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2016 ; 1
(3
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
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English Wikipedia
Trimeprazine increases IRS2 in human islets and promotes pancreatic ? cell growth
and function in mice
#MMPMID27152363
Kuznetsova A
; Yu Y
; Hollister-Lock J
; Opare-Addo L
; Rozzo A
; Sadagurski M
; Norquay L
; Reed JE
; El Khattabi I
; Bonner-Weir S
; Weir GC
; Sharma A
; White MF
JCI Insight
2016[]; 1
(3
): ä PMID27152363
show ga
The capacity of pancreatic ? cells to maintain glucose homeostasis during chronic
physiologic and immunologic stress is important for cellular and metabolic
homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein
that links the insulin and IGF1 receptors to downstream signaling cascades. Since
strategies to maintain or increase IRS2 expression can promote ? cell growth,
function, and survival, we conducted a screen to find small molecules that can
increase IRS2 mRNA in isolated human pancreatic islets. We identified 77
compounds, including 15 that contained a tricyclic core. To establish the
efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate,
was investigated in isolated human islets and in mouse models. Trimeprazine is a
first-generation antihistamine that acts as a partial agonist against the
histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human
islets. Trimeprazine promoted CREB phosphorylation and increased the
concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase
nuclear Pdx1, islet mass, ? cell replication and function, and glucose tolerance
in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the
progression of diabetes in NOD mice. Finally, it increased the function of human
islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus,
trimeprazine, its analogs, or possibly other compounds that increase IRS2 in
islets and ? cells without adverse systemic effects might provide mechanism-based
strategies to prevent the progression of diabetes.
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