The alpha subunit of the heterotrimeric Gz protein, Gαz, promotes beta-cell death and inhibits be... more The alpha subunit of the heterotrimeric Gz protein, Gαz, promotes beta-cell death and inhibits beta-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional beta-cell mass in the non-obese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in Gαz knockout mice. By 17 weeks of age, Gαz-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets from these mice had reduced markers of pro-inflammatory immune cell infiltration, both on the histological and the transcript levels, and secreted more insulin in response to glucose. Further analyses of pancreas sections revealed significantly fewer TUNEL+ beta-cells in Gαz-null islets, despite similar immune infiltration in control mice. Islets from Gαz-null mice also exhibited a higher percentage of Ki-67-positive beta-cells, a measure o...
Type 1 diabetes (T1D) occurs when β-cell death causes insufficient β-cell mass to maintain normog... more Type 1 diabetes (T1D) occurs when β-cell death causes insufficient β-cell mass to maintain normoglycemia. Although select T1D patients are candidates for transplantation, no pharmaceutical cure for T1D exists. Such cures would augment the residual β-cell mass had by most, if not all, T1D patients. We showed the α subunit of the heterotrimeric Gz protein, Gαz, inhibits production of cAMP, a second messenger proposed to potentiate β-cell function and mass. In an obesity-linked T2D model, we demonstrated islets from Gαz-null mice have constitutively increased β-cell cAMP production, insulin secretion, and replicative capacity. We hypothesized Gαz-null mice subjected to chemical induction of T1D would have improved β-cell replication, survival, and, ultimately, mass, especially when treated with drugs known to stimulate cAMP production. To test our hypothesis, we induced diabetes in mice with streptozotocin. The Gαz-null mutation partially protected against hyperglycemia, as did treatme...
The alpha subunit of the heterotrimeric Gz protein, Gαz, promotes beta-cell death and inhibits be... more The alpha subunit of the heterotrimeric Gz protein, Gαz, promotes beta-cell death and inhibits beta-cell replication when pancreatic islets are challenged by stressors. Thus, we hypothesized that loss of Gαz protein would preserve functional beta-cell mass in the non-obese diabetic (NOD) model, protecting from overt diabetes. We saw that protection from diabetes was robust and durable up to 35 weeks of age in Gαz knockout mice. By 17 weeks of age, Gαz-null NOD mice had significantly higher diabetes-free survival than wild-type littermates. Islets from these mice had reduced markers of pro-inflammatory immune cell infiltration, both on the histological and the transcript levels, and secreted more insulin in response to glucose. Further analyses of pancreas sections revealed significantly fewer TUNEL+ beta-cells in Gαz-null islets, despite similar immune infiltration in control mice. Islets from Gαz-null mice also exhibited a higher percentage of Ki-67-positive beta-cells, a measure o...
Type 1 diabetes (T1D) occurs when β-cell death causes insufficient β-cell mass to maintain normog... more Type 1 diabetes (T1D) occurs when β-cell death causes insufficient β-cell mass to maintain normoglycemia. Although select T1D patients are candidates for transplantation, no pharmaceutical cure for T1D exists. Such cures would augment the residual β-cell mass had by most, if not all, T1D patients. We showed the α subunit of the heterotrimeric Gz protein, Gαz, inhibits production of cAMP, a second messenger proposed to potentiate β-cell function and mass. In an obesity-linked T2D model, we demonstrated islets from Gαz-null mice have constitutively increased β-cell cAMP production, insulin secretion, and replicative capacity. We hypothesized Gαz-null mice subjected to chemical induction of T1D would have improved β-cell replication, survival, and, ultimately, mass, especially when treated with drugs known to stimulate cAMP production. To test our hypothesis, we induced diabetes in mice with streptozotocin. The Gαz-null mutation partially protected against hyperglycemia, as did treatme...
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