Transgenic mouse models have been fundamental in the discovery of factors that regulate β-cell development, mass, and function. Several groups have recently shown that some of these models display previously uncharacterized phenotypes due to the transgenic system itself. These include impaired islet function and increased β-cell mass due to the presence of a human growth hormone (hGH) minigene as well as impaired β-cell proliferation in response to tamoxifen (TM) administration. We aimed to determine how these systems impact β-cell mass and proliferation during high fat diet (HFD). To this end, we utilized C57Bl6/J male MIP-Cre(ER) mice, which are known to express hGH, or wild-type (WT) mice treated with vehicle corn oil or TM In the absence of TM, MIP-Cre(ER) mice fed a chow diet have increased β-cell mass due to hypertrophy, whereas replication is unchanged. Similarly, after 1 week on HFD, MIP-Cre(ER) mice have increased β-cell mass compared to WT, and this is due to hypertrophy rather than increased proliferation. To assess the impact of TM on β-cell proliferation and mass, WT mice were treated with vehicle corn oil or TM and then fed a chow diet or HFD for 3 days. We observed that TM-treated mice have improved glucose homeostasis on chow diet but impaired β-cell proliferation in response to 3 days HFD feeding. These results unveil additional complications associated with commonly used pancreas-specific mouse models.