There are two intra-pancreatic axes of communication between the endocrine and exocrine pancreas (insular-acinar & acinar-insular axes) yet the study of the endocrine and exocrine pancreas have generally been conducted separately. We previously showed that loss of acinar cells improved glucose homeostasis in wild type mice. Here, we examined the effect of loss of acinar cells on diet-induced hyperglycemia.We used a genetic mouse model (ElaCreERT2; R26DTR) , wherein diphtheria toxin (DT) ablates acinar cells, allowing for the study of β-cell function in the absence of acinar cells. We included 3 groups [ElaCreERT2; R26DTR + high fat diet (HFD) ], [R26DTR + HFD], and [R26DTR + regular diet (RD) ]. These groups were on their respective diets for 12 weeks, then underwent glucose tolerance testing (GTT) and glucose stimulated insulin secretion (GSIS) after DT injection. Four days post-DT, the ElaCreERT2; R26DTR+HFD mice had a significantly improved glucose tolerance compared to R26DTR + HFD (AUC p=0.0003) . Importantly, the ElaCreERT2; R26DTR + HFD were not different from R26DTR+RD, indicating complete reversal of the hyperglycemia. GSIS done during GTT showed significantly lower insulin secretion in ElaCreERT2; R26DTR + HFD compared to R26DTR + HFD (AUC p=0.0388) , but similar to R26DTR+ RD, again indicating normalization. Islets were isolated from the 3 groups for in vitro GSIS, which showed no difference in the insulin secretion between ElaCreERT2; R26DTR + HFD and R26DTR + RD, but both had increased insulin secretion compared to R26DTR + HFD. Four weeks post-DT, when full regeneration of acinar cells from duct cells takes place, repeat GTT in the same animals showed that HFD groups had worse glucose tolerance compared to the RD group, suggesting that it was specifically the loss of the acinar cells that improved glucose tolerance. We conclude that the acute ablation of exocrine pancreas improves glucose tolerance and reverses HFD-induced hyperglycemia by enhancing insulin secretion.
S.Abi raad: None. M.Saleh: None. G.Gittes: None.