In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived

Improved β-cell function seems to be essential for better glucose homeostasis after Roux-en-Y gastric bypass but is less studied after sleeve gastrectomy (SG). We evaluated the effects of SG on β- cell function in obese patients with diabetes (DM group) and without (Control group) in response to both oral and intravenous glucose stimulation. The DM group demonstrated impaired insulin sensitivity and

The mechanisms accounting for the functional changes of α- and β-cells over the course of Type 1 Diabetes (T1D) development are largely unknown. Permitted by our established technology of high spatiotemporal resolution imaging of cytosolic Ca2+ ([Ca2+]c) dynamics on fresh pancreas tissue slices, we tracked the [Ca2+]c dynamic changes, as the assessment of function, in islet α- and β-cells of female

Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM)

The induction of beige adipocytes in white adipose tissue, also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of Mettl3 gene undermines

Lactate is an important metabolic substrate for sustaining brain energy requirements when glucose supplies are limited. Recurring exposure to hypoglycemia (RH) raises lactate levels in the ventromedial hypothalamus (VMH) which contributes to counter-regulatory failure. However, the source of this lactate remains unclear. The present study investigates whether astrocytic glycogen serves as the major

The loss of pancreatic β-cell identity emerges as an important feature of type 2 diabetes development, but the molecular mechanisms are still elusive. Here, we explore the cellautonomous role of the cell cycle regulator and transcription factor E2F1 in the maintenance of β-cell identity, insulin secretion and glucose homeostasis. We show that the β-cell-specific loss of E2f1 function in mice triggers

Obesity is a global health threat, and the induction of white adipose tissue (WAT) browning presents a promising therapeutic method for it. Recent publications revealed the essential role of protein arginine methyltransferase 4 (PRMT4) in lipid metabolism and adipogenesis, but its involvement in WAT browning has not been investigated. Our initial studies found that the expression of PRMT4 in adipocytes

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic beta cells that produce insulin. The latest advances in stem cell (SC)-beta cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC-beta cells. A promising strategy to overcome immune rejection is to genetically engineer SC-beta

Diabetes is characterized by elevation of plasma glucose due to an insufficiency of the hormone insulin and is associated with both inadequate insulin secretion and impaired insulin action. The Banting Medal for Scientific Achievement Commemorates the work of Sir Frederick Banting, a member of the team that first used insulin to treat a patient with diabetes almost exactly one hundred years ago on

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance

In Table 2 of the article cited above, the univariable MR analyses for microalbuminuria were erroneously cited as inverse variance weighted analyses. The row headings in Table 2 have been revised to show the correct analyses performed: MR-Egger, weighted median and mode, and simple mode analyses. In Fig. 3, the confidence intervals were erroneously plotted as error bars. Fig. 3 has been updated with

The advanced cessation of lactation elevates the risk of programmed obesity and obesity-related metabolic disorders in adulthood. The study used multi-omics analysis to investigate the mechanism behind this phenomenon and the effects of leucine supplementation on ameliorating programmed obesity development. Wistar/SD rat offspring were subjected to early weaning (EW) at d 17 (EWWIS and EWSD groups)

In the original version of the article cited above, there are two confirmed instances of duplication.In Fig. 3A, the bottom left (siPrkaα1-exo) and top right (siCtr/PA-exo) panels were duplicates.In Supplementary Fig. 8A, the bottom left corner of the “Metformin −/AMPKα1fl/fl” panel and the “Metformin +/AMPKα1−/−” panel were identical. The corresponding author of the article contacted the journal to

Sphingolipids are thought to promote skeletal muscle insulin resistance. 1-Deoxysphingolipids (dSL) are atypical sphingolipids that are increased in plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle in unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and

In the article cited above, the affiliations for authors Stephen J. Pandol and Maike Sander were inadvertently transposed. The correct affiliation for Stephen J. Pandol is Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA. The correct affiliation for Maike Sander is Department of Pediatrics and Department of Cellular and Molecular Medicine, University of California San Diego

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance

Sphingolipids are thought to promote skeletal muscle insulin resistance. 1-Deoxysphingolipids (dSL) are atypical sphingolipids that are increased in plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle in unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared

Serum apolipoprotein C3 (APOC3) predicts incident cardiovascular events in people with type 1 diabetes and silencing of APOC3 prevents both lesion initiation and advanced lesion necrotic core expansion in a mouse model of type 1 diabetes. APOC3 acts by slowing the clearance of triglyceride-rich lipoproteins, but lipid-free APOC3 has recently been reported to activate an inflammasome pathway in monocytes

Diabetic retinopathy (DR) is a common complication in patients with diabetes, and PDR has become an important cause of blindness; however, the mechanisms involved have not been fully elucidated. Long noncoding RNAs (lncRNAs) and microRNAs can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: competing endogenous RNAs (ceRNAs)

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carried pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity, using an inhouse computational staged approach. This included analysis of whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals

The glucose homeostasis system ensures that the circulating glucose level is maintained within narrow physiological limits both in the fasting (or basal) state and following a nutrient challenge. Although glucose homeostasis is traditionally conceptualized as a single overarching system, evidence reviewed here suggests that basal glycemia and glucose tolerance are governed by distinct control systems

Inflammation-induced vascular insulin resistance is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise and glucagon-like peptide 1 (GLP-1) receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development, we performed a euglycemic insulin clamp in adult male rats after 2 weeks of high-fat

The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated

In the article cited above, there was inadvertent echocardiographic image overlap between Fig. 2A and Fig. 6B due to errors during image processing. The correct Fig. 6B is shown below. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db11-0549) has been updated with the correct figure.

In the article cited above, due to a coding error, the RNA-Seq heat map in Fig. 3C displayed the first 100 genes in chromosomal order rather than the top 100 most significant genes expressed. The correct RNA-Seq heat map, shown below, accurately represents the 100 most significant genes in the RNA-Seq analysis, clustered according to gene expression value. This correction does not change any of the

Intrahepatic transplantation of islets of Langerhans (ITx) is a treatment option for individuals with complicated type 1 diabetes and profoundly unstable glycemic control, but its therapeutic success is hampered by deterioration of graft function over time. To improve ITx strategies, technologies to non-invasively monitor the fate and survival of transplanted islets over time, are of great potential

Alterations in the resting state functional connectivity and hyperperfusion of pain processing areas of the brain have been demonstrated in painful-Diabetic Peripheral Neuropathy (DPN). However, the mechanisms underlying these abnormalities are poorly understood. There is thus a good rationale to explore if there is higher energy consumption in the pain processing areas of the brain. We performed a

Endothelial cell (EC) activation is a crucial determinant of retinal vascular inflammation associated with diabetic retinopathy (DR), a major microvascular complication of diabetes. We previously showed that, similar to abnormal biochemical factors, aberrant mechanical cues in the form of lysyl oxidase (LOX)-dependent subendothelial matrix stiffening also contribute significantly to retinal EC activation

Insulin resistance and hyperglycemia are risk factors for periodontitis and poor wound healing in diabetes, which have been associated with selective loss of insulin- activation of the PI3K/Akt pathway in the gingiva. This study showed that insulin resistance in the mouse gingiva due to selective deletion of smooth muscle and fibroblast insulin receptor (SMIRKO mice) or systemic metabolic changes induced

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-alpha (PPARα), has shown robust therapeutic effects on DR in type 2 diabetic patients. Here we found that PPARα levels were significantly down-regulated

Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepidermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a non-invasive diagnostic modality for DPN. Direct comparisons of skin biopsy and IVCM in controlled cohorts are lacking, while

In the article cited above, the nomenclature for a novel long noncoding RNA (lncRHL, regulator of hyperlipidemia) was similar to that used for a novel long noncoding RNA in the 2021 Cell Proliferation article below (lnc-RHL, regulator of hepatic lineages). Prabhakar B, Lee S, Bochanis A, He W, Manautou JE, Rasmussen TP. lnc-RHL, a novel long non-coding RNA required for the differentiation of hepatocytes

Youth onset type 2 diabetes (T2D) is becoming increasingly prevalent especially among Latinos, and there is limited information on its pathophysiology and causative factors. Here we describe findings from a longitudinal cohort study in 262 Latino children with overweight/obesity at risk of developing T2D with annual measures of oral and intravenous glucose tolerance (IVGTT), body composition and fat

Glucokinase variant-induced maturity-onset diabetes of the young (GCK-MODY) exhibits the unique clinical features of mild fasting hyperglycaemia. However, formal studies of its glucose excursion pattern in daily life in comparison with those with or without other types of diabetes are lacking. We conducted a case-control study including 25 patients with GCK-MODY, 25 A1c-matched, drug naive patients

Low-dose IL-2 is a promising immunotherapy in clinical trials for treating type 1 diabetes. A new IL-2 analog, IL-2/CD25 fusion protein, has been shown to more efficiently delay or prevent diabetes in NOD mice by expanding the population of activated regulatory T cells. This therapy is intended for use before clinical diagnosis, in the early stages of type 1 diabetes progression. During this prediabetic

The Integrated Physiology of the Exocrine and Endocrine Compartments in Pancreatic Diseases workshop was a 1.5-day scientific conference at the National Institutes of Health (Bethesda, MD) that engaged clinical and basic science investigators interested in diseases of the pancreas. This report provides a summary of the proceedings from the workshop. The goals of the workshop were to forge connections

Inflammation plays an important role in the pathogenesis of diabetic retinopathy (DR). To precisely define the inflammatory mediators, we examined the transcriptomic profile of human retinal endothelial cells exposed to advanced glycation end products which revealed the neutrophil chemoattractant chemokine, CXCL1 as one of the top genes upregulated. The effect of neutrophils in the alteration of BRB

Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. Here we hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells

Intra-hepatic islet transplantation for type-1 diabetes is limited by the need for multiple infusions and poor islet viability post-transplantation. The development of alternative transplantation sites is necessary to improve islet survival, and facilitate monitoring and retrieval. We tested a clinically proven Biodegradable Temporizing Matrix (BTM), a polyurethane-based scaffold, to generate a well

The transcriptional activity of Pdx1 is modulated by a diverse array of coregulatory factors that govern chromatin accessibility, histone modifications, and nucleosome distribution. We previously identified the Chd4 subunit of the Nucleosome Remodeling and Deacetylase complex as a Pdx1- interacting factor. To identify how loss of Chd4 impacts glucose homeostasis and gene expression programs in β-cells

Genetic modification of non-β cells to produce insulin is a promising therapeutic strategy for type 1 diabetes, however, it is associated with issues including biosafety and precise regulation of insulin supply. In this study, a glucose-activated singlestrand insulin analogue (SIA) switch (GAIS) was constructed to achieve repeatable pulse activation of SIA secretion in response to hyperglycemia. In

The β2-receptor mediates the metabolic response to epinephrine. This study investigates the impact of the β2-receptor gene (ADRB2) polymorphism Gly16Arg on the metabolic response to epinephrine before and after repetitive hypoglycemia. Twenty-five healthy male subjects selected according to ADRB2 genotype being homozygous for either Gly16 (GG; n=12) or Arg16 (AA; n=13) participated in 4 trial days

Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide-1 (GLP-1) secretion, and notably promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon

NADPH oxidases (NOX) are major players in generating reactive oxygen species (ROS), implicated in various neurodegenerative ocular pathologies. The aim of this study was to investigate the role of NOX4 inhibitor (GLX7013114), in two in vivo experimental streptozotocin (STZ) paradigms depicting the early events of diabetic retinopathy (DR). Diabetic-treated animals received GLX7013114 topically (20μl/eye

Ectopic lipid accumulation in renal tubules is closely related to the pathogenesis of diabetic kidney disease (DKD) and mitochondrial dysfunction is thought to play a key role in lipid accumulation. Therefore, maintaining mitochondrial homeostasis holds considerable promise as therapeutic strategies for the treatment of DKD. Here we reported that Meteorin-like (Metrnl) gene product mediates lipid accumulation

Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed

High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan® proteins

Few studies have examined the differentiation of human embryonic stem cell (hESC)-derived pancreatic endoderm cells (PECs) in different implantation sites. Here, we investigate the influence of implantation site and recipient sex on the differentiation of hESC-derived PECs in vivo. Male and female mice were implanted with 5x106 hESC-derived PECs either under the kidney capsule, in the gonadal fat pad

Thyroid hormone (TH) has a profound effect on energy metabolism and systemic homeostasis. Adipose tissues are crucial for maintaining whole-body homeostasis, however, whether TH regulates systemic metabolic homeostasis through its action on the adipose tissues is unclear. Here, we demonstrate that systemic administration of triiodothyronine (T3), the active form of TH, affects both inguinal white adipose

Chronic hyperglycemia increases pancreatic β-cell metabolic activity, contributing to glucotoxicity-induced β-cell failure and loss of functional β-cell mass, potentially in multiple forms of diabetes. In this perspective we discuss the novel paradoxical and counterintuitive concept of inhibiting glycolysis, particularly by targeted inhibition of glucokinase, the first enzyme in glycolysis, as an approach

Diabetes is associated with decreased epoxyeicosatrienoic acids (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase (sEH) inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of VEGF-A signaling pathway attenuates diabetes-induced glomerular injury

In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA1c Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA1c and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA1c. We also used data from

Reversible phosphorylation is an important regulatory mechanism. Regulation of protein phosphorylation in β-cells has been extensively investigated, but less is known about protein dephosphorylation. To understand the role of protein dephosphorylation in β-cells and type 2 diabetes (T2D), we first examined mRNA expression of type 2C family (PP2C) of protein phosphatases in islets from T2D donors. Phosphatase

Hyaluronic acid, or hyaluronan (HA), is a nonsulfated glucosaminoglycan that has long been recognized for its hydrophilic properties and is widely used as a dermal filler. Despite much attention given to the study of other extracellular matrix (ECM) components, in the field of ECM properties and their contribution to tissue fibroinflammation, little is known of HA’s potential role in the extracellular

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission

Innate immune cells infiltrate growing adipose and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by Oncostatin M (OSM) in the metabolic consequences of overfeeding is debated at least in part because prior studies did not distinguish OSM

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from 3 cases with ICI-related T1D, and their histopathological data were compared those from 3 patients who had received ICI therapy but did not develop T1D (non-T1D) and 7 normal glucose-tolerant subjects as controls. All ICI-related