Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic ß cells.

Male mice lacking the androgen receptor (AR) in pancreatic ß cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in ß cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male ß cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO2, activating the HCO3--sensitive soluble adenylate cyclase; and (2) increased Gαs recruitment to GLP-1 receptor and AR complexes, activating transmembrane adenylate cyclase. Additionally, testosterone enhances GSIS in human islets via a focal adhesion kinase/SRC/phosphatidylinositol 3-kinase/mammalian target of rapamycin complex 2 actin remodeling cascade. We describe the testosterone-stimulated AR interactome, transcriptome, proteome, and metabolome that contribute to these effects. This study identifies AR genomic and non-genomic actions that enhance GLP-1-stimulated insulin exocytosis in male ß cells.

SARS-CoV-2 infection of the pancreas promotes thrombofibrosis and is associated with new-onset diabetes.

Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the cell entry factors for SARS-CoV-2, using publicly available single-cell RNA sequencing data sets, and pancreatic tissue from control male and female nonhuman primates (NHPs) and humans. We also examined SARS-CoV-2 immunolocalization in pancreatic cells of SARS-CoV-2-infected NHPs and patients who had died from coronavirus disease 2019 (COVID-19). We report expression of ACE2 in pancreatic islet, ductal, and endothelial cells in NHPs and humans. In pancreata from SARS-CoV-2-infected NHPs and COVID-19 patients, SARS-CoV-2 infected ductal, endothelial, and islet cells. These pancreata also exhibited generalized fibrosis associated with multiple vascular thrombi. Two out of 8 NHPs developed new-onset diabetes following SARS-CoV-2 infection. Two out of 5 COVID-19 patients exhibited new-onset diabetes at admission. These results suggest that SARS-CoV-2 infection of the pancreas may promote acute and especially chronic pancreatic dysfunction that could potentially lead to new-onset diabetes.

Mitochondrial Biogenesis Is Positively Regulated by Casein Kinase I Hrr25 Through Phosphorylation of Puf3 in Saccharomyces cerevisiae.

Mitochondrial biogenesis requires coordinated expression of genes encoding mitochondrial proteins, which in Saccharomyces cerevisiae is achieved in part via post-transcriptional control by the Pumilio RNA-binding domain protein Puf3 Puf3 binds to the 3'-UTR of many messenger RNAs (mRNAs) that encode mitochondrial proteins, regulating their turnover, translation, and/or mitochondrial targeting. Puf3 hyperphosphorylation correlates with increased mitochondrial biogenesis; however, the kinase responsible for Puf3 phosphorylation is unclear. Here, we show that the casein kinase I protein Hrr25 negatively regulates Puf3 by mediating its phosphorylation. An hrr25 mutation results in reduced phosphorylation of Puf3 in vivo and a puf3 deletion mutation reverses growth defects of hrr25 mutant cells grown on medium with a nonfermentable carbon source. We show that Hrr25 directly phosphorylates Puf3, and that the interaction between Puf3 and Hrr25 is mediated through the N-terminal domain of Puf3 and the kinase domain of Hrr25 We further found that an hrr25 mutation reduces GFP expression from GFP reporter constructs carrying the 3'-UTR of Puf3 targets. Downregulation of GFP expression due to an hrr25 mutation can be reversed either by puf3Δ or by mutations to the Puf3-binding sites in the 3'-UTR of the GFP reporter constructs. Together, our data indicate that Hrr25 is a positive regulator of mitochondrial biogenesis by phosphorylating Puf3 and inhibiting its function in downregulating target mRNAs encoding mitochondrial proteins.