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Vascularised small intestinal segment as an alternative site for pancreatic islet transplantation

Ekaterine Berishvili^1,2,3, Zurab Kakabadze^1,2,3, Sanjeev Gupta⁴, Ekaterina Liponava²

¹Tbilisi State Medical University, Department of Clinical Anatomy; ²Georgian National Institute of Medical Research, Division of Cell Transplantation; ³Central University Hospital, Cell transplantation Unit, Tbilisi, Georgia; ⁴Albert Einstein College of Medicine, Departments of Medicine and Pathology, Diabetes Center, Marion Bessin Liver Research Center, Cancer Center, Gottesman Institute for Stem Cell Research and Regenerative Medicine, and Institute for Clinical and Translational Research, Bronx, NY, United States

Background: Islet transplantation into the liver via the portal vein is a potential treatment for patients with type 1 diabetes mellitus that can restore normal blood sugar without the need for insulin injections and can improve quality of life. However, complications such as hemorrhage, thrombosis and an immediate loss of islets through the ‘instant blood-mediated inflammatory reaction’ (IBMIR) represent main disadvantages of this modality.

Methods: Animal groups were established to determine engraftment, survival and function of islets transplanted into either intestinal segments or portal vein. Islets were isolated from adult male Lewis rats and transplanted into the small intestinal segments, preliminary ablated from mucosa of diabetic syngeneic recipients. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests carried out. Histological assessment for insulin, glucagon, von Willebrand factor (vWF) was performed. The reverse transcription-polymerase chain reaction was performed to analize the expression of insulin, glucagon, somatostatin, Glut1, PDX1, PAX6, TGF α, TGFß, bFGF and VEGF.

Results: Syngeneic islets transplanted into the intestinal segment ablated from mucosa restored euglycemia within 20 days and sustained function for over a year. Animals treated with islet transplants showed normal responses to glucose challenges. Removal of graft-bearing segments resulted in hyperglycemia. Transplanted islets demonstrated expression of insulin and glucagon. The PCR analysis showed that expression of multiple growth factors was generally retained in the transplanted islets, including beta cell transcription factors and hormones.

Conclusions: These encouraging features of the isolated intestinal segment open new research avenues for addressing biological mechanisms and clinical applications. We assume that clinical islet transplantation outcome can be significantly improved utilizing extrahepatic sites for islet implantation avoiding detrimental IBMIR that is associated with intraportal islet transplantation.