Gastrointestinal hormones are essential for nutrient handling and regulation of glucose metabolism and may affect postprandial blood redistribution. In a randomized cross-over design in 10 healthy men, the involvement of glucose-dependent insulinotropic polypeptide (GIP) in splanchnic blood flow regulation was investigated using an infusion of GIP receptor antagonist (GIPR-An) GIP(3-30)NH2 during ingestion

Circulating glucagon concentrations differ between individuals with no diabetes (ND) and those with type 1 diabetes (T1D). We combined isotope dilution technique using stable tracers [6,22 13C9, 15N1]-glucagon and [6,14,19,22 13C9, 15N1]-glucagon with splanchnic and leg catheterization in participants with ND (n = 8; age 23.1 ± 2.9 years, BMI 26.6 ± 3.5 kg/m2, HbA1c 5.0 ± 0.2% [31 ± 2 mmol/mol]) and

Intraportal islet transplantation to treat insulin-dependent diabetes has been clinically validated. However, the hypoxic environment and sinusoidal architecture of the liver are unsuitable for the long-term survival of transplanted islets, leading to the loss of therapeutic effects within 1 year. The spleen has oxygen levels that meet islet needs, but intense instant blood-mediated inflammatory reactions

Diabetic peripheral neuropathy (DPN) poses significant clinical challenges due to progressive nerve degeneration and vascular insufficiency. To address both neural and vascular complications simultaneously, we employed an mRNA-based protein replacement therapy. In this study, leveraging mRNA template design, structure-based screening identified NGFR100W as a variant dissociating neuroprotective and

Individuals with type 1 diabetes (T1D) or permanent neonatal diabetes (PND) due to an INS gene mutation (INS-PND) have a marked reduction in pancreas volume by MRI compared with control individuals with no diabetes (ND). One possible explanation for this is loss of islet-acinar insulin signaling in these forms of severe insulin deficiency. To test the hypothesis that insulin deficiency drives the loss

Glucokinase activators (GKA) are a long-sought therapeutic modality for the treatment of Type 2 Diabetes (T2D). However, all GKAs failed clinical trials, with the recent exception of dorzagliatin (Hua Medicine). A comprehensive approach using human islet perfusions, enzyme kinetics, x-ray crystallography, and modeling studies was applied to compare the effects of dorzagliatin with the failed GKA MK-0941

Pancreatic β-cell ATP-sensitive K+ (KATP) channel closure underlies electrical excitability and insulin release, but loss or inhibition of KATP channels can lead to paradoxical crossover from hyperinsulinism plus hypoglycemia, to glucose intolerance or diabetes. We report genotype-phenotype information from a set of patients clinically diagnosed with maturity-onset diabetes of the young (MODY) and

Accurate measurement of GLUT4 translocation is crucial for understanding insulin resistance in skeletal muscle, a key factor in the development of metabolic diseases. However, current methods rely on overexpressed epitope-tagged GLUT4 constructs or indirect measurements, limiting their physiological relevance and applicability. To overcome these challenges, we developed an innovative high-sensitivity

We tested genetic variants in GCK, GCKR, and PNPLA3 for association with type 2 diabetes-related phenotypes under the hypothesis they may regulate metabolic balance across the liver and contribute to hepatic steatosis and insulin resistance in a large sample of self-identified Mexican Americans from the BetaGene Study. We further tested whether interactions with dietary fructose and total sugar contributes

Diabetes is a metabolic disorder associated with an increased risk of systemic vascular complications. Notably, diabetic retinopathy (DR) represents a major microvascular complication and a leading cause of blindness and vision impairment. Despite its clinical significance, the precise molecular mechanisms underlying vascular dysfunction and the associated metabolic disturbances in DR remain incompletely

We aimed to identify distinct axes of obesity using advanced MRI-derived phenotypes. We used 24 MRI-derived fat distribution and muscle volume measures (UK Biobank, n= 33,122) to construct obesity axes through principal component analysis (PCA). Genome-wide association studies were performed for each axis to uncover genetic factors, followed by pathway enrichment, genetic correlation, and Mendelian

