Long-term Western diet impairs islet blood vessel function and insulin transport even after diet reversal and weight loss, according to a new study from researchers at Karolinska Institutet.
A new study led by researchers from Karolinska Institutet shows that obesogenic diet-induced damage to the blood vessels of pancreatic islets may be long-lasting and resistant to reversal, even after returning to a healthy diet. The findings, published in the Journal of Clinical Investigation, highlight a previously underappreciated mechanism linking islet vessel dysfunction to impaired glucose metabolism.
Pancreatic islets are microorgans responsible for detecting blood glucose and releasing hormones, including insulin, which controls blood sugar levels. The dense and fenestrated blood vessels within the islets act as gateways to ensure optimal glucose sensing and hormone secretion.
Using advanced in vivo imaging of pancreatic islets transplanted into the eyes of mice, the researchers monitored changes in islet blood vessels over 48 weeks. Mice fed a Western diet developed progressive islet vessel abnormalities and desensitization to VEGF-A, a key molecule controlling blood vessel morphology and function.
"This desensitization hindered the proper regulation of islet blood flow and vessel barrier function, delaying the release of insulin into the bloodstream during glucose challenges," explains Dr. Yan Xiong , researcher at the Department of Molecular Medicine and Surgery , Karolinska Institutet and first author of this study.
When the mice were switched back to a healthy control diet after 24 weeks, some metabolic abnormalities reversed; however, the structural and functional impairments in the islet blood vessels persisted, which continued to undermine glucose metabolism.
Existence of a "metabolic memory"
Mechanistic studies identified that diet-induced overactivation of atypical protein kinase C (aPKC) in endothelial cells was a key driver of VEGF-A resistance. Importantly, this signaling defect persisted even after removal of dietary stressors, highlighting the vascular "metabolic memory."
"This study reveals that islet vessel dysfunction is a hidden but significant contributor to glucose intolerance in obesity, and that these defects may become permanent if not addressed early," says Professor Per-Olof Berggren , at the same department and senior author of the study.
"Understanding islet vessel pathology opens up new therapeutic opportunities aimed at preserving islet vascular health in metabolic diseases."
The study was supported by funding from Karolinska Institutet, the Strategic Research Program in Diabetes at Karolinska Institutet, the Swedish Research Council, the STINT foundation, the Novo Nordisk Foundation, the Swedish Diabetes Association, the Family Knut and Alice Wallenberg Foundation, the Jonas & Christina af Jochnick Foundation, the Family Erling-Persson Foundation, Berth von Kantzow's Foundation and European Research Council grant ERC-2018-AdG 834860 EYELETS.
Publication
"Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice", Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren, The Journal of Clinical Investigation, online June 9, 2025, doi: 10.1172/JCI177601
