Insulin resistance, a hallmark of type 2 diabetes, accelerates muscle breakdown and impairs energy metabolism. However, the role of Ubiquitin Specific Peptidase 2 (USP2), a key regulator of insulin resistance, in sarcopenia remains unclear. Peroxisome proliferator activated receptor γ (PPARγ) plays a critical role in regulating muscle atrophy. This study investigates the role of deubiquitinase USP2

Increasing evidence suggests that individuals infected with Coronavirus disease 2019 (COVID-19) are at a higher risk of developing type 2 diabetes (T2D) compared to those who are not infected. However, the mechanisms underlying this relationship remain poorly understood. In this study, we aimed to systematically evaluate the mediating roles of 3,283 plasma proteins in the link between COVID-19 susceptibility

PPARγ is the pharmacological target of thiazolidinediones (TZDs), potent insulin sensitizers that prevent metabolic disease morbidity but are accompanied by side effects such as weight gain, in part due to non-physiological transcriptional agonism. Using high throughput genome engineering, we targeted nonsense mutations to every exon of PPARG, finding an ATG in Exon 2 (chr3:12381414, CCDS2609 c.A403)

Many cell types are involved in the regulation of cutaneous wound healing in diabetes. Clarifying the mechanism of cell-cell interactions is important for identifying therapeutic targets for diabetic cutaneous ulcers. The function of vascular endothelial cells in the cutaneous microenvironment is critical, and a decrease in their biological function leads directly to refractory wound healing. In this

The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters

Endurance exercise is widely recognized for its role in mitigating insulin resistance, yet the precise mechanisms remain unclear. In this Classics in Diabetes article, we revisit the article by Amati et al., “Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance: Another Paradox in Endurance-Trained Athletes?” Published in the October 2011 issue of Diabetes, this article

Diabetes mellitus (DM) leads to a more rapid development of DM cardiomyopathy (dbCM) and progression to heart failure in women than men. Combination of high-fat diet (HFD) and freshly-injected streptozotocin (STZ) has been widely used for DM induction, however emerging data shows that anomer-equilibrated STZ produces an early onset and robust DM model. We designed a novel protocol utilising a combination

Type 1 Diabetes (T1D) is an autoimmune disease mediated by autoreactive T cells. Our studies indicate that CD4 T cells reactive to Hybrid Insulin Peptides (HIPs) play a critical role in T cell-mediated beta-cell destruction. We have shown that HIPs form in human islets between fragments of the C-peptide and cleavage products of secretory granule proteins. To identify T cell specificities contributing

Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes than age- and sex-matched controls. Surprisingly, the impact of cisplatin on pancreatic islets has not been reported. Our study aimed to determine if mouse islet function

Clonal haematopoiesis of indeterminate potential (CHIP) is associated with macrovascular diseases, including coronary artery disease and stroke. However, the effects of CHIP on microvascular complication have not been evaluated in individuals with type 2 diabetes (T2D). This study included 20,712 T2D participants without prevalent diabetic microvascular complication (DMCs) and hematologic malignancy

Diabetic microvascular dysfunction is evidenced by disrupted endothelial cell junctions and increased microvascular permeability. However, effective strategies against these injuries remain scarce. In this study, the type 2 diabetes mouse model was established by high-fat diet combined with streptozotocin injection in Rnd3 endothelial- specific transgenic and knockout mice. Echocardiography was employed

Diabetes is a major risk factor for cardiovascular disease, but the molecular mechanisms underlying diabetic vasculopathy have been elusive. Here we report that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by rewiring the liver kinase B1 (LKB1) signaling from activating the adenosine monophosphate-activated protein kinase (AMPK) pathway to the p53

To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation

Adipocyte hypertrophy significantly contributes to insulin resistance and metabolic dysfunction. Our previous research established JMJD8 as a mediator of insulin resistance, noting its role in promoting adipocyte hypertrophy within an autonomous adipocyte context. Nevertheless, the precise mechanisms underlying this phenomenon remained elusive. In this study, we employed a proteomics approach to identify

Pancreatic cystic changes in adults are increasingly identified through advanced cross-sectional imaging. However, the impact of initial/intra-lobular epithelial remodeling on the local β-cell population remains unclear. In this study, we examined 10 human cadaveric donor pancreases (tail and body regions) via integration of stereomicroscopy, clinical H&E histology, and 3D immunohistochemistry, identifying

