Exendin-4 treatment expands graft beta-cell mass in diabetic mice transplanted with a marginal number of fresh islets.
Exendin-4 stimulates insulin secretion, suppresses glucagons secretion, increases beta-cell replication and neogenesis, and reduces beta-cell apoptosis. However, it has been shown that posttransplant exendin-4 treatment did not improve glucose homeostasis in diabetic mice transplanted with a large number of freshly isolated islets. The aim of this study was to test if exendin-4 is beneficial for hyperglycemic recipients with a marginal number of fresh islets. We transplanted 150 C57BL/6 mouse islets under the kidney capsule of inbred streptozotocin-diabetic mice, and then treated the recipients with and without exendin-4 for 6 weeks. Before and after transplantation, recipients' blood glucose, body weight, and intraperitoneal glucose tolerance test were measured. At 6 weeks, the grafts were removed to determine beta-cell mass. Blood glucose levels in both groups decreased progressively after transplantation, and the exendin-4-treated group had had lower blood glucose than controls since day 3. By 6 weeks, euglycemia was achieved more in mice treated with exendin-4 than in controls (100% vs. 62.5%, p = 0.018). The time to obtain normoglycemia was shorter in the exendin-4-treated group than in controls (12 +/- 8 vs. 29 +/- 13 days, p < 0.001). Blood glucose at 6 weeks was 123 +/- 18 and 170 +/- 62 mg/dl in the exendin-4-treated group and controls, respectively (p = 0.008). Additionally, the exendin-4-treated group had better glucose tolerance than controls at 2 and 4 weeks (p <0.02). However, both groups exhibited increased body weight over time, and weight changes did not significantly differ between the two groups throughout the study period. At 6 weeks after transplantation, grafts in the exendin-4-treated group were more prominent and contained more insulin-stained cells than those of controls. They had 2.3-fold beta-cell mass of the graft compared with controls (0.30 +/- 0.11 vs. 0.13 +/- 0.03 mg, p = 0.012). These results indicate posttransplant exendin-4 treatment in the diabetic recipient with a marginal number of fresh islets expands graft beta-cell mass and improves transplantation outcome.
Juang
Jyuhn-Huarng
JH
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Memorial Hospital, Taoyuan, Taiwan. jjuang@adm.cgmh.org.tw
Kuo
Chien-Hung
CH
Wu
Chun-Hsing
CH
Juang
Charity
C
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D000077270:Exenatide; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D013311:Streptozocin; D014184:Transplantation, Homologous; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D013311:Streptozocin; D000077270:Exenatide