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E-GEOD-48815 - Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

Status
Released on 1 April 2014, last updated on 3 June 2014
Organism
Mus musculus
Samples (15)
Array (1)
Protocols (7)
Description
Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
Experiment type
transcription profiling by array 
Contacts
Stephen Turner <geo@ncbi.nlm.nih.gov>, Mehboob A Hussain, Stephen D Turner, Woo-Jin Song
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-48815.idf.txt
Sample and data relationshipE-GEOD-48815.sdrf.txt
Processed data (1)E-GEOD-48815.processed.1.zip
Additional data (1)E-GEOD-48815.additional.1.zip
Array designA-MEXP-1174.adf.txt
Links