Combination treatment of db/db mice with exendin-4 and gastrin preserves β-cell mass by stimulating β-cell growth and differentiation

Aim/Introduction: Preservation of beta-cell mass is crucial for maintaining long-term glucose homeostasis. Therapies based on incretin and its mimetics are expected to achieve this goal through various biological functions, particularly the restoration of beta-cell mass. Here we tested the effects of gastrin and exendin-4 in type 2 diabetic animals. Materials and Methods: The effects of exendin-4 and gastrin on beta-cell function and mass were examined in 8-week-old db/db mice. INS-1 beta cells and AR42J cells were used to determine the molecular mechanism underlying the effects of the two agents. Immunohistochemistry, western blotting and RT-PCR assays were used to assess the biological effects of the two agents. Results: Two weeks of combination administration of exendin-4 plus gastrin resulted in a significant improvement of glucose tolerance associated with a marked preservation of beta-cell mass in db/db mice. Immunohistochemical analysis showed that such treatment resulted in the appearance of numerous irregularly-shaped small islets and single insulin-positive cells. While gastrin had little biological effect on INS-1 beta-cells consistent with low expression of its intrinsic receptor on these cells, it caused differentiation of AR42J cells into insulin-producing cells. Co-stimulation with exendin-4 significantly enhanced gastrin-induced endocrine differentiation of AR42J precursor cells. These findings were further supported by enhanced expression of key genes involved in beta-cell differentiation and maturation, such as neurogenin3 (Ngn3) and MafA. Conclusions: These results suggest that combination treatment of db/db mice with exendin-4 and gastrin preserves beta-cell mass by stimulating beta-cell growth and differentiation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.00044.x, 2010)