Biology Reference
In-Depth Information
Enhanced gluconeogenesis is another important component of insulin
resistance in T2DM. Interestingly, the induction of acute ER stress results
in reduced hepatic glucose output mediated by ATF6 interaction with the
CREB-regulated transcription coactivator 2 (CRTC2) that releases CREB,
which regulates fasting gluconeogenesis (
Wang et al., 2009c
). Moreover,
in CRTC2-knockout animals, decreased fasting gluconeogenesis and
improved insulin sensitivity are observed upon diet-induced obesity (
Wang
et al., 2010
). Additionally, chronic ER stress also increases gluconeogenesis.
Obese mice have lower levels of hepatic ATF6 and XBP-1, which reduces
the interaction of ATF6 with CRTC2, thereby favoring upregulation of the
gluconeogenesis program (
Wang et al., 2009c
). Furthermore, XBP-1 reduc-
tion contributes to enhanced JNK activation that triggers insulin resistance
(
Ozcan et al., 2004
).
PERK, the third branch of the UPR, acutely and chronically phosphor-
ylates eIEF2α during hepatic ER stress (
Ozcan et al., 2004
;
Lin et al., 2007
),
increasing gluconeogenesis via the translational activation of C/EBP. Addi-
tionally, the dephosphorylation of hepatic eIEF2α improves insulin sensi-
tivity in HFD mice (
Oyadomari et al., 2008
). eIF2α is also implicated in
hepatic lipogenesis. Thus, ATF6 knockout and chronic dephosphorylation
of eIF2α in a mouse model decrease C/EBP expression and downstream
lipogenic transcription factor activity (
Oyadomari et al., 2008
;
Rutkowski
et al., 2008
). Finally, ER stress contributes to hepatic fat accumulation
through changes in the nuclear localization of SREBP1c by an insulin-
independent pathway (
Kammoun et al., 2009
).
During the development of T2DM, insulin production by β-cells
is increased to compensate for insulin resistance. This increase in insu-
lin demand, together with increased fatty acid levels and hyperglycemia,
activates UPR in pancreatic cells (
Cnop et al., 2005
). Different kinds of
mutations are associated with diabetes. Missense mutations that interrupt
disulphide bridge formation and correct proinsulin folding cause neonatal
diabetes (
Støy et al., 2007
;
Colombo et al., 2008
). Moreover, mutations in
several UPR genes, like eif 2ak3 (which codes for PERK) and wsf1, are con-
sidered risk factors for the development of diabetes, in the Wolcott-Rallison
and Wolfram
syndromes, respectively (
Inoue et al., 1998
) (
Delépine et al.,
2000
). Prolonged T2DM can activate the UPR by hyperglycemia. In con-
trast, free fatty acids (FFA) may trigger ER stress early in diabetes. Sev-
eral groups have demonstrated that chronically high glucose levels cause
ER stress (
Wang et al., 2005
;
Lipson et al., 2006
;
Elouil et al., 2007
). For
example, cultured rat pancreatic islets exposed to high glucose (30 mM)
Search WWH ::
Custom Search