J. M. Ramirez Decrescenzo1, A. R. Munoz1, A. S. Liss1, F. M. Kuehn1, F. Adiliaghdam1, S. R. Hamarneh1, R. A. Hodin1 1Massachusetts General Hospital,Surgery,Boston, MA, USA
Introduction: Type 2 diabetes is characterized by insulin resistance, inadequate insulin secretion and declined pancreatic β-cell mass. Intestinal alkaline phosphatase (IAP) is an endogenous anti-inflammatory factor which is thought to be exclusively expressed in the gut. Mice lacking IAP are more prone to the development of metabolic syndrome and hyperglycemia. Given the embryological association between the intestinal epithelia and the pancreas, we explored the expression and functional role of IAP in pancreatic beta cells.
Methods: Pancreatic and colon tissue from 17 unique human donors were used to measure the expression level of IAP mRNA by qPCR. IAP expression levels were additionally assessed in pancreatic and duodenal tissue from the same donors (n=3). Cell specific localization of IAP in the pancreas was performed by immunohistochemistry using an antibody against human IAP (n=3). Furthermore, 12-week-old C57BL/6 wild-type and IAP-knockout mice (n=6) were used to study the levels of IAP in pancreatic tissue, its activity and its effect on inflammation.
Results: In human tissues, IAP mRNA levels in the pancreas were abundant compared to the intestinal tissues (Pancreas vs. Duodenum, 2.21 ± 1.45 vs. 1.02 ± 0.21 Relative Expression = 0.5). Remarkably, immuno-histochemistry staining showed specific localization of IAP to pancreatic β-cells, whereas it was absent in acinar cells. Deletion of the IAP gene in mice resulted in the expected absence of IAP mRNA expression as well as a nearly four-fold lower activity of alkaline phosphate enzyme in pancreatic tissue when compared to WT mice (IAP-KO vs. WT, 12.57 ± 6.56 vs. 46.21 ± 2.3 PNPP p= <0.01). Additionally, mice deficient for IAP had dramatically higher inflammatory cytokine mRNA levels in pancreatic tissue: TNF-α, IL1-β (IAP-KO vs. WT, 4.00 ± 0.53 vs 1.18 ± 0.49 Relative Expression = 0.017) and IL-6 (IAP-KO vs. WT, 10.11 ± 1.83 vs. 1.20 ± 0.43 Relative Expression = <0.01) compared to WT-littermates.
Conclusion: IAP is specifically expressed in pancreatic β-cells and likely exerts an anti-inflammatory activity within that tissue. Given the importance of the anti-inflammatory pathway in regard to beta cell dysfunction, the IAP pathway may represent a novel therapeutic target for the prevention or treatment of diabetes in humans.