Islet cell replacement therapies have evolved as a viable treatment option for type 1 diabetes complicated by problematic hypoglycemia and glycemic lability. Refinements of islet manufacturing, islet transplantation procedures, peritransplant recipient management, and immunosuppressive protocols allowed most recipients to achieve favorable outcomes. Subsequent phase 3 trials of transplantation of deceased

The identification of a “rundlichen Häuflein” by Paul Langerhans more than 150 years ago marked the initiation of a global effort to unravel the mysteries of pancreatic islets, an intricate system of nutrient-sensing, hormone-secreting, and signaling cells. In type 1 diabetes, this interconnected network is vulnerable to malfunction and immune attack, with strategies to prevent or repair islet damage

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in individuals with diabetes. Individuals with type 1 diabetes have a two- to fourfold higher risk of CVD in comparison with the general population, driven by an earlier onset and increased lifetime incidence of CVD events and mortality. Similarly, type 2 diabetes confers two- to threefold increased CVD risk, usually alongside

This year marks the 75th anniversary of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health. NIDDK’s long history of research and innovation includes support of four types of collaborative research centers focused on diabetes, endocrinology, and metabolic diseases. The Diabetes Research Centers promote basic and clinical diabetes research

G protein-coupled receptor 35 (GPR35) is a poorly characterized receptor with unclear intracellular mechanisms in endothelial cells (ECs). Oxidative stress responsive 1 (OXSR1) is a serine/ threonine protein kinase that modulates cell morphology and has recently been found to promote angiogenesis. We hypothesized that GPR35 inhibition promotes EC angiogenesis via augmenting OXSR1 activity and accelerating

In this month’s Classics in Diabetes featured article, published in Diabetes in 1993, the description by Kahn et al. of the relationship between insulin secretion and insulin sensitivity in 93 healthy adults without diabetes provided a model for the regulation of glucose tolerance that continues to be used today. In the study, data from a large sample of individuals studied with intravenous glucose

Oxidative stress has a major pathogenic role in diabetic retinopathy, and neuroretina dysfunction is recognized as an early and important problem. Soluble guanylate cyclase (sGC) has been implicated for its neuroprotective effects in the central nervous system, but its role in the retina remains unclear. Here we demonstrated expression of sGC subunits GUCY1A1 and GUCY1B1 in healthy human and rodent

Obesity-induced biological changes often persist after weight loss and are difficult to reverse, a phenomenon known as ‘obesogenic memory’. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterise a mouse model of obesogenic memory and evaluate the efficacy of the unimolecular conjugate GLP-1/Dexa, which selectively and safely delivers

Obesity is a growing global health threat, and inducing browning of white adipose tissue (WAT) to increase energy expenditure has become an attractive strategy for treating obesity and related metabolic complications. BRCA1-associated protein 1 (BAP1), a ubiquitin C-terminal hydrolase (UCH) domain-containing deubiquitinase (DUB) expressed broadly across tissues, has previously been shown to play an

Wolfram Syndrome 1 (WS1) is a rare genetic disorder caused by WFS1 variants that disrupt Wolframin, an endoplasmic reticulum-associated protein essential for cellular stress responses, Ca2+ homeostasis, and autophagy. Here, we investigated how the c.316-1G>A and c.757A>T WFS1 mutations, which yield partially functional Wolframin, affect the molecular functions of β cells and explored the therapeutic

Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. It is generally defined as glucose intolerance with onset or first recognition during pregnancy. The pathogenesis of GDM has long been attributed to inadequate pancreatic β-cell compensation for the physiological insulin resistance of pregnancy. This defect is thought to resolve after pregnancy but become

By stimulating hepatic glucose production, glucagon (released by islet α-cells) restores normal blood glucose levels when they fall below the normal range. We used optogenetics in conjunction with electrophysiology, [Ca2+]i imaging and hormone release measurements to explore the intrinsic and paracrine regulation of glucagon secretion. Many α-cells were spontaneously active at 1mM glucose. However

Glycated haemoglobin (HbA1c) has shown disagreements with other glycaemic indices; termed the glycation gap. The glycation gap can be influenced by non-glycaemic factors like protein deglycation, through the fructosamine 3 kinase (FN3K) enzyme. This cross-sectional study aimed to examine whether single nucleotide polymorphisms (SNPs) in the FN3K gene can explain the glycation gap. Amongst the 826 participants