The aim of this work was to describe the DNA methylation signature and to identify genes associated with neuropathic pain in type 2 diabetes mellitus. We analyzed two independent diabetic neuropathy cohorts: PROPGER consisting of 72 painful and 67 painless patients recruited at the German Diabetes Center in Düsseldorf (DE), and PROPENG comprising 27 painful and 65 painless diabetic neuropathy patients

Circulating proteins may be promising biomarkers or drug targets. Leveraging genome-wide association studies of type 1 diabetes (18,942 cases and 501,638 controls of European ancestry) and circulating protein abundances (10,708 European ancestry individuals), Mendelian randomization analyses were conducted to assess the associations between circulating abundances of 1,560 candidate proteins and the

Individuals with type 2 diabetes are at high risk of postprandial falls in blood pressure (BP) (i.e., a reduction in systolic BP of ≥20mmHg, termed postprandial hypotension (PPH)), which increases the risk of falls and mortality. This study evaluated the effects of oral metformin on postprandial BP, heart rate (HR), glucagon-like peptide-1 (GLP-1) and gastric emptying (GE) in individuals with type

The role of the intrarenal renin-angiotensin system (iRAS) in diabetic kidney disease (DKD) progression remains unclear. In this study, we generated mice with renal tubule-specific deletion of angiotensinogen (Agt; RT-Agt-/-) in both Akita and streptozotocin (STZ)-induced mouse model of diabetes. Both Akita RT-Agt-/- and STZ-RT-Agt-/- mice exhibited significant attenuation of glomerular hyperfiltration

The COVID-19 pandemic has profoundly affected human health, yet the mechanisms underlying its impact on metabolic and vascular systems remain incompletely understood. Clinical evidence suggests that SARS-CoV-2 directly disrupts vascular homeostasis, with perfusion abnormalities observed in various tissues. The pancreatic islet, a key endocrine mini-organ reliant on its microvasculature for optimal

There is an increasing need for new biomarkers improving prediction of chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D). We aimed to identify blood-based epigenetic biomarkers associated with incident CKD and develop a methylation risk score (MRS) predicting CKD in newlydiagnosed individuals with T2D. DNA methylation was analysed epigenome-wide in blood from 487 newly-diagnosed

Advances in fundus imaging are revealing disruptions in the neurovascular unit in diabetic retinopathy (DR). In the era of anti-VEGF treatment, a thorough characterization of neurodegeneration is imperative until DR patients are sufficiently cured. Here we demonstrate that extracellular mitochondria exacerbate retinal pigment epithelium (RPE) degeneration and inflammation in DR. Extracellular mitochondria

Loss-of-function (LOF) mutations in KATP channels cause hyperexcitability and insulin hypersecretion, resulting in congenital hyperinsulinism (CHI). Paradoxically, despite the initial insulin hypersecretion, many CHI cases, as well as KATP knockout (KO) animals, eventually ‘crossover’ to undersecretion and even diabetes. Here we confirm that Sur1 KO islets exhibit higher intracellular [Ca2+] ([Ca2+]i)

Lipedema is a lipodystrophic disease that is typically characterized by a marked increase in lower-body subcutaneous adipose tissue that is purported to have increased inflammation and fibrosis, impaired microvascular/lymphatic circulation and to be resistant to reduction by weight loss therapy. However, these outcomes have not been adequately studied. We evaluated body composition, insulin sensitivity

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant

Transplanted islet functional β-cell mass is measured by the β-cell secretory capacity derived from the acute insulin response to glucose-potentiated arginine (AIRpot), however, data are limited beyond one-year post-transplant for individuals with type 1 diabetes. We evaluated changes in β-cell secretory capacity in a single-center longitudinal analysis and examined relationships with measures of islet

The biomarkers connecting obesity and cardiometabolic diseases are not fully understood. We aimed to (i) evaluate the associations between body mass index (BMI), waist circumference (WC), and ∼5,000 plasma proteins (SomaScan v4), (ii) identify protein signatures of BMI and WC, and (iii) evaluate the associations between the protein signatures and cardiometabolic health including metabolically unhealthy

The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout mice are unexpectedly protected from

Murine pancreatic endocrinogenesis has been extensively studied, but human data remain scarce due to limited sample availability. Here, we first built a large collection of human embryonic and fetal pancreases covering the first trimester of pregnancy to explore human endocrinogenesis. Using an experimental pipeline combining in toto staining, tissue clearing, and light-sheet fluorescence microscopy

