Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2026
Pancreatic cancer cell and stellate cell-derived exosome crosstalk mediates pancreatic cancer-related diabetes.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Sarkar Rohit, Perera Chamini J, Hossain Md J, Tyma Victoria, Perera Dinuki, Khan Tanzila, Binang Helen, Rajan Parvathy, Mekapogu Alpha Raj, Zahid Hosen S M, Xu Zhihong, Yan-Wing Cheung Joseph, Greenfield Jerry, Chari Suresh, Hoehn Kyle L, Horadagoda Neil, Pirola Romano, Wilson Jeremy, Apte Minoti
Аннотация
BACKGROUND: Diabetes is a known risk factor, and a distinct form termed pancreatic cancer-related diabetes (PCRD) often precedes the diagnosis of cancer by 3-5 years, offering a potential window for intervention. We hypothesised that interactions between stromal pancreatic stellate cells (PSCs) and cancer cells trigger secretion of exosomal factors that impair islet function and insulin signalling, contributing to PCRD pathogenesis.
METHODS: KC (KrasLSL-G12D/+; Pdx1-Cre) mice were fed a high-fructose diet (HFrD) or control diet for 16 weeks. Exosomes were isolated from monocultures and co-cultures of cancer/PanIN cells with PSCs, characterised by nanoparticle tracking analysis and transmission electron microscopy, and incubated with mouse β-cells (MIN6) and peripheral cells (hepatocytes, adipocytes, skeletal myocytes). Effects on insulin secretion and insulin-signalling factors were examined. Exosomal glucose-6-phosphate dehydrogenase (G6PD) expression was modulated by siRNA to assess functional impact.
RESULTS: HFrD induced marked glucose intolerance in KC mice and was accompanied by enhanced PSC activation, macrophage infiltration, inflammation, and accelerated PanIN progression. Exosomes from PSCs, cancer cells, and co-cultures displayed typical morphology and marker expression and were efficiently internalised by β-cells and hepatocytes. Functionally, exosomes significantly impaired glucose-stimulated insulin secretion in mouse and human β-cells without altering insulin content. In hepatocytes, PSC-, cancer-, and co-culture-derived exosomes reduced key insulin-signalling components, including IR, IRS, AKT, FOXO1 and GLUT2, and inhibited glucose uptake. Silencing exosomal G6PD partially restored hepatocyte insulin signalling.
CONCLUSION: This study identifies a potential contributor to PCRD and suggests a possible mechanistic role for exosomal G6PD in impaired insulin signalling associated with PCRD.
METHODS: KC (KrasLSL-G12D/+; Pdx1-Cre) mice were fed a high-fructose diet (HFrD) or control diet for 16 weeks. Exosomes were isolated from monocultures and co-cultures of cancer/PanIN cells with PSCs, characterised by nanoparticle tracking analysis and transmission electron microscopy, and incubated with mouse β-cells (MIN6) and peripheral cells (hepatocytes, adipocytes, skeletal myocytes). Effects on insulin secretion and insulin-signalling factors were examined. Exosomal glucose-6-phosphate dehydrogenase (G6PD) expression was modulated by siRNA to assess functional impact.
RESULTS: HFrD induced marked glucose intolerance in KC mice and was accompanied by enhanced PSC activation, macrophage infiltration, inflammation, and accelerated PanIN progression. Exosomes from PSCs, cancer cells, and co-cultures displayed typical morphology and marker expression and were efficiently internalised by β-cells and hepatocytes. Functionally, exosomes significantly impaired glucose-stimulated insulin secretion in mouse and human β-cells without altering insulin content. In hepatocytes, PSC-, cancer-, and co-culture-derived exosomes reduced key insulin-signalling components, including IR, IRS, AKT, FOXO1 and GLUT2, and inhibited glucose uptake. Silencing exosomal G6PD partially restored hepatocyte insulin signalling.
CONCLUSION: This study identifies a potential contributor to PCRD and suggests a possible mechanistic role for exosomal G6PD in impaired insulin signalling associated with PCRD.