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The traditional complications of diabetes mellitus are well known and continue to pose a considerable burden on millions of people living with diabetes mellitus. However, advances in the management of diabetes mellitus and, consequently, longer life expectancies, have resulted in the emergence of evidence of the existence of a different set of lesser-acknowledged diabetes mellitus complications. With declining mortality from vascular disease, which once accounted for more than 50% of deaths amongst people with diabetes mellitus, cancer and dementia now comprise the leading causes of death in people with diabetes mellitus in some countries or regions. Additionally, studies have demonstrated notable links between diabetes mellitus and a broad range of comorbidities, including cognitive decline, functional disability, affective disorders, obstructive sleep apnoea and liver disease, and have refined our understanding of the association between diabetes mellitus and infection. However, no published review currently synthesizes this evidence to provide an in-depth discussion of the burden and risks of these emerging complications. This Review summarizes information from systematic reviews and major cohort studies regarding emerging complications of type 1 and type 2 diabetes mellitus to identify and quantify associations, highlight gaps and discrepancies in the evidence, and consider implications for the future management of diabetes mellitus.This article discusses evidence for the emergence of a different set of complications associated with diabetes mellitus from the traditional ones, outlines the risks and burden of these associated complications and considers implications for the future management of diabetes mellitus.

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.

At the time of its first clinical application 100 years ago, insulin was presented as the cure for people with diabetes mellitus. That transpired to be an overstatement, yet insulin has proven to be the lifesaver for people with type 1 diabetes mellitus and an essential therapy for many with type 2 diabetes mellitus or other forms of diabetes mellitus. Since its discovery, insulin (a molecule of only 51 amino acids) has been the subject of pharmaceutical research and development that has paved the way for other protein-based therapies. From purified animal-extracted insulin and human insulin produced by genetically modified organisms to a spectrum of insulin analogues, pharmaceutical laboratories have strived to tailor the preparations to the needs of patients. Nonetheless, overall glycaemic control often remains poor as exogenous insulin is still not able to mimic the physiological insulin profile. Circumventing subcutaneous administration and the design of analogues with profiles that mimic that of physiological insulin are ongoing areas of research. Novel concepts, such as once-weekly insulins or glucose-dependent and oral insulins, are on the horizon but their real-world effectiveness still needs to be proven. Until a true cure for type 1 diabetes mellitus is found and the therapeutic arsenal for other forms of diabetes mellitus is expanded, insulin will remain central in the treatment of many people living with diabetes mellitus.It is 100 years since the famous experiments that identified insulin and showed that this protein could be used to treat people with type 1 diabetes mellitus. This Review charts the developments in insulin research over the past century and highlights future directions for this field.

Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.This article discusses the latest advances in the mechanisms of diabetic sensorimotor peripheral neuropathy (DSPN) and painful DSPN, originating both from the periphery and the central nervous system, and outlines the emerging diagnostics and treatments.

Key Points Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) are serious acute metabolic complications of diabetes mellitus, representing points along a spectrum of hyperglycaemic emergencies caused by poor glycaemic control DKA comprises hyperglycaemia, hyperketonaemia and metabolic acidosis; diagnostic criteria for HHS include a plasma glucose level >33.3 mmol/l, serum osmolality >320 mmol/kg and no appreciable metabolic acidosis and ketonaemia Management objectives for DKA and HHS include restoration of circulatory volume and tissue perfusion; correction of hyperglycaemia, ketogenesis and electrolyte imbalance; and identification and treatment of the precipitating event Hypoglycaemia is defined as a blood glucose level <3.9 mmol/l in both the inpatient and outpatient settings Severe hypoglycaemic events can negate the beneficial effects of intensive glycaemic management strategies that target near normoglycaemia among patients with diabetes mellitus Patient and family education regarding the signs and symptoms of hypoglycaemia, as well as the methods available for treatment, can effectively reduce the risk of severe hypoglycaemic episodes Diabetic ketoacidosis, hyperglycaemic osmolar state and hypoglycaemia are serious complications of diabetes mellitus. Here, Guillermo Umpierrez and Mary Korytkowski discuss the clinical presentation, precipitating causes, diagnosis and acute management of these diabetic emergencies and suggest practical strategies for their prevention. Diabetic ketoacidosis (DKA), hyperglycaemic hyperosmolar state (HHS) and hypoglycaemia are serious complications of diabetes mellitus that require prompt recognition, diagnosis and treatment. DKA and HHS are characterized by insulinopaenia and severe hyperglycaemia; clinically, these two conditions differ only by the degree of dehydration and the severity of metabolic acidosis. The overall mortality recorded among children and adults with DKA is <1%. Mortality among patients with HHS is ∼10-fold higher than that associated with DKA. The prognosis and outcome of patients with DKA or HHS are determined by the severity of dehydration, the presence of comorbidities and age >60 years. The estimated annual cost of hospital treatment for patients experiencing hyperglycaemic crises in the USA exceeds US$2 billion. Hypoglycaemia is a frequent and serious adverse effect of antidiabetic therapy that is associated with both immediate and delayed adverse clinical outcomes, as well as increased economic costs. Inpatients who develop hypoglycaemia are likely to experience a long duration of hospital stay and increased mortality. This Review describes the clinical presentation, precipitating causes, diagnosis and acute management of these diabetic emergencies, including a discussion of practical strategies for their prevention.

