The last two decades have witnessed an explosion of interest in adipocyte biology, coinciding with the upsurge of obesity and metabolic syndrome. Now we have new perspectives on the distinct developmental origins of white, brown, and beige adipocytes and their role in metabolic physiology and disease. Beyond fuel metabolism, adipocytes communicate with the immune system and other tissues by releasing diverse paracrine and endocrine factors to orchestrate adipose tissue remodeling and maintain systemic homeostasis. Significant progress has been made in delineating the regulatory networks that govern different aspects of adipocyte biology. Here we provide an overview on the emerging role of long noncoding RNAs (lncRNAs) in the regulation of adipocyte development and metabolism and discuss the implications of the RNA-protein regulatory interface in metabolic control.

The twin epidemics of obesity and type 2 diabetes (T2D) are a serious health, social, and economic issue. The dysregulation of adipose tissue biology is central to the development of these two metabolic disorders, as adipose tissue plays a pivotal role in regulating whole-body metabolism and energy homeostasis (1). Accumulating evidence indicates that multiple aspects of adipose biology are regulated, in part, by epigenetic mechanisms. The precise and comprehensive understanding of the epigenetic control of adipose tissue biology is crucial to identifying novel therapeutic interventions that target epigenetic issues. Here, we review the recent findings on DNA methylation events and machinery in regulating the developmental processes and metabolic function of adipocytes. We highlight the following points: 1) DNA methylation is a key epigenetic regulator of adipose development and gene regulation, 2) emerging evidence suggests that DNA methylation is involved in the transgenerational passage of obesity and other metabolic disorders, 3) DNA methylation is involved in regulating the altered transcriptional landscape of dysfunctional adipose tissue, 4) genome-wide studies reveal specific DNA methylation events that associate with obesity and T2D, and 5) the enzymatic effectors of DNA methylation have physiological functions in adipose development and metabolic function.

Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ≥1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ≤ 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.

Diabetic kidney disease (DKD) is now the principal cause of chronic kidney disease leading to end-stage kidney disease worldwide. As a primary contributor to the excess risk of all-cause and cardiovascular death in diabetes, DKD is a major contributor to the progressively expanding global burden of diabetes-associated morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a newer class of antihyperglycemic agents that exert glucose-lowering effects via glycosuric actions. Preclinical studies and clinical trials of SGLT2 inhibitors have consistently demonstrated reduction of albuminuria and preservation of kidney function. In particular, SGLT2 inhibitors lower risk of congestive heart failure, a major cardiovascular complication in DKD. This Perspective summarizes proposed mechanisms of action for SGLT2 inhibitors, integrates these data with results of recent cardiovascular outcomes trials, and discusses clinical applications for patients with DKD. The American Diabetes Association/European Association for the Study of Diabetes Consensus Report published online in October 2018 recommends SGLT inhibitors as preferred add-on therapy for patients with type 2 diabetes and established cardiovascular disease or chronic kidney disease, if kidney function is adequate. Results of the ongoing and just completed clinical trials conducted in patients with established DKD will facilitate further refinement of current guidelines.

Diabetic retinopathy remains the leading cause of acquired blindness in working-age adults. While the cutting-edge research in the field has identified many molecular, functional, and structural abnormalities, the exact molecular mechanism of this devastating disease remains obscure. Diabetic environment drives dysfunction of the power generator of the cell and disturbs the homeostasis of mitochondrial dynamic. Mitochondrial DNA (mtDNA) is damaged, the transcription of mtDNA-encoded genes is impaired, and the electron transport chain is compromised, fueling into a vicious cycle of free radicals. The hyperglycemic milieu also alters the epigenetic machinery, and mtDNA and other genes associated with mitochondrial homeostasis are epigenetically modified, further contributing to the mitochondrial damage. Thus, mitochondria appear to have a significant role in the development of diabetic retinopathy, and unraveling the mechanism responsible for their damage as well as the role of epigenetic modifications in mitochondrial homeostasis should identify novel therapeutic targets. This will have a major impact on inhibiting/halting diabetic retinopathy and preventing the loss of vision.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem.

