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Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice

Surgical Medical Research Institute (S.M., W.T., J.A.E., C.T., A.M.J.S.), Faculty of Medicine and Dentistry, and Clinical Islet Transplant Program (A.M.J.S.), University of Alberta, Edmonton, Canada T6G 2C8; and Novo Nordisk (L.B.K.), BK-2880 Bagsvaerd, Denmark

Address all correspondence and requests for reprints to: Dr. A. M. James Shapiro, M.D., Ph.D., F.R.C.S.(Eng) F.R.C.S.C., Professor of Surgery, Director, Clinical Islet Transplant Program, University of Alberta, Roberts Centre, 2000 College Plaza, Edmonton, Alberta, Canada T6G 2C8. E-mail: shapiro{at}islet.ca.

The current scarcity of high-quality deceased pancreas donors prevents widespread application of islet transplantation for treatment of labile type 1 diabetes mellitus. Opportunities for the improvement of current techniques include optimization of islet isolation and purification, use of culture with pharmacological insulinotropic agents, strategies to reduce graft rejection and inflammation, and the search for alternative insulin producing tissue. Here, we report our findings on the efficacy of the long-acting human glucagon-like peptide 1 analog, liraglutide, in a mouse model of marginal mass islet transplantation. Liraglutide was administered (200 µg/kg sc twice daily) after a marginal mass syngeneic islet transplant in streptozotocin-induced diabetic BALB/c mice. Time-to-normoglycemia was significantly shorter in liraglutide-treated animals (median 1 vs. 7 d; P = 0.0003), even in recipients receiving sirolimus (median 1 vs. 72.5 d; P < 0.0001). Liraglutide-treated animals also demonstrated improved glucose tolerance as assessed by an ip glucose tolerance test. Liraglutide discontinuation at postoperative d 90 resulted in diminished glucose tolerance during the ip glucose tolerance test, whereas a late-start liraglutide therapy 90 d after transplant resulted in no improvement. These findings suggest that liraglutide therapy mediates early and late insulinotropic effects. In accord with this hypothesis, insulin/terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling fluorescence microscopy showed reduced transplanted β-cell apoptosis in liraglutide-treated recipients 48 h after transplant. In addition, liraglutide resulted in improved glucose-dependent insulin secretion. Overall, our data show that liraglutide has a beneficial impact on the engraftment and function of syngeneic islet transplants in mice, when administered continuously starting on the day of transplant.