Adipocyte Thyroid Hormone β Receptor–Mediated Hormone Action Fine-tunes Intracellular Glucose and Lipid Metabolism and Systemic Homeostasis
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 adipose tissues is unclear. Here, we demonstrate that systemic administration of triiodothyronine (T3), the active form of TH, affects both inguinal white adipose tissue (iWAT) and whole-body metabolism. Taking advantage of the mouse model lacking adipocyte TH receptor (TR) α or TRβ, we show that TRβ is the major TR isoform that mediates T3 action on the expression of genes involved ...
Source: Diabetes - February 1, 2023 Category: Endocrinology Source Type: research
DNA Methylation –Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic β-Cell Heterogeneity
The molecular and functional heterogeneity of pancreatic β-cells is well recognized, but the underlying mechanisms remain unclear. Pancreatic islets harbor a subset of β-cells that co-express tyrosine hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of the TH+β-cells within islets is essential for appropriate function in mice, such that a higher proportion of these cells corresponds to reduced insulin secretion. Here, we use these cells as a model to dissect the developmental control of β-cell heterogeneity. We define the specific molecular and metabol ic c...
Source: Diabetes - January 6, 2023 Category: Endocrinology Source Type: research
Perilipin 1 Antibodies in Patients With Acquired Generalized Lipodystrophy
Wellcome Trust10.13039/100010269219417 (Source: Diabetes)
Source: Diabetes - December 14, 2022 Category: Endocrinology Source Type: research
In This Issue of Diabetes
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Source: Diabetes - December 14, 2022 Category: Endocrinology Source Type: research
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Source: Diabetes - December 14, 2022 Category: Endocrinology Source Type: research
Roles of Pancreatic Islet Catecholamine Neurotransmitters in Glycemic Control and in Antipsychotic Drug –Induced Dysglycemia
Catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE) are essential for a myriad of functions throughout the central nervous system, including metabolic regulation. These molecules are also present in the pancreas, and their study may shed light on the effects of peripheral neurotransmission on glycemic control. Though sympathetic innervation to islets provides NE that signals at local α-cell and β-cell adrenergic receptors to modify hormone secretion, α-cells and β-cells also synthesize catecholamines locally. We propose a model where α-cells and β-cells take up catecholamine precursors in response t...
Source: Diabetes - December 14, 2022 Category: Endocrinology Source Type: research
Sustained Upregulation of Endothelial Nox4 Mediates Retinal Vascular Pathology in Type 1 Diabetes
NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in retinal endothelial cells (ECs) and is upregulated under hyperglycemic and hypoxic conditions. However, the role of endothelial Nox4 upregulation in long-term retinal blood vessel damage in diabetic retinopathy (DR) remains undefined. Here, we attempted to address this question using humanized EC-specificNox4 transgenic (hNox4EC-Tg) and EC-specificNox4 knockout (Nox4EC-KO) mouse models. Our results show thathNox4EC-Tg mice at age of 10 –12 months exhibited increased tortuosity of retinal blood vessels, focal vascular leakage, and acellular capil...
Source: Diabetes - November 2, 2022 Category: Endocrinology Source Type: research
FGF13-Sensitive Alteration of Parkin Safeguards Mitochondrial Homeostasis in Endothelium of Diabetic Nephropathy
In this study, we found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression. Endothelial-specific deletion ofFgf13 potentially alleviates T2DN damage, whileFgf13 overexpression has the opposite effect. Mechanistically,Fgf13 deficiency results in improved mitochondrial homeostasis and endothelial barrier integrity in T2DN. Moreover, FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in endothelium of T2DN through promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects ofFgf13 deficiency on T2DN are abolis...
Source: Diabetes - October 18, 2022 Category: Endocrinology Source Type: research
Endothelial-Specific Expression of CIDEC Improves High-Fat Diet –Induced Vascular and Metabolic Dysfunction
Cell death-inducing DNA fragmentation factor- α–like effector C (CIDEC), originally identified to be a lipid droplet–associated protein in adipocytes, positively associates with insulin sensitivity. Recently, we discovered that it is expressed abundantly in human endothelial cells and regulates vascular function. The current study was desi gned to characterize the physiological effects and molecular actions of endothelial CIDEC in the control of vascular phenotype and whole-body glucose homeostasis. To achieve this, we generated a humanized mouse model expressing endothelial-specific human CIDEC (E-CIDECtg). E-CIDECtg...
Source: Diabetes - October 18, 2022 Category: Endocrinology Source Type: research
The Antipsychotic Dopamine 2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA:3-Ketoacid CoA Transferase
Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), the condition remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent pimozide is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We now extend those observations here, using comp...
Source: Diabetes - October 18, 2022 Category: Endocrinology Source Type: research
Human T2D-Associated Gene IMP2/IGF2BP2 Promotes the Commitment of Mesenchymal Stem Cells Into Adipogenic Lineage
Excessive adiposity is the main cause of obesity and type two diabetes (T2D). Variants in humanIMP2/IGF2BP2 gene are associated with increased risk of T2D. However, little is known about its role in adipogenesis and in insulin resistance. Here, we investigate the function of IMP2 during adipocyte development. Mice with Imp2 deletion in mesenchymal stem cells (MSC) are resistant to diet-induced obesity without glucose and insulin tolerance affected. Imp2 is essential for the early commitment of adipocyte-derived stem cells (ADSC) into preadipocytes, but the deletion of Imp2 in MSC is not required for the proliferation and t...
Source: Diabetes - October 11, 2022 Category: Endocrinology Source Type: research
Genetic Mapping of Multiple Traits Identifies Novel Genes for Adiposity, Lipids, and Insulin Secretory Capacity in Outbred Rats
Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids, and other metabolic traits. Physiological traits were measured in 1,519 male HS rats, with liver and adipose transcriptomes measured in>410 rats. Genotypes were imputed from low-coverage whole-genome sequencing. Linear mixed models were used to detect physiological and express...
Source: Diabetes - October 11, 2022 Category: Endocrinology Source Type: research
Causal Associations Between Basal Metabolic Rate and COVID-19
Many coronavirus disease 2019 (COVID-19) risk factors, including obesity and diabetes, are associated with an abnormal basal metabolic rate (BMR). We aimed to evaluate whether BMR could impact the susceptibility to or severity of COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic correlations and potential causal associations between BMR (n = 448,348) and three COVID-19 outcomes: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, and critical COVID-19 (n = 1,086,211 –2,597,856). A multivariable MR (MVMR) analysis was used t...
Source: Diabetes - October 10, 2022 Category: Endocrinology Source Type: research
Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4 + T Cells in Type 1 Diabetes
A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with de...
Source: Diabetes - October 6, 2022 Category: Endocrinology Source Type: research
Single-Cell RNA Sequencing Reveals a Role for Reactive Oxygen Species and Peroxiredoxins in Fatty Acid –Induced Rat β-Cell Proliferation
The functional mass of insulin-secreting pancreatic β-cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing β-cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the β-cell compensatory response, but their underlying mechanisms of action remain poorly understood. We investigated the transcriptional mechanisms of β-cell proliferation in response to fatty acids. Isolated rat islets were exposed to 16.7 mmol/L glucose with or without 0.5 mmol/L oleate (C18:1) or palmitat...
Source: Diabetes - October 3, 2022 Category: Endocrinology Source Type: research