Glucose tolerance improves significantly upon consuming a second, identical meal later in the day (second meal phenomenon). We previously established that morning hyperinsulinemia primes the liver for increased afternoon hepatic glucose uptake (HGU). Although the route of insulin delivery is an important determinant of the mechanisms by which insulin regulates liver glucose metabolism (direct hepatic

Thermogenesis of brown adipose tissues (BAT) provides metabolic benefits against pathological conditions such as Type 2 diabetes, obesity, cardiovascular diseases, and cancer. The thermogenic function of BAT relies on mitochondria, but whether mitochondrial remodeling is required for the beneficial effects of BAT remains unclear. We have recently identified FAM210A as a BAT-enriched mitochondrial protein

Glucose-stimulated beta-cells exhibit synchronized calcium dynamics across the islet that recruit beta-cells to enhance insulin secretion. Compared to calcium dynamics, the formation and cell-to-cell propagation of electrical signals within the islet are poorly characterized. To determine factors that influence the propagation of electrical activity across the islet underlying calcium oscillations

The gold standard for assessing the function of human islets or β-like cells derived from stem cells involves their engraftment under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment of severely immunodeficient mice or the NRG-Akita strain are limited due to unstable and variable hyperglycemia and/or high morbidity of these models. To

Dysregulation and loss of immune tolerance towards pancreatic β-cell autoantigens are features of type 1 diabetes (T1D). Until recently, life-long insulin injection was the only approved treatment for T1D, and this does not address the underlying disease pathology. Antigen-specific immunotherapy (ASI) seeks to restore tolerance and holds potential as a new therapeutic strategy for treating autoimmune

Human embryonic stem cell (hESC)-derived pancreatic alpha and beta cells can be used to develop cell replacement therapies to treat diabetes. However, recent published differentiation protocols yield varying amounts of alpha and beta cells amidst heterogeneous cell populations. To visualize and isolate hESC-derived alpha and beta cells, we generated a GLUCAGON-2AmScarlet and INSULIN-2A-EGFP dual fluorescent

The obesity diagnosis by body mass index (BMI) exhibits considerable interindividual heterogeneity in metabolic phenotypes and risk of developing type 2 diabetes (T2D). We investigated the association of proteomic signature of BMI and T2D and examined whether the proteomic signature of BMI improves prediction of T2D risk. This study included 41,427 adults in the UK Biobank who were free of T2D at baseline

Glucagon-like peptide 1 receptor (GLP-1R) agonists fail to reduce weight and improve glucose control in a sizable minority of people with type 2 diabetes. We hypothesized that stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by GLP-1R agonists, thus inducing cortisol secretion, could explain this unresponsiveness to GLP-1R agonists. To assess the effects of GLP-1R agonist treatment on the

Identified genetic loci for C-peptide and age at diagnosis (AAD) in individuals with type 1 diabetes (T1D) explain only a small proportion of their variation. Here, we aimed to perform large metagenome-wide association studies (GWAS) of C-peptide and AAD in T1D; and to identify the HLA allele/haplotypes associated with C-peptide and AAD. 7,252 and 7,923 European individuals with T1D were included in

Embedded in the Developmental Origins of Health and Disease hypothesis, maternal hyperglycemia in utero, from pre-existing diabetes or gestational diabetes mellitus, predisposes the offspring to excess adiposity and heightened risk of prediabetes and type 2 diabetes development. This transmission creates a vicious cycle increasing the presence of diabetes from one generation to another, leading to

Maternally inherited diabetes and deafness (MIDD) is a monogenic mitochondrial disorder caused by a pathogenic variant in the MT-TL1 gene encoding for a leucine transfer RNA. We propose a new hypothesis that explains how the MT-TL1 variant causes impaired glucose tolerance and diabetes in MIDD. We suggest that diabetes in MIDD primarily depends on a variable combination of insulin resistance and impaired

High-affinity islet autoantibodies predict type 1 diabetes in mice and humans and implicate germinal centers (GCs) in type 1 diabetes pathogenesis. T follicular helper (Tfh) cells are increased in type 1 diabetic individuals and alterations in Tfh-like cells in the peripheral blood predicted individual responses to abatacept. Tfh cells support GC responses and depend on the transcriptional repressor

Resolving metabolic heterogeneity in patients with type 2 diabetes mellitus (T2DM) gives them access to precision medicine. Despite ethnic diversity in pathophysiological processes in individuals with T2DM, studies on subtypes of diabetes related to clinical characteristics in Asians are insufficient. This study aims to identify metabolic patterns in middle-aged patients with T2DM in Republic of Korea