Intrahepatic islet transplantation is followed by islet loss due to instant blood-mediated inflammatory response (IBMIR), in which platelet activation plays a key role. The KEATSTF-fragment (KF7), a newly discovered platelet inhibitor that interferes with the formation of the 14-3-3z–c-Src–integrin-β3 complex, holds significant potential in inhibiting IBMIR without causing significant bleeding. This

Pathological signaling via the receptor for advanced glycation end-products (RAGE) is critical in diabetic kidney disease (DKD) development, while RAGE deletion is reno-protective. Non-coding RNAs (ncRNAs), including microRNAs (miRs), also play key roles in DKD, including renal fibrosis. However, the involvement of ncRNAs in RAGE signaling remains unclear. This study investigated the regulation of

Since little is known about the disposition index (DI) in autoantibody-positive individuals, we have assessed whether DI has a similar association between insulin secretion and resistance to the association observed in other populations. In TrialNet Pathway to Prevention (TNPTP; n=6620) and Diabetes Prevention Trial-Type 1 (DPT-1; n=704) study participants, two secretion-sensitivity pairs each representing

Activation of GPR119 receptors, expressed on enteroendocrine and pancreatic islet cells, augments glucagon counterregulatory responses to hypoglycemia in pre-clinical models. We hypothesized that MBX-2982, a GPR119 agonist, would augment counterregulatory responses to experimental hypoglycemia in participants with type 1 diabetes. To assess this, we designed a phase 2a double-masked, cross-over trial

G protein-coupled receptor 119 (GPR119) is predominantly expressed in pancreatic β-cells, enteroendocrine cells, and the liver. It is a novel therapeutic for dyslipidemia and type 2 diabetes. DA-1241, a GPR119 agonist, improves glucose tolerance by inhibiting gluconeogenesis and enhancing insulin secretion. It mitigates hepatic inflammation by inhibiting NFĸB signaling. However, the mechanism by which

Effective treatment strategies for diabetes-related pain are limited due to its complex pathogenesis, particularly brain mechanisms underlying this disease. The acid-sensing ion channel 1a (ASIC1a) emerges as a key player in the development and treatment of various types of pain. Here, we investigated the role of ASIC1a in diabetes-related pain and its molecular mechanisms in the anterior cingulate

Diabetes calls on thousands of scientific and medical experts each year to review manuscript submissions. The editors of Diabetes sincerely appreciate the efforts of all of our reviewers who volunteer their time and expertise to provide valuable feedback to ensure the consistently high quality of the research published in each issue. We would like to recognize the “top” reviewers—based on the number

Glucagon stimulates hepatic glucose production, in part by promoting the uptake and catabolism of amino acids. Inhibition of liver glucagon receptor (GCGR) results in elevated plasma amino acids, which triggers the proliferation of pancreatic alpha-cells, forming a liver-alpha cell loop. This study aims to delineate hepatic signaling molecules downstream of GCGR which mediate the liver-alpha cell loop

Diabetic patients are at an increased risk of diabetic cardiomyopathy (DCM) and acute myocardial infarction (AMI). Protecting the heart against AMI is more challenging in DCM than non-diabetic hearts. We investigated whether intravenous atorvastatin administration during AMI exerts cardioprotection in DCM as seen in non-diabetic hearts. Sprague-Dawley rats were divided into streptozotocin-induced DCM

Recent evidence has shown that adipose tissue eventually develops fibrosis through complex cellular crosstalk. Although advances in single-cell transcriptomics have provided new insights into cell diversity during this process, little is known about the interactions among the distinct cell types. In this study, we employed single-cell analytical approaches to investigate cell-tocell communications

HLA class I (HLA-I) molecules present intracellular antigenic peptides to CD8+ T lymphocytes during immune surveillance. In donors with type 1 diabetes, hyperexpression of HLA-I occurs in islets with residual insulin-producing β-cells as a hallmark of the disease. HLA-I hyperexpression is frequently detected beyond the islet boundary, forming a ‘halo’. We hypothesized that this halo may reflect the

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D. Fine mapping has demonstrated the most credible causative variant is the single nucleotide rs3184504*T polymorphism in SH2B3. To better characterize the role of

