Compromised function of insulin-secreting pancreatic β cells is central to the development and progression of Type 2 Diabetes (T2D). However, the mechanisms underlying β cell failure remain incompletely understood. Here, we report that metabolic stress markedly enhances macroautophagy-independent lysosomal degradation of nascent insulin granules. In different model systems of diabetes including of human origin, stress-induced nascent granule degradation (SINGD) contributes to loss of insulin along with mammalian/mechanistic Target of Rapamycin (mTOR)-dependent suppression of macroautophagy. Expression of Protein Kinase D (PKD), a negative regulator of SINGD, is reduced in diabetic β cells. Pharmacological activation of PKD counters SINGD and delays the onset of T2D. Conversely, inhibition of PKD exacerbates SINGD, mitigates insulin secretion and accelerates diabetes. Finally, reduced levels of lysosomal tetraspanin CD63 prevent SINGD, leading to increased insulin secretion. Overall, our findings implicate aberrant SINGD in the pathogenesis of diabetes and suggest new therapeutic strategies to prevent β cell failure.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658524 | PMC |
http://dx.doi.org/10.1038/s41467-019-11170-4 | DOI Listing |
Br J Pharmacol
December 2024
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Background And Purpose: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiovascular benefits in diabetic patients, but the underlying mechanisms remain incompletely understood. Semaglutide, a novel long-acting GLP-1RA, has shown a reduced risk of cardiovascular events. Based on these results, we investigated the therapeutic potential of semaglutide in diabetic cardiomyopathy and sought to elucidate the underlying mechanisms.
View Article and Find Full Text PDFJ Allergy Clin Immunol
December 2024
Department of Women and Children's Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom; Children's Allergy Service, Evelina London Children's Hospital, Guy's and St Thomas' Hospital, London, United Kingdom. Electronic address:
Food allergy is increasing in prevalence, and poses significant challenges for individuals and their families, adversely impacting their quality of life. Misdiagnosis can lead to unnecessary dietary and social limitations, and increased food allergy risk, while failure to diagnose may result in life-threatening anaphylaxis. Therefore, a precise diagnosis is of the utmost importance; however, barriers exist at every stage of the diagnostic process.
View Article and Find Full Text PDFPediatr Neonatol
December 2024
Division of Fetal Medicine, Center for Maternal-Fetal, Neonatal and Reproductive Medicine at the National Center for Child Health and Development, Tokyo, Japan.
Introduction: Type 1 congenital pulmonary airway malformation (CPAM) is characterized by large, dilated cysts that rapidly expand due to aeration immediately after birth, often necessitating surgical resection. In atypical cases of CPAM type 1, fetal T2-weighted magnetic resonance imaging (MRI) reveals a low-intensity solid lung mass containing multiple irregular T2 high-intensity areas.
Methods: Data were retrospectively collected for infants with atypical CPAM type 1 born at our hospital between March 2002 and December 2022.
Cell Mol Gastroenterol Hepatol
December 2024
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Broad Institute, Cambridge, MA. Electronic address:
Background And Aims: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.
Methods: ACLF was triggered by a single alcohol binge (5g/Kg) in a bile duct ligation (BDL) liver fibrosis murine model.
Cell Signal
December 2024
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan, China. Electronic address:
Through bioinformatics screening, we previously found that AlkB homolog 5 (ALKBH5) expression, an mA demethylase, was higher in patients with heart failure than in the normal population. This study aimed to investigate the molecular mechanisms by which ALKBH5 regulates heart failure. We established a myocardial infarction (MI)-induced heart failure model in rats in vivo and an in vitro hypoxia model using rat primary cardiac fibroblasts (RCFs).
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!