Childhood obesity and its comorbidities continue to accelerate across the globe. Two-thirds of pregnant women are obese/overweight, as are 20% of preschoolers. Gestational diabetes mellitus (GDM) is escalating, affecting up to 1 in 5 pregnant women. The field of developmental origins of health and disease has begun to move beyond associations to potential causal mechanisms for developmental programming. Evidence across species compellingly demonstrates that maternal obesity, diabetes, and Western-style diets create a long-lasting signature on multiple systems, including infant stem cells, the early immune system, and gut microbiota. Such exposures accelerate adipogenesis, disrupt mitochondrial metabolism, and impair energy sensing, affecting neurodevelopment, liver, pancreas, and skeletal muscle. Attempts to prevent developmental programming have met with very limited success. A challenging level of complexity is involved in how the host genome, metabolome, and microbiome throughout pregnancy and lactation increase the offspring's risk of metabolic diseases across the life span. Considerable gaps in knowledge include the timing of exposure(s) and permanence or plasticity of the response, encompassing effects from both maternal and paternal dysmetabolism. Basic, translational, and human intervention studies targeting pathways that connect diet, microbiota, and metabolism in mothers with obesity/GDM and their infants are a critical unmet need and present new challenges for disease prevention in the next generation.

Hyperinsulinemia is the hallmark of insulin resistance in obesity, and the relative importance of insulin clearance, insulin resistance, and insulin hypersecretion has been widely debated. On the basis of recent experimental evidence, we summarize existing evidence to suggest hepatic insulin clearance as a major and immediate regulator of systemic insulin concentrations responding within days to altered dietary energy and, in particular, carbohydrate intake. Hepatic insulin clearance seems to be closely associated with opposite alterations in hepatic lipid content and glucose production, providing a potential mechanistic link to hepatic insulin sensitivity. The molecular regulation of insulin clearance in the liver is likely to involve changes in insulin binding and receptor internalization in response to the dietary alterations, the molecular mechanisms of which await further research.

Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that 1) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle; 2) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and 3) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation.

Bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective interventions available for sustained weight loss and improved glucose metabolism. Bariatric surgery alters the enterohepatic bile acid circulation, resulting in increased plasma bile levels as well as altered bile acid composition. While it remains unclear why both VSG and RYGB can alter bile acids, it is possible that these changes are important mediators of the effects of surgery. Moreover, a molecular target of bile acid synthesis, the bile acid-activated transcription factor FXR, is essential for the positive effects of VSG on weight loss and glycemic control. This Perspective examines the relationship and sequence of events between altered bile acid levels and composition, FXR signaling, and gut microbiota after bariatric surgery. We hypothesize that although bile acids and FXR signaling are potent mediators of metabolic function, unidentified downstream targets are the main mediators behind the benefits of weight-loss surgery. One of these targets, the gut-derived peptide FGF15/19, is a potential molecular and therapeutic marker to explain the positive metabolic effects of bariatric surgery. Focusing research efforts on identifying these complex molecular mechanisms will provide new opportunities for therapeutic strategies to treat obesity and metabolic dysfunction.

Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

Type 1 diabetes (T1D) arises from a failure to maintain tolerance to specific β-cell antigens. Antigen-specific immunotherapy (ASIT) aims to reestablish immune tolerance through the supply of pertinent antigens to specific cell types or environments that are suitable for eliciting tolerogenic responses. However, antigen-presenting cells (APCs) in T1D patients and in animal models of T1D are affected by a number of alterations, some due to genetic polymorphism. Combination of these alterations, impacting the number, phenotype, and function of APC subsets, may account for both the underlying tolerance deficiency and for the limited efficacy of ASITs so far. In this comprehensive review, we examine different aspects of APC function that are pertinent to tolerance induction and summarize how they are altered in the context of T1D. We attempt to reconcile 25 years of studies on this topic, highlighting genetic, phenotypic, and functional features that are common or distinct between humans and animal models. Finally, we discuss the implications of these defects and the challenges they might pose for the use of ASITs to treat T1D. Better understanding of these APC alterations will help us design more efficient ways to induce tolerance.

Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti-PD-1 or anti-PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti-PD-1 or -PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.

Diabetes is a complex group of metabolic disorders that can be accompanied by several comorbidities, including increased risk of early death. Decades of diabetes research have elucidated many genetic drivers of normal islet function and dysfunction; however, a lack of suitable treatment options suggests our knowledge about the disease remains incomplete. The establishment of long noncoding RNAs (lncRNAs), once dismissed as "junk" DNA, as essential gene regulators in many biological processes has redefined the central role for RNA in cells. Studies showing that misregulation of lncRNAs can lead to disease have contributed to the emergence of lncRNAs as attractive candidates for drug targeting. These findings underscore the need to reexamine islet biology in the context of a regulatory role for RNA. This review will 1) highlight what is known about lncRNAs in the context of diabetes, 2) summarize the strategies used in lncRNA discovery pipelines, and 3) discuss future directions and the potential impact of studying the role of lncRNAs in diabetes.

There is wide variation in the age at diagnosis of diabetes in individuals with maturity-onset diabetes of the young (MODY) due to a mutation in the HNF1A gene. We hypothesized that common variants at the HNF1A locus (rs1169288 [I27L], rs1800574 [A98V]), which are associated with type 2 diabetes susceptibility, may modify age at diabetes diagnosis in individuals with HNF1A-MODY. Meta-analysis of two independent cohorts, comprising 781 individuals with HNF1A-MODY, found no significant associations between genotype and age at diagnosis. However after stratifying according to type of mutation (protein-truncating variant [PTV] or missense), we found each 27L allele to be associated with a 1.6-year decrease (95% CI -2.6, -0.7) in age at diagnosis, specifically in the subset (n = 444) of individuals with a PTV. The effect size was similar and significant across the two independent cohorts of individuals with HNF1A-MODY. We report a robust genetic modifier of HNF1A-MODY age at diagnosis that further illustrates the strong effect of genetic variation within HNF1A upon diabetes phenotype.

Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of autoreactive T cells. Continued autoimmune activity leads to the destruction of pancreatic β-cells and loss of insulin secretion. Studies of samples from patients with type 1 diabetes and of murine disease models have generated important insights about genetic and environmental factors that contribute to susceptibility and immune pathways that are important for pathogenesis. However, important unanswered questions remain regarding the events that surround the initial loss of tolerance and subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve functional β-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic β-cells, their recognition by autoreactive T cells and antibodies, and potential roles for such responses in the pathology of disease. Emerging evidence supports the relevance of neoepitopes generated through processes that are mechanistically linked with β-cell stress. Together, these observations support a paradigm in which neoepitope generation leads to the activation of pathogenic immune cells that initiate a feed-forward loop that can amplify the antigenic repertoire toward pancreatic β-cell proteins.

Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.

The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.

Glucose tolerance after meal ingestion in vivo is the result of multiple processes that occur in parallel. Insulin secretion together with reciprocal inhibition of glucagon secretion contributes to glucose tolerance. However, other factors beyond glucose effectiveness and insulin action require consideration. The absorption of ingested nutrients and their subsequent systemic rate of appearance largely depend on the rate of delivery of nutrients to the proximal small intestine. This is determined by the integrated response of the upper gastrointestinal tract to a meal. While gastric emptying is probably the most significant component, other factors need to be considered. This review will examine all processes that could potentially alter the fraction and rate of appearance of ingested nutrients in the peripheral circulation. Several of these processes may be potential therapeutic targets for the prevention and treatment of diabetes. Indeed, there is increased interest in gastrointestinal contributions to nutritional homeostasis, as demonstrated by the advent of antidiabetes therapies that alter gastrointestinal motility, the effect of bariatric surgery on diabetes remission, and the potential of the intestinal microbiome as a modulator of human metabolism. The overall goal of this review is to examine current knowledge of the gastrointestinal contributions to metabolic control.