Roux-en-Y gastric bypass (RYGB) has been shown to inhibit β-cell apoptosis, but the underlying mechanisms are not yet fully understood. Cytochrome c oxidase subunit 6A2 (COX6A2) is expressed in β-cells. Here, we sought to investigate the role of COX6A2 in β-cell apoptosis, especially following RYGB. We found that RYGB significantly reduced β-cell apoptosis, accompanied by decreased COX6A2 expression

MG53 is predominantly expressed in striated muscles. The role of MG53 in diabetes mellitus has been gradually elucidated but is still full of controversy. Some reports have indicated that MG53 is upregulated in animal models with metabolic disorders, and that muscle-specific MG53 upregulation is sufficient to induce whole-body insulin resistance and metabolic syndrome through targeting both the insulin

Shared medical appointments (SMAs) for diabetes and group prenatal care (GPC) for pregnant patients, have emerged as innovative care delivery models. They have the potential to transform diabetes care by overcoming many of the time limitations of traditional one-on-one clinical visits. There is compelling evidence that SMAs improve glycemic control for non-pregnant patients with diabetes, GPC reduces

Small glycemic increments (≤0.5 mmol/L) can exert suppressive actions on endogenous glucose production (EGP) however it is unclear if this is an insulin dependent or independent process. Here, we performed a low-rate glucose infusion in control participants without diabetes and in people with type 1 diabetes (T1D) to better understand this phenomenon. Glucose kinetics, hormones and metabolites were

Smoking is widely regarded as a risk factor for type 2 diabetes, as nicotine contributes to insulin resistance by desensitizing the insulin receptors in muscle, liver, or fat. Little is known, however, about the immediate regulation of islet hormonal output by nicotine, an agonist of ionotropic cholinergic receptors. We investigated this by imaging cytosolic Ca2+ dynamics in mouse and human islets

Diabetic vasculopathy, encompassing complications such as diabetic retinopathy, represents a significant source of morbidity, with inflammation playing a pivotal role in the progression of these complications. This study investigates the influence of m6A modification and the m6A demethylase FTO on macrophage polarization and its subsequent effects on diabetic microvasculopathy. We found that diabetes

Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomics, we profiled the transcriptional

Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the

Diabetic keratopathy (DK) is a common chronic metabolic disorder that causes ocular surface complications. Among various therapeutic approaches, local delivery of nerve growth factor (NGF) remains the most effective treatment for DK. However, achieving a sustained therapeutic effect with NGF and the frequent drug delivery burden remain challenging during clinical practice. Here, we developed a novel

We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction ≤50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma β-OH-B concentration throughout the physiologic

Immediate early response 3 interacting-protein 1 (IER3IP1) is an endoplasmic reticulum resident protein, highly expressed in pancreatic cells and the developing brain cortex. Homozygous mutations in IER3IP1 have been found in individuals with microcephaly and neonatal diabetes, yet the underlying mechanism causing beta cell failure remains unclear. Here, we utilized differentiation of genome edited-stem

Incidences of childhood obesity and type 2 diabetes (T2D) are climbing at alarming rates. Evidence points to prenatal exposures to maternal obesity and gestational diabetes mellitus (GDM) as key contributors to these upward trends. Children born to mothers with these conditions face higher risks of obesity and T2D, beyond genetic or shared environmental factors. The underpinnings of this maternal-fetal

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects

Early, intensive glycemic control in T2D patients is associated with long-term benefits on cardiovascular disease (CVD) development. Evidence on benefits of achieving HbA1c targets close to normal values is scant. Subjects with newly-diagnosed T2D, without CVD at baseline, were identified in an Italian clinical registry (N=251,339). We adopted three definitions of early exposure periods (0–1, 0–2 and

Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging

There is evidence that 1-h plasma glucose (PG) during the 75-g oral glucose tolerance test (OGTT) is superior to 2-h PG in predicting diabetes. We aimed to investigate the characteristics of insulin sensitivity and β-cell function behind this observation. After age, sex and BMI matching, 496 subjects selected from 3965 non-diabetic individuals at high risk of type 2 diabetes in a tertiary medical center

The Ventromedial hypothalamic nucleus (VMN) maintains healthy metabolic function through several important roles. Collectively, homeostasis is maintained via intermingled cells within the VMN that raise blood glucose, lower blood glucose, and stimulate energy expenditure when needed. This perspective discusses the defining factors for the VMN cell types that govern distinct functions induced by the

Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization