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 β‐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 β‐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 β‐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 β‐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 β‐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 β‐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 β‐cell mass by stimulating β‐cell growth and differentiation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.00044.x, 2010)