We aim to investigate the association between plasma angiogenin and the risk of progression to end-stage kidney disease (ESKD) in Type 2 Diabetes (T2D) patients and attempted to infer the causal relationship between plasma angiogenin and chronic kidney disease. A total of 1863 outpatients with T2D were included in this prospective cohort study. ESKD was defined as a composite of progression to sustained

Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes (T1D). To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that utilize diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained

Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning

Diabetic peripheral neuropathy (DPN) is a common diabetic complication with no currently available curative treatments. Here, we demonstrated that the protein level of G-protein-coupled receptor 40 (GPR40) is significantly repressed in the sciatic nerves (SN) of DPN patients, as well as in the peripheral nerves, including dorsal root ganglia (DRG) and SN, of streptozotocin (STZ)-induced type 1 diabetic

Revascularization strategies failed to improve outcome in diabetic (DM) patients with peripheral artery disease (PAD). Histone modifications are key modulators of gene expression and could play a role in angiogenic response. This study investigates the role of chromatin remodelling in modulating angiogenesis in DM. RNA sequencing (RNA-seq) and angiogenic assays (cell migration and tube formation) were

The association between KCNJ5 mutations and the risk of developing new-onset diabetes mellitus (NODM) in patients with unilateral primary aldosteronism (uPA) remains underexplored. To investigate this association, we conducted a longitudinal study using data from the Taiwan Primary Aldosteronism Investigation database. Our sample included 360 uPA patients with adrenalectomies between 2012 and 2017

Obesity in childhood is associated with adulthood obesity, type 2 diabetes (T2D), and future metabolic complications. The gut microbiome is a modifier of host metabolic function with altered bacterial composition associated with disease risk. Few studies have investigated the relationships between metabolic disease, inflammation and the gut microbiota in youth where these connections likely originate

The discovery and development of the radioimmunoassay (RIA) for insulin by Berson and Yalow fundamentally changed biomedical science. The story of this accomplishment began with the pairing of brilliant scientists with complementary expertise who identified a key gap in knowledge they were able to bridge through a series of insightful experiments. Through a succession of important publications over

The unfolded protein response (UPR) drives events that promote diabetic retinopathy including VEGF upregulation in Müller cells. How UPR is activated in vivo in the diabetic retina is not well understood. CD40 is required for development of diabetic retinopathy but whether CD40 mediates activation of UPR sensors is unknown. CD40 ligation in Müller cells caused phospholipase Cγ1 (PLCγ1)-dependent activation

Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO is a metabolite of glycolysis that causes pain hypersensitivity in mice by stimulating the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and subsequently activating the integrated stress response (ISR). We first established that Zucker Diabetic Fatty (ZDF) rats have enhanced MGO signaling

Microbial signals trigger the release of neutrophil extracellular traps (NETs) through peptidyl-arginine-deiminase-4 (PADI4). In turn, NETosis can propagate inflammation to distant tissues. We hypothesize that PADI4 mediates the interactions between diet-modified microbiota and host metabolism. We report that in the adipose tissue of individuals with obesity, NETosis was associated with dysglycemia

Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective treatment of severe diabetic retinopathy (DR) and macular edema, but a significant subset of people showed inadequate response to anti-VEGF intervention. Since elevation or overexpressing retinol binding protein 3 (RBP3) decreased risks for retinal pathologies and progression to severe DR, we compared the therapeutic profile

Sodium-glucose transporter-2 inhibitor (SGLT2i) drugs are widely used for lowering blood glucose levels independent of insulin. Beyond this, these drugs induce various metabolic changes, including weight loss and impaired bone integrity. There is a significant gap in understanding SGLT2i-induced skeletal changes, as SGLT2 is not expressed in osteoblasts or osteocytes, which use glucose to remodel the

There remained no head-to-head research to evaluate the cardiovascular and renal benefits of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM) at different baseline renal function. We performed a network meta-analysis to compare the two drugs indirectly. Systematic literature searches were conducted

Insulin regulates glucose uptake and metabolism in muscle via the insulin receptor. Here we show that Lrtm1 (Leucine Rich Repeats and Transmembrane Domains 1), a protein of unknown function enriched in insulin-responsive metabolic tissues, senses changes in insulin signaling in muscle and serves as a regulator of metabolic response. Thus, whole-body Lrtm1 deficient mice exhibit a reduced the percentage

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function

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