The effect of HNF4alpha knockout in beta cells is age and gender dependent

Abstract

HNF4 is important for beta cells ability to adequately secrete insulin in response to glucose concentration and endoplasmic reticulum (ER) homeostasis. In humans, HNF4 mutation is responsible for Diabetes mellitus subtype MODY1, which has age determined onset. In addition, in other types of DM, there are evidences that gender can influence beta cell dysfunction, with possible involvement of ER stress pathways. Thus, we assessed the influence of gender and age on beta cell dysfunction induced by HNF4 absence. We used an animal model with specific beta cells KO for HNF4, induced after birth (Ins. CRE HNF4 loxP/loxP). Glucose intolerance is observed after 10 days of KO induction, at 50 days of age, with KO males (MKO) showing greater glucose intolerance than KO females (FKO). Percentage of insulin-positive cells in KO mice islets is lower compared to Control at all ages evaluated, with MKO having a lower percentage at later ages compared to FKO. Both KO groups have reduced beta cell mass and increased -cell mass, which is higher in MKO. ER stress is induced in both KO groups. However, ER stress-mediated apoptosis is observed only in MKO. FKO shows evidence of beta cell differentiated state loss. Thus, loss of beta cells in HNF4 KO is influenced by gender and age, involves induction of ER stress, and is more pronounced in males, where ER stress-induced beta cell death is observed. Partial protection observed in females seems to involve dedifferentiation of beta cells.