Primary diabetes care and diabetic retinopathy (DR) screening persist as major public health challenges due to a shortage of trained primary care physicians (PCPs), particularly in low-resource settings. Here, to bridge the gaps, we developed an integrated image–language system (DeepDR-LLM), combining a large language model (LLM module) and image-based deep learning (DeepDR-Transformer), to provide individualized diabetes management recommendations to PCPs. In a retrospective evaluation, the LLM module demonstrated comparable performance to PCPs and endocrinology residents when tested in English and outperformed PCPs and had comparable performance to endocrinology residents in Chinese. For identifying referable DR, the average PCP’s accuracy was 81.0% unassisted and 92.3% assisted by DeepDR-Transformer. Furthermore, we performed a single-center real-world prospective study, deploying DeepDR-LLM. We compared diabetes management adherence of patients under the unassisted PCP arm ( n  = 397) with those under the PCP+DeepDR-LLM arm ( n  = 372). Patients with newly diagnosed diabetes in the PCP+DeepDR-LLM arm showed better self-management behaviors throughout follow-up ( P  < 0.05). For patients with referral DR, those in the PCP+DeepDR-LLM arm were more likely to adhere to DR referrals ( P  < 0.01). Additionally, DeepDR-LLM deployment improved the quality and empathy level of management recommendations. Given its multifaceted performance, DeepDR-LLM holds promise as a digital solution for enhancing primary diabetes care and DR screening. Tailored to provide diabetes management recommendations from large training and validation datasets, an artificial intelligence system integrating language and computer vision capabilities is shown to improve self-management of patients in a prospective implementation study.

Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus — type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK–eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.Understanding the mechanisms behind β-cell failure in diabetes mellitus is critical to prevent or revert disease. This Review highlights new findings from studies performed on human β-cells or on samples obtained from patients with type 1 or type 2 diabetes mellitus.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1 . However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes 2 , 3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs 4 . This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes. Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.

Women with pre-existing (type 1 or type 2) diabetes mellitus are at increased risk of pregnancy complications, such as congenital malformations, preeclampsia and preterm delivery, compared with women who do not have diabetes mellitus. Approximately half of pregnancies in women with pre-existing diabetes mellitus are complicated by fetal overgrowth, which results in infants who are overweight at birth and at risk of birth trauma and, later in life, the metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus. Strict glycaemic control with appropriate diet, use of insulin and, if necessary, antihypertensive treatment is the cornerstone of diabetes mellitus management to prevent pregnancy complications. New technology for managing diabetes mellitus is evolving and is changing the management of these conditions in pregnancy. For instance, in Europe, most women with pre-existing diabetes mellitus are treated with insulin analogues before and during pregnancy. Furthermore, many women are on insulin pumps during pregnancy, and the use of continuous glucose monitoring is becoming more frequent. In addition, smartphone application technology is a promising educational tool for pregnant women with diabetes mellitus and their caregivers. This Review covers how modern diabetes mellitus management with appropriate diet, insulin and antihypertensive treatment in patients with pre-existing diabetes mellitus can contribute to reducing the risk of pregnancy complications such as congenital malformations, fetal overgrowth, preeclampsia and preterm delivery.Women with pre-existing diabetes mellitus are at increased risk of complications during pregnancy. This Review outlines the latest management strategies that have been designed to reduce this risk, including diet and pharmacotherapy options.

Key Points Hepatic glucose metabolism encompasses several catabolic and anabolic fluxes that have distinct modes of hepatocyte-autonomous (direct) and hepatocyte- non-autonomous (indirect) regulatory mechanisms Acute regulation of hepatic glucose metabolism is achieved through changes in protein phosphorylation, substrate availability, allostery and redox state Chronic regulation of hepatic glucose metabolism occurs through transcriptional mechanisms and the development of insulin resistance Acute suppression of hepatic gluconeogenesis by insulin is largely an indirect effect that is mediated mostly through the suppression of adipose lipolysis, which reduces delivery of nonesterified fatty acids and glycerol to the liver The major direct effect of insulin on hepatic glucose metabolism is the acute regulation of hepatic glycogen metabolism; however, hyperglycaemia and hyperinsulinaemia are required to maximally stimulate net hepatic glycogenesis Lipid-induced hepatic insulin resistance, hyperglucagonaemia and excessive adipose lipolysis represent three pathophysiological processes that might be amenable to pharmacological intervention in humans who have impaired hepatic glucose metabolism The balance of catabolic and anabolic glucose fluxes in the liver is crucial for glucose homeostasis and is disturbed in diabetes mellitus. In this Review, the authors discuss progress in our understanding of the regulation of hepatic glucose metabolism and highlight potential therapeutic targets for decreasing hepatic glucose production in T2DM, including lipid-induced hepatic insulin resistance, hyperglucagonaemia and excessive adipose lipolysis. The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.