Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy
Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the a...
Source: Diabetes - June 30, 2022 Category: Endocrinology Source Type: research
Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy
Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radiol...
Source: Diabetes - June 16, 2022 Category: Endocrinology Source Type: research
Response to Comment on Wendt et al. Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1. Diabetes 2021;70:2796 –2809
We thank Drs. Kj øbsted and Wojtaszewski (1) for their comments on our article. In our study, we identified a cooperative AMPK-RabGTPase –activating protein (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 and pharmacological inactivation of Rac1. In their letter, the authors pointed out a limitation in our study, as we did not discriminate glucose uptake during and immediately after muscle contraction. (Source: Diabetes)
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
The Need to Increase Clinical Skills and Change the Genetic Testing Strategy for Monogenic Diabetes
In this issue ofDiabetes, Colclough et al. (1) report interesting data suggesting that the current genetic testing strategy for monogenic diabetes should be modified, extending it by default to genes known to cause syndromic forms of the disease. (Source: Diabetes)
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
Imeglimin to the Rescue: Enhanced CHOP/GADD34/eIF2 α Signaling Axis Promotes β-Cell Survival
Pancreatic β-cells are the main source of insulin in the body, and this hormone is required to maintain glucose homeostasis and normal metabolic health. Circulating insulin level is impacted by total β-cell mass in the pancreas, which is maintained by the ability of the β-cells to self-duplicate and survive from various stressors, such as apoptosis and endoplasmic reticulum (ER) stress. Given the inherently low rate of turnover in β-cells (1,2), apoptosis can play a key pathogenic role in the development of diabetes. While many factors contribute to the death of β-cells, such as inflammation and oxidative stress, ER h...
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
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(Source: Diabetes)
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
Comment on De Wendt et al. Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1. Diabetes 2021;70:2796 –2809
In their study, de Wendt et al. (1) present evidence to suggest that the full effect of contraction on muscle glucose uptake is regulated by a framework of proteins consisting of AMPK, TBC1D1, TBC1D4, and Rac1. Their work is based on experiments performed in isolated and incubated skeletal muscle from a novel mouse model deficient in muscle AMPK combined with whole-body knockout of TBC1D1 and TBC1D4. From a mechanistic point of view, the experimental ex vivo mouse muscle model used is strong, as it permits accurate assessment of glucose uptake in isolated muscle during contraction in the absence of confounding factors that...
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes: Inconvenient Paradox or New Paradigm?
Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, h...
Source: Diabetes - February 23, 2022 Category: Endocrinology Source Type: research
Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the NOD Mouse
In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-in...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4 + T Cells That Mark Progression to Type 1 Diabetes
Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk ...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
Endosomal Sequestration of TLR4 Antibody Induces Myeloid-Derived Suppressor Cells and Reverses Acute Type 1 Diabetes
We previously showed that treating NOD mice with an agonistic monoclonal anti-TLR4/MD2 antibody (TLR4-Ab) reversed acute type 1 diabetes (T1D). Here, we show that TLR4-Ab reverses T1D by induction of myeloid-derived suppressor cells (MDSCs). Unbiased gene expression analysis after TLR4-Ab treatment demonstrated upregulation of genes associated with CD11b+Ly6G+ myeloid cells and downregulation of T-cell genes. Further RNA sequencing of purified, TLR4-Ab –treated CD11b+ cells showed significant upregulation of genes associated with bone marrow –derived CD11b+ cells and innate immune system genes. TLR4-Ab significantly in...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
A Cycle of Inflammatory Adipocyte Death and Regeneration in Murine Adipose Tissue
Adipose tissue (AT) expands by a combination of two fundamental cellular mechanisms: hypertrophic growth of existing adipocytes or through generation of new adipocytes, also known as hyperplastic growth. Multiple lines of evidence suggest a limited capacity for hyperplastic growth of AT in adulthood and that adipocyte number is relatively stable, even with fluctuations in AT mass. If the adipocyte number is stable in adulthood, despite well-documented birth and death of adipocytes, then this would suggest that birth may be coupled to death in a regenerative cycle. To test this hypothesis, we examined the dynamics of birth ...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
Clinical Predictors and Long-term Impact of Acute Kidney Injury on Progression of Diabetic Kidney Disease in Chinese Patients With Type 2 Diabetes
We aim to assess the long-term impact of acute kidney injury (AKI) on progression of diabetic kidney disease (DKD) and all-cause mortality and investigate determinants of AKI in Chinese patients with type 2 diabetes (T2D). A consecutive cohort of 9,096 Chinese patients with T2D from the Hong Kong Diabetes Register was followed for 12 years (mean ± SD age 57 ± 13.2 years; 46.9% men; median duration of diabetes 5 years). AKI was defined based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria using serum creatinine. Estimated glomerular filtration rate measurements were used to identify the first episode wit...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
Seroreactivity Against Tyrosine Phosphatase PTPRN Links Type 2 Diabetes and Colorectal Cancer and Identifies a Potential Diagnostic and Therapeutic Target
In this study, we explore the value of autoantibodies against receptor-type tyrosine-protein phosphatase-like N (PTPRN; full-length or selected domains) as diagnostic markers using a cohort of individuals with type 2 diabetes (T2D), CRC, or both diseases or healthy individuals. We show that PTPRN autoantibody levels in plasma discriminated between patients with T2D with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of patients with CRC. Mechanistically, PTPRN depletion significantly reduced invasiveness of CRC cells in vitro and liver homing and metastasis in vivo by means of a dys...
Source: Diabetes - January 18, 2022 Category: Endocrinology Source Type: research
Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-Cell Proliferation Through the CPEB1/CDKN1B Pathway
Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to themiR-455 promoter inducedmiR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed thatmiR-455 overexpression facilitated β-cell proliferation. Knockdown ofmiR-455 inob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed ...
Source: Diabetes - January 14, 2022 Category: Endocrinology Source Type: research
