Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes
Signal regulatory protein SIRP γ (CD172G) is expressed on the surface of lymphocytes, where it acts by engaging its ligand, CD47.SIRPG, which encodes SIRP γ, contains a nonsynonymous coding variant, rs6043409, which is significantly associated with risk for type 1 diabetes.SIRPG produces multiple transcript isoforms via alternative splicing, all encoding potentially functional proteins. We show that rs6043409 alters a predicted exonic splicing enhancer, resulting in significant shifts in the distribution ofSIRPG transcript isoforms. All of these transcript isoforms produced protein upon transient expression in vitro. How...
Source: Diabetes - November 19, 2021 Category: Endocrinology Source Type: research
Syndromic Monogenic Diabetes Genes Should Be Tested in Patients With a Clinical Suspicion of Maturity-Onset Diabetes of the Young
At present, outside of infancy, genetic testing for monogenic diabetes is typically for mutations in maturity-onset diabetes of the young (MODY) genes that predominantly result in isolated diabetes. Monogenic diabetes syndromes are usually only tested for when supported by specific syndromic clinical features. How frequently patients with suspected MODY have a mutation in a monogenic syndromic diabetes gene is unknown and thus missed by present testing regimes. We performed genetic testing of 27 monogenic diabetes genes (including 18 associated with syndromic diabetes) for 1,280 patients with a clinical suspicion of MODY w...
Source: Diabetes - November 17, 2021 Category: Endocrinology Source Type: research
Ancestry-Matched and Cross-Ancestry Genetic Risk Scores of Type 2 Diabetes in Pregnant Women and Fetal Growth: A Study in an Ancestrally Diverse Cohort
In conclusion, T2D genetic susceptibility may influence fetal growth starting at midsecond trimester among Europeans. Absence of similar associations in non-Europeans urges the need for further genetic T2D studies in diverse ancestri es. (Source: Diabetes)
Source: Diabetes - November 17, 2021 Category: Endocrinology Source Type: research
Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multicohort Nontargeted Metabolomics Observational and Mendelian Randomization Study
Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity and circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data were generated with nontargeted ultraperformance liquid chromatography coupled to time-of-flight mass spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N = 1,135), PIVUS (N = 970), and TwinGene (N = 2,059). We assessed associations of general adiposity measured as BMI and central body fat distribution measured as wa...
Source: Diabetes - November 16, 2021 Category: Endocrinology Source Type: research
Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research’s Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases
This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes. (Source: Diabetes)
Source: Diabetes - November 15, 2021 Category: Endocrinology Source Type: research
Exercise-Induced Improvement in Insulin-Stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wild-Type AS160
One exercise session can elevate insulin-stimulated glucose uptake (ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic approaches to rigorously test this idea. The initial experiment evaluated the role of AS160 in postexercise increase in ISGU using muscles from male wild-type (WT) and AS160-knockout (KO) rats. The next experiment used AS160-KO rats with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160 deficiency could restore the ability of exercise to improve ISGU. The third expe...
Source: Diabetes - November 9, 2021 Category: Endocrinology Source Type: research
Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes
Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in hu...
Source: Diabetes - November 9, 2021 Category: Endocrinology Source Type: research
An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript
In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association nearGCK (rs3757840, βmeta = 0.0062; minor allele frequency [MAF] = 0.49;Pmeta = 3.66 × 10−8) and confirmed the association nearRCN3 (rs113886122, βmeta = 0.0134; MAF = 0.17;Pmeta = 5.71 × 10−18). Colocalization analysis with whole-blood expression quantitative trait loci data suggestedFCGRT as the effector transcript at theRCN3 locus. We further showed tha...
Source: Diabetes - November 9, 2021 Category: Endocrinology Source Type: research
Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion
MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets are not clear. Here we report increased expression of miR-200c in islets from T2D as compared with nondiabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC- βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis o...
Source: Diabetes - November 9, 2021 Category: Endocrinology Source Type: research
Distinct Characteristics Between Perivascular and Subcutaneous Adipose-Derived Stem Cells
In this study, we applied single-cell analysis to compare SUB-ADSCs and PV-ADSCs regarding their subpopulations, functions, and cell fates. We uncovered four subpopulations of PV-ADSCs (Dpp4+,Col4a2+/Icam1+,Clec11a+/Cpe+, andSult1e1+ cells), among which theClec11a+ subpopulation potentially participated in and regulated PV-ADSC differentiation toward a smooth muscle cell (SMC) phenotype. Distinct characteristics between PV-ADSCs and SUB-ADSCs were revealed. (Source: Diabetes)
Source: Diabetes - November 9, 2021 Category: Endocrinology Source Type: research
Intermittent Leucine Deprivation Produces Long-lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression
Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended are unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles of treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after a control diet was resumed for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepat...
Source: Diabetes - November 5, 2021 Category: Endocrinology Source Type: research
Liraglutide Improves Forced Vital Capacity in Individuals With Type 2 Diabetes: Data From the Randomized Crossover LIRALUNG Study
In conclusion, liraglutide increased FVC in patients with type 2 diabetes. This effect was associated with a significant decrease of circulating SP-D, thus pointing to a beneficial effect in the alveolar-capillary function. (Source: Diabetes)
Source: Diabetes - November 4, 2021 Category: Endocrinology Source Type: research
Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes
A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or T...
Source: Diabetes - November 4, 2021 Category: Endocrinology Source Type: research
Withaferin A Promotes White Adipose Browning and Prevents Obesity Through Sympathetic Nerve –Activated Prdm16-FATP1 Axis
In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet –induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or F ATP1 knockdown in iWAT abrogated the WAT browning–inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together...
Source: Diabetes - November 3, 2021 Category: Endocrinology Source Type: research
Metabolic and Metabo-Clinical Signatures of Type 2 Diabetes, Obesity, Retinopathy, and Dyslipidemia
In this study, using a total of 1,300 metabolites from 996 Qatari adults (57% with T2D) and 1,159 metabolites from an independent cohort of 2,618 individuals from the Qatar BioBank (11% with T2D), we identified 373 metabolites associated with T2D, obesity, retinopathy, dyslipidemia, and lipoprotein levels, 161 of which were novel. Novel metabolites included phospholipids, sphingolipids, lysolipids, fatty acids, dipeptides, and metabolites of the urea cycle and xanthine, steroid, and glutathione metabolism. The identified metabolites enrich pathways of oxidative stress, lipotoxicity, glucotoxicity, and proteolysis. Second, ...
Source: Diabetes - November 3, 2021 Category: Endocrinology Source Type: research
