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Glucagon regulates hepatic kisspeptin to impair insulin secretion
#MMPMID24703698
Song WJ
; Mondal P
; Wolfe A
; Alonso LC
; Stamateris R
; Ong BW
; Lim OC
; Yang KS
; Radovick S
; Novaira HJ
; Farber EA
; Farber CR
; Turner SD
; Hussain MA
Cell Metab
2014[Apr]; 19
(4
): 667-81
PMID24703698
show ga
Early in the pathogenesis of type 2 diabetes mellitus (T2DM), dysregulated
glucagon secretion from pancreatic ? cells occurs prior to impaired
glucose-stimulated insulin secretion (GSIS) from ? cells. However, whether
hyperglucagonemia is causally linked to ? cell dysfunction remains unclear. Here
we show that glucagon stimulates via cAMP-PKA-CREB signaling hepatic production
of the neuropeptide kisspeptin1, which acts on ? 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 Lepr(db/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.
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