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thereby attenuated insulin-induced degradation of IRS-1, leading to an
increased insulin signaling downstream of IRS-1.
29
When endogenous
b
-arrestin-1 was knocked down by
b
-arrestin-1 siRNA, insulin-induced
IRS-1 degradation was enhanced. Thus,
b
-arrestin-1 participates in long-
term and
b
-arrestin-2 in short-term insulin signaling.
3.2. Signals mediating insulin secretion
Normal islet function is a prerequisite for normal glucose homeostasis.
In fact, islet dysfunction is a key event underlying development of type 2
diabetes, as manifested by impaired insulin secretion.
30
Islet function is reg-
ulated by a number of different signals including hormones, neurotransmit-
ters, and nutrients. Several of these factors signal through GPCRs for
regulation of insulin secretion and glucose homeostasis.
31
Current studies
show that
b
-arrestin-1 functions to mediate GPCR signaling in islets.
32
GLP-1 is a polypeptide hormone secreted from enteroendocrine L cells
and potentiates glucose-dependent insulin secretion in pancreatic cells.
Recently, the GLP-1 receptor (GLP-1R) has been the focus of a new form
of antidiabetic therapy, with the introduction of GLP-1 analogs and dipeptidyl
peptidase type IV inhibitors. This has stimulated additional interest in the
mechanisms of GLP-1 signaling.
33
b
-Arrestin-1 mediates the effects of
GLP-1 to stimulate cAMP production and insulin secretion in cells.
34
Using
a coimmunoprecipitation technique, Sonoda
et al.
found a physical association
between the GLP-1R and
b
-arrestin-1 in cultured INS-1 pancreatic cells.
Knockdown of
b
-arrestin-1 broadly attenuated GLP-1 signaling, causing
decreased ERK and CREB activation, and IRS-2 expression, as well as
reduced cAMP levels and impaired insulin secretion. However,
b
-arrestin-1
knockdown did not affect GLP-1R surface expression or ligand-induced
GLP-1R internalization/desensitization. Further, Queyer
et al.
found that
in MIN6
b
-cells, GLP-1 stimulates the phosphorylation of the proapoptotic
protein BAD through the
b
-arrestin-1-dependent ERK1/2-p90RSK cas-
cade.
35
Thus,
b
-arrestin-1 seems to play important roles in mediating
GLP-1-stimulated insulin secretion as well as
b
-cell survival.
The pituitary adenylate cyclase-activating polypeptide (PACAP) is
expressed in islet parasympathetic nerve terminals and strongly potentiates
insulin secretion in a glucose-dependent manner. PACAP functions
through three GPCRs (PAC1, VPAC1, and VPAC2) via the G
a
s/
cAMP/PKA pathway.
36
Broca
et al.
found that,
in the rat pancreatic
INS-1E cell
line, PACAP via PAC1R activates ERK1/2 by two
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