The protection of Gαz-null NOD mice from hyperglycemia is sexually dimorphic and only partially β-cell autonomous

Abstract

AbstractThe mechanisms that underlie the β-cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our group has defined the unique heterotrimeric G protein alpha-subunit, Gαz, as a key negative regulator of β-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gαz throughout the body are protected from developing T1D-like hyperglycemia. To determine whether this phenotype is β-cell autonomous, we generated and validated a β-cell-specific Gαz knockout (βKO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gαz βKO mice as compared to wild-type (WT) controls, but, unlike global Gαz knockout mice, this protection was incomplete. While young male and female Gαz βKO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gαz βKO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, β-cell-specific Gαz loss only influenced insulitis in 28-29-week old male NOD mice, a phenotype correlating directly with body burden of glucose during oral glucose challenge. Using surrogates for β-cell function and apoptosis, the partial penetrance of euglycemia in Gαz βKO NOD was best explained by an early failure to up-regulate β-cell proliferation. We conclude β-cell Gαz is an important regulator of the sexually-dimorphic T1D-like phenotype of NOD mice. Yet, other factors must be important in imparting full protection from the disease.