Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes
In the attempt to understand the origin of autoantibody (AAb) production in patients with and at risk for type 1 diabetes (T1D), multiple studies have analyzed and reported alterations in T follicular helper (Tfh) cells in presymptomatic AAb+ subjects and patients with T1D. Yet, whether the regulatory counterpart of Tfh cells, represented by T follicular regulatory (Tfr) cells, is similarly altered is still unclear. To address this question, we performed analyses in peripheral blood, spleen, and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb− and AAb+ subje...
Source: Diabetes - October 7, 2021 Category: Endocrinology Source Type: research
Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9
Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene,Pde9a, were fed nutrient-matched high-fat (HFD) or low-fat diets.Pde9a−/− mice were resistant to HFD-induced ob...
Source: Diabetes - October 7, 2021 Category: Endocrinology Source Type: research
Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism
We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B ( β [SE] −0.23 [0.03],P = 2.15 × 10−19). In addition, theANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: β [SE] 0.17 [0.03],P = 5.76 × 10−10; XXL...
Source: Diabetes - October 5, 2021 Category: Endocrinology Source Type: research
Empagliflozin Treatment Is Associated With Improvements in Cardiac Energetics and Function and Reductions in Myocardial Cellular Volume in Patients With Type 2 Diabetes
Sodium –glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization for heart failure (HF) in patients with type 2 diabetes (T2D). Using CV MRI (CMR) and31P-MRS in a longitudinal cohort study, we aimed to investigate the effects of the selective SGLT2 inhibitor empagliflozin on myocardial energetics and cellular volume, function, and perfusion. Eighteen patients with T2D underwent CMR and31P-MRS scans before and after 12 weeks ’ empagliflozin treatment. Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels were measured. Ten volunteers ...
Source: Diabetes - October 5, 2021 Category: Endocrinology Source Type: research
The Tetracycline-Controlled Transactivator (Tet-On/Off) System in β-Cells Reduces Insulin Expression and Secretion in Mice
In this study, we investigated whether an inducible Tetracycline (Tet)-Off system with β-cell–specific mouse insulin promoter (MIP)-itTA–driven expression of tetracycline oper on (TetO)-CreJaw/J could circumvent previous issues of specificity and efficacy. Following assessment of tissue-specific gene recombination, β-cell architecture, in vitro and in vivo glucose-stimulated insulin secretion, and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g., improved itTA, reverse rtTA, or tTA) in β-cells significantly reducedInsulin gene expression and decreased ...
Source: Diabetes - October 5, 2021 Category: Endocrinology Source Type: research
Imeglimin Ameliorates β-Cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway
The effects of imeglimin, a novel antidiabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression o f endoplasmic reticulum (ER)–related molecules, includingChop (Ddit3),Gadd34 (Ppp1r15a),Atf3, andSdf2l1, and decreased eIF2 α phosphorylation after treatment with thapsigargin and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protec...
Source: Diabetes - September 29, 2021 Category: Endocrinology Source Type: research
Diabetes, Drug Treatment, and Mortality in COVID-19: A Multinational Retrospective Cohort Study
In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility. (Source: Diabetes)
Source: Diabetes - September 27, 2021 Category: Endocrinology Source Type: research
Diabetes and the Risk of Long-term Post-COVID Symptoms
This study investigated the association of diabetes in patients who recovered from severe acute respiratory syndrome coronavirus 2 infection with the presence of long-term post –coronavirus disease (COVID) symptoms. A case-control study that included individuals hospitalized during the first wave of the pandemic was conducted. Patients with a previous diagnosis of diabetes and under medical control were considered case subjects. Two age- and sex-matched patients without presenting diabetes per case subject were recruited as control subjects. Hospitalization and clinical data were collected from hospital medical records. ...
