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

ABSTRACT:

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Aim/Introduction:? Preservation of ?-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 ?-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 ?-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 ?-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 ?-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 ?-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 ?-cell mass by stimulating ?-cell growth and differentiation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.00044.x, 2010).

SUBMITTER: Tamaki M

PROVIDER: S-EPMC4020718 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Tamaki Motoyuki M Fujitani Yoshio Y Uchida Toyoyoshi T Hirose Takahisa T Kawamori Ryuzo R Watada Hirotaka H

Journal of diabetes investigation 20101001 5

<h4>Unlabelled</h4>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.<h4>Materials and methods</h4> The effects of exendin-4 and gastrin on β-cell function and mass were examined in 8-week-old db/db mice ...[more]

PMID: 24843429

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