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Early studies showed nitric oxide as a pro-inflammatory-cytokine-induced toxin involved in pancreatic β-cell destruction during pathogenesis of type-1 diabetes. However, nitric oxide has both cytotoxic and cytoprotective effects on mammalian cells, depending on concentration and micro-environmental surroundings. Our studies have shown that low/physiological-level nitric oxide selectively activates protein kinase G type Iα isoform, promoting cytoprotective/pro-cell-survival effects in many cell types. In bone marrow–derived stromal/mesenchymal stem cells, protein kinase G type Iα mediates autocrine effects of nitric oxide and atrial natriuretic peptide, promoting DNA-synthesis/proliferation and cell survival. In this study, endothelial nitric oxide synthase/neuronal nitric oxide synthase inhibitor L-NIO (L-N(5)-(1-iminoethyl)ornithine), soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one), atrial natriuretic peptide–receptor inhibitor A71915 and protein kinase G type Iα kinase activity inhibitor DT-2 all increased apoptosis and decreased insulin secretion in RINm5F pancreatic β-cells, suggesting autocrine regulatory role for endogenous nitric oxide– and atrial natriuretic peptide–induced activation of protein kinase G type Iα. In four pancreatic β-cell lines, Beta-TC-6, RINm5F, INS-1 and 1.1B4, protein kinase G type Iα small-interfering RNA decreased phospho-serine-239-VASP (indicator of endogenous protein kinase G type Iα kinase activity), increased apoptosis and decreased proliferation. In protein kinase G type Iα–knockdown β-cell lines, expressions of phospho-protein kinase B (PKB/AKT) (AKT), phospho-Forkhead box protein O1 (FOXO1) (transcriptional repressor of pancreas duodenum homobox-1) and pancreas duodenum homobox-1 were decreased, suppressing proliferation and survival in pancreatic β-cells. The data suggest autocrine nitric oxide/atrial natriuretic peptide–induced activation of protein kinase G type Iα/p-AKT/p-FOXO1 promotes survival and proliferation in pancreatic β-cells, providing therapeutic implications for development of new therapeutic agents for diabetes.