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SummaryEarly in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated glucagon secretion from pancreatic α cells occurs prior to impaired glucose-stimulated insulin secretion (GSIS) from β cells. However, whether hyperglucagonemia is causally linked to β cell dysfunction remains unclear. Here we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production of the neuropeptide kisspeptin1, which acts on β cells to suppress GSIS. Synthetic kisspeptin suppresses GSIS in vivo in mice and from isolated islets in a kisspeptin1 receptor-dependent manner. Kisspeptin1 is increased in livers and in serum from humans with T2DM and from mouse models of diabetes mellitus. Importantly, liver Kiss1 knockdown in hyperglucagonemic, glucose-intolerant, high-fat-diet fed, and Leprdb/db mice augments GSIS and improves glucose tolerance. These observations indicate a hormonal circuit between the liver and the endocrine pancreas in glycemia regulation and suggest in T2DM a sequential link between hyperglucagonemia via hepatic kisspeptin1 to impaired insulin secretion.

SummaryImpaired insulin secretion contributes to the pathogenesis of type 2 diabetes mellitus (T2DM). Treatment with the incretin hormone glucagon-like peptide-1 (GLP-1) potentiates insulin secretion and improves metabolic control in humans with T2DM. GLP-1 receptor-mediated signaling leading to insulin secretion occurs via cyclic AMP stimulated protein kinase A (PKA)- as well as guanine nucleotide exchange factor-mediated pathways. However, how these two pathways integrate and coordinate insulin secretion remains poorly understood. Here we show that these incretin-stimulated pathways converge at the level of snapin, and that PKA-dependent phosphorylation of snapin increases interaction among insulin secretory vesicle-associated proteins, thereby potentiating glucose-stimulated insulin secretion (GSIS). In diabetic islets with impaired GSIS, snapin phosphorylation is reduced, and expression of a snapin mutant, which mimics site-specific phosphorylation, restores GSIS. Thus, snapin is a critical node in GSIS regulation and provides a potential therapeutic target to improve β cell function in T2DM.

The high plasma levels of lipoprotein(a) [Lp(a)] are associated with atherosclerosis. The apo(a) gene is responsible for the variance of Lp(a) concentration and its expression is liver-specific. By 5'-deletion analysis, we, in a luciferase gene reporter assay, have identified a 64-bp AT-rich region of upstream apo(a) gene (-703 to -640) that binds to multiple liver-specific factors. The 64 bp cis-element contained three dyad symmetry elements (DSEs) that are crucial for synergistic binding to the factors. We have demonstrated that both DSE-2 and -3 together are responsible for factor binding in vitro, and for gene activation in liver cells. Further, we have purified one of the UV cross-linked DNA-protein complexes to homogeneity by streptavidin magnetic bead chromatography. The identification of a further upstream negative regulatory region (-1432 to -704) led us to predict that as yet unidentified transcriptional repressor(s) might also repress apo(a) gene transcription.