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

The 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, Gα z , as a key negative regulator of β-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gα z 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 Gα z knockout (βKO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gα z βKO mice as compared to wild-type (WT) controls, but, unlike global Gα z knockout mice, this protection was incomplete. While young male and female Gα z βKO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gα z βKO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, β-cell-specific Gα z 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 Gα z βKO NOD was best explained by an early failure to up-regulate β-cell proliferation. We conclude β-cell Gα z 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.