Insulin and glucagon regulate pancreatic α-cell proliferation

Zhuo Liu, Wook Kim, Zhike Chen, Yu Kyong Shin, Olga D. Carlson, Jennifer L. Fiori, Li Xin, Joshua K. Napora, Ryan Short, Juliana O. Odetunde, Qizong Lao, Josephine M. Egan

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53 Scopus citations

Abstract

Type 2 diabetes mellitus (T2DM) results from insulin resistance and β-cell dysfunction, in the setting of hyperglucagonemia. Glucagon is a 29 amino acid peptide hormone, which is secreted from pancreatic α cells: excessively high circulating levels of glucagon lead to excessive hepatic glucose output. We investigated if α-cell numbers increase in T2DM and what factor (s) regulate α-cell turnover. Leprdb/Leprdb (db/db) mice were used as a T2DM model and αTC1 cells were used to study potential α-cell trophic factors. Here, we demonstrate that in db/db mice α-cell number and plasma glucagon levels increased as diabetes progressed. Insulin treatment (EC50 = 2 nM) of α cells significantly increased α-cell proliferation in a concentration-dependent manner compared to non-insulin-treated α cells. Insulin up-regulated α-cell proliferation through the IR/IRS2/AKT/mTOR signaling pathway, and increased insulin-mediated proliferation was prevented by pretreatment with rapamycin, a specific mTOR inhibitor. GcgR antagonism resulted in reduced rates of cell proliferation in αTC1 cells. In addition, blockade of GcgRs in db/db mice improved glucose homeostasis, lessened α-cell proliferation, and increased intraislet insulin content in β cells in db/db mice. These studies illustrate that pancreatic α-cell proliferation increases as diabetes develops, resulting in elevated plasma glucagon levels, and both insulin and glucagon are trophic factors to α-cells. Our current findings suggest that new therapeutic strategies for the treatment of T2DM may include targeting α cells and glucagon.

Original languageEnglish
Article numbere16096
JournalPloS one
Volume6
Issue number1
DOIs
StatePublished - Feb 7 2011
Externally publishedYes

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    Liu, Z., Kim, W., Chen, Z., Shin, Y. K., Carlson, O. D., Fiori, J. L., Xin, L., Napora, J. K., Short, R., Odetunde, J. O., Lao, Q., & Egan, J. M. (2011). Insulin and glucagon regulate pancreatic α-cell proliferation. PloS one, 6(1), [e16096]. https://doi.org/10.1371/journal.pone.0016096