Source: Diabetes - September 27, 2021 Category: Endocrinology Source Type: research
CD8 + T Cells Variably Recognize Native Versus Citrullinated GRP78 Epitopes in Type 1 Diabetes
In type 1 diabetes, autoimmune β-cell destruction may be favored by neoantigens harboring posttranslational modifications (PTMs) such as citrullination. We studied the recognition of native and citrullinated glucose-regulated protein (GRP)78 peptides by CD8+ T cells. Citrullination modulated T-cell recognition and, to a lesser extent, HLA-A2 binding. GRP78-reactive CD8+ T cells circulated at similar frequencies in healthy donors and donors with type 1 diabetes and preferentially recognized either native or citrullinated versions, without cross-reactivity. Rather, the preference for native GRP78 epitopes was associated wit...
Source: Diabetes - September 24, 2021 Category: Endocrinology Source Type: research
Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1
In this study, we investigated the cooperative AMPK-RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK combined with knockout of eitherTbc1d1,Tbc1d4, or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion ofTbc1d1 but notTbc1d4 resulted in a further decrease in exercise capacity. In oxidative soleus muscle, AMPK deficiency reduced contraction-mediated glucose uptake, and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic extensor digitorum longus muscle, AMP...
Source: Diabetes - September 24, 2021 Category: Endocrinology Source Type: research
Gene Panel Sequencing of Patients With Monogenic Diabetes Brings to Light Genes Typically Associated With Syndromic Presentations
Gene panel sequencing (NGS) offers the possibility of analyzing rare forms of monogenic diabetes (MgD). To that end, 18 genes were analyzed in 1,676 patients referred for maturity-onset diabetes of the young genetic testing. Among the 307 patients with a molecular diagnosis of MgD, 55 (17.9%) had a mutation in a gene associated with a genetic syndrome. Of the patients with mutations, 8% (n = 25) carried the m.3243A>G variant associated with maternally inherited diabetes and deafness. At the time of referral very few had reported hearing loss or any other element of the typical syndromic presentation. Of the patients, 6%...
Source: Diabetes - September 23, 2021 Category: Endocrinology Source Type: research
Syntaxin 4 Enrichment in β-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice
Syntaxin 4 (STX4), a plasma membrane –localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To te st this hypothesis, we generated inducible β-cell–specific STX4-expressing NOD mice (NOD-iβSTX4). Of NOD-iβSTX4 mice, 73% had sustained normoglycemia vs.<20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before diabetes conversion, NOD-i βSTX4 mice demonstra...
Source: Diabetes - September 23, 2021 Category: Endocrinology Source Type: research
The Deterrence of Rapid Metabolic Decline Within 3 Months After Teplizumab Treatment in Individuals at High Risk for Type 1 Diabetes
In conclusion, an analytic approach combining visual evidence with novel end points demonstrated that teplizumab delays rapid metabolic decline and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months. (Source: Diabetes)
Source: Diabetes - September 22, 2021 Category: Endocrinology Source Type: research
Developmental Timing of High-Fat Diet Exposure Impacts Glucose Homeostasis in Mice in a Sex-Specific Manner
In this study, we investigated how HFD in Swiss Webster males and females during preweaning, peripubertal, and postpubertal periods alters glucose homeostasis and diabetes susceptibility. In males, HFD throughout life resulted in the highest diabetes incidence. Notably, switching to chow postpuberty was protective against diabetes relative to switching to chow at weaning, despite the longer period of HFD exposure. Similarly, HFD throughout life in males resulted in less liver steatosis relative to mice with shorter duration of postpubertal HFD. Thus, HFD timing relative to weaning and puberty, not simply exposure length, c...
Source: Diabetes - September 20, 2021 Category: Endocrinology Source Type: research
Different Effects of Lifestyle Intervention in High- and Low-Risk Prediabetes: Results of the Randomized Controlled Prediabetes Lifestyle Intervention Study (PLIS)
In conclusion, it is possible in HR individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk phenotype –based LI may be beneficial for the prevention of diabetes. (Source: Diabetes)
Source: Diabetes - September 16, 2021 Category: Endocrinology Source Type: research
