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Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of
Rapamycin Signaling Independently of Insulin Receptor
#MMPMID26400569
Villarreal R
; Mitrofanova A
; Maiguel D
; Morales X
; Jeon J
; Grahammer F
; Leibiger IB
; Guzman J
; Fachado A
; Yoo TH
; Busher Katin A
; Gellermann J
; Merscher S
; Burke GW
; Berggren PO
; Oh J
; Huber TB
; Fornoni A
J Am Soc Nephrol
2016[Apr]; 27
(4
): 1029-41
PMID26400569
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Nephrin belongs to a family of highly conserved proteins with a well
characterized function as modulators of cell adhesion and guidance, and nephrin
may have a role in metabolic pathways linked to podocyte and pancreatic ?-cell
survival. However, this role is incompletely characterized. In this study, we
developed floxed nephrin mice for pancreatic ?-cell-specific deletion of nephrin,
which had no effect on islet size and glycemia. Nephrin deficiency, however,
resulted in glucose intolerance in vivo and impaired glucose-stimulated insulin
release ex vivo Glucose intolerance was also observed in eight patients with
nephrin mutations compared with three patients with other genetic forms of
nephrotic syndrome or nine healthy controls.In vitro experiments were conducted
to investigate if nephrin affects autocrine signaling through insulin receptor A
(IRA) and B (IRB), which are both expressed in human podocytes and pancreatic
islets. Coimmunoprecipitation of nephrin and IRB but not IRA was observed and
required IR phosphorylation. Nephrin per se was sufficient to induce
phosphorylation of p70S6K in an phosphatidylinositol 3-kinase-dependent but
IR/Src-independent manner, which was not augmented by exogenous insulin. These
results suggest a role for nephrin as an independent modulator of podocyte and
pancreatic ?-cell nutrient sensing in the fasting state and the potential of
nephrin as a drug target in diabetes.
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