Background
Insulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin
Conclusion
Altogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance.
Methods
We generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo.
Results
Beta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease.