Cholecystokinin attenuates β-cell apoptosis in both mouse and human islets

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 243; pp. 1 - 13
• Main Authors: Kim, HUNG TAE, DESOUZA, ARNALDO H., UMHOEFER, HEIDI, HAN, JEEYOUNG, ANZIA, LUCILLE, SACOTTE, STEVEN J., WILLIAMS, RASHAUN A., BLUMER, JOSEPH T., BARTOSIAK, JACOB T., FONTAINE, DANIELLE A., BAAN, MIEKE, KIBBE, CARLY R., DAVIS, DAWN BELT
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022
• Subjects: Animals; Apoptosis; Cholecystokinin - metabolism; Cholecystokinin - pharmacology; Cytokines - metabolism; Diabetes Mellitus, Type 2 - metabolism; Humans; Islets of Langerhans - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; GLP-1; T1D; T2D; DM; CCK; MAPK; VEGF-A; ER; ERK1/2; CCKAR; TUNEL; CCKBR; IEQ; STZ; ABKO; ICT; WT
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2021.10.005

Loss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.