The islet in type 2 diabetes is characterized by an ~60% beta cell deficit, increased beta cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) but not rodent IAPP (r-IAPP) forms toxic oligomers and amyloid fibrils in an aqueous environment. We previously reported that overexpression of h-IAPP in transgenic rats triggered endoplasmic reticulum (ER) stress induced apoptosis in beta cells. In the present study we sought to establish if the cytotoxic effects of h-IAPP depend on its propensity to oligomerize, rather than as a consequence of protein overexpression. To accomplish this we established a novel homozygous mouse model overexpressing r-IAPP at a comparable expression rate, and on the same background, as a homozygous transgenic h-IAPP mouse model previously reported to develop diabetes associated with beta cell loss. We report that by ten weeks of age h-IAPP mice develop diabetes with a deficit in beta cell mass due to increased beta cell apoptosis. The r-IAPP transgenic mice counterparts do not develop diabetes or have decreased beta cell mass. Both r-IAPP and h-IAPP transgenic mice have increased expression of BiP, but only h-IAPP transgenic mice have elevated ER stress markers (XBP1, nuclear localized CHOP, active caspase-12 and accumulation of ubiquitinated proteins). These findings indicate that the beta cell toxic effects of h-IAPP depend on the propensity of IAPP to aggregate, but not on the consequence of protein overexpression.