-insensitive’ diabetes. Only during the 1950s, when a reliable measure of circulating insulin was available, was it possible to translate these clinical observations into pathophysiological and biochemical differences, and the terms ‘insulin-dependent’ (indicating undetectable insulin levels) and ‘non-insulin-dependent’ (normal or high insulin levels) started to emerge. The next 30 years were characterised by pivotal progress in the field of immunology that were instrumental in demonstrating an immune-mediated loss of insulin-secreting β-cells in subjects with ‘insulin-dependent’ diabetes. At the same time, new experimental techniques allowing measurement of insulin ‘impedance’ showed a reduced peripheral effect of insulin in subjects with ‘non-insulin-dependent’ diabetes (insulin resistance). The difference between the two types of diabetes emerging from decades of observations and experiments was further formally recognised in 1979, when the definitions ‘type I’ and ‘type II’ diabetes were introduced to replace the former ‘insulin-dependent’ and ‘non-insulin-dependent’ terms. In the following years, many studies elucidated the natural history and temporal contribution of insulin resistance and β-cell insulin secretion in ‘type II’ diabetes. Furthermore, a central role for insulin resistance in the development of a cluster of cardiometabolic alterations (dyslipidaemia, inflammation, high blood pressure) was suggested. Possibly as a consequence of the secular changes in diabetes risk factors, in the last 10 years the limitation of a simple distinction between ‘type I’ and ‘type II’ diabetes has been increasingly recognised, with subjects showing the coexistence of insulin resistance and immune activation against β-cells. With the advancement of our cellular and molecular understanding of diabetes, a more pathophysiological classification that overcomes the historical and simple ‘glucocentric’ view could result in a better patient phenotyping and therapeutic approach.

The Diabetes Complications Severity Index (DCSI) converts diagnostic codes and laboratory results into a 14-level metric quantifying the long-term effects of diabetes on seven body systems. Adoption of the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) necessitates translation from ICD-9-CM and creates refinement opportunities. ICD-9 codes for secondary and primary diabetes plus all five ICD-10 diabetes categories were incorporated into an updated tool. Additional modifications were made to improve the accuracy of severity assignments. The tools were tested in a Medicare Advantage population. In the type 2 subpopulation, prevalence steadily declined with increasing score according to the updated DCSI tool, whereas the original tool resulted in an aberrant local prevalence peak at DCSI = 2. In the type 1 subpopulation, score prevalence was greater in type 1 versus type 2 subpopulations (3 versus 0) according to both instruments. Both instruments predicted current-year inpatient admissions risk and near-future mortality, using either purely ICD-9 data or a mix of ICD-9 and ICD-10 data. While the performance of the tool with purely ICD-10 data has yet to be evaluated, this updated tool makes assessment of diabetes patient severity and complications possible in the interim.

Aims/hypothesis Diabetes has been identified as a risk factor for poor prognosis of coronavirus disease-2019 (COVID-19). The aim of this study is to identify high-risk phenotypes of diabetes associated with COVID-19 severity and death. Methods This is the first edition of a living systematic review and meta-analysis on observational studies investigating phenotypes in individuals with diabetes and COVID-19-related death and severity. Four different databases were searched up to 10 October 2020. We used a random effects meta-analysis to calculate summary relative risks (SRR) with 95% CI. The certainty of evidence was evaluated by the GRADE tool. Results A total of 22 articles, including 17,687 individuals, met our inclusion criteria. For COVID-19-related death among individuals with diabetes and COVID-19, there was high to moderate certainty of evidence for associations (SRR [95% CI]) between male sex (1.28 [1.02, 1.61], n  = 10 studies), older age (>65 years: 3.49 [1.82, 6.69], n  = 6 studies), pre-existing comorbidities (cardiovascular disease: 1.56 [1.09, 2.24], n  = 8 studies; chronic kidney disease: 1.93 [1.28, 2.90], n  = 6 studies; chronic obstructive pulmonary disease: 1.40 [1.21, 1.62], n  = 5 studies), diabetes treatment (insulin use: 1.75 [1.01, 3.03], n  = 5 studies; metformin use: 0.50 [0.28, 0.90], n  = 4 studies) and blood glucose at admission (≥11 mmol/l: 8.60 [2.25, 32.83], n  = 2 studies). Similar, but generally weaker and less precise associations were observed between risk phenotypes of diabetes and severity of COVID-19. Conclusions/interpretation Individuals with a more severe course of diabetes have a poorer prognosis of COVID-19 compared with individuals with a milder course of disease. To further strengthen the evidence, more studies on this topic that account for potential confounders are warranted. Registration PROSPERO registration ID CRD42020193692. Graphical abstract

The severity of the metabolic abnormality can progress, regress, or stay the same. [...] the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself.

The review presents modern views about the role of oxidative stress reactions in the pathogenesis of types 1 and 2 diabetes mellitus and their complications based on the analysis of experimental and clinical studies. The sources of increased ROS generation in diabetes are specified, including the main pathways of altered glucose metabolism, oxidative damage to pancreatic β-cells, and endothelial dysfunction. The relationship between oxidative stress, carbonyl stress, and inflammation is described. The significance of oxidative stress reactions associated with hyperglycemia is considered in the context of the “metabolic memory” phenomenon. The results of our studies demonstrated significant ethnic and age-related variability of the LPO—antioxidant defense system parameters in patients with diabetes mellitus, which should be considered during complex therapy of the disease. Numerous studies of the effectiveness of antioxidants in diabetes mellitus of both types convincingly proved that antioxidants should be a part of the therapeutic process. Modern therapeutic strategies in the treatment of diabetes mellitus are aimed at developing new methods of personalized antioxidant therapy, including ROS sources targeting combined with new ways of antioxidant delivery.

A clinical trial assessed the efficacy of three treatments, all involving metformin, on glycemic control in youth-onset type 2 diabetes. This follow-up study shows that the risk of complications increased steadily over time, and complications developed in most participants by young adulthood.