2011 ADA Posters 1261-2041.indd - Diabetes

In multiple logistic regression analysis, serum A-FABP was an independent
risk factor for CAD in women (OR=12.078, P=0.031). Serum A-FABP increased
signifi cantly in multi-vessel diseased patients than in non-CAD subjects
(P=0.011 in men, P=0.004 in women), and showed a positive correlation
with CAI (r=0.134, P=0.032) after adjustment for age and gender. In addition,
amino terminal pro-brain natriuretic peptide (NT-proBNP) was demonstrated
to be positively and independently correlated with A-FABP in all subjects
(β=0.075, P=0.014).
Conclusions: Serum A-FABP is closely associated with the presence and
severity of CAD in Chinese women. A-FABP levels are also associated with
the circulating levels of NT-proBNP.
Supported by: Chinese National 973 Project (2007CB914702)
1799-P
SIRT1-Mediated Regulation of FGF21 Expression in Lean Mice Probed
with Small Molecule Activators and Genetic SIRT1 Deletion
ANGELA M. COTE, MARC O. JOHNSON, KRISTINE STEARNS, MEGHAN L. DAVIS,
DAVID J. GAGNE, MARIE YEAGER, JAMES L. ELLIS, VIPIN SURI, GEORGE P.
VLASUK, Cambridge, MA
The endocrine hormone Fibroblast Growth Factor 21 (FGF21) has broad
metabolic actions including weight loss, increased insulin sensitivity
and reduction of triglycerides in rodent models of obesity and metabolic
dysfunction. FGF21 is induced in mouse liver by prolonged fasting, a
ketogenic diet, and by agonists of peroxisome proliferator activated
receptor alpha (PPARa). The protein deacetylase SIRT1 also modulates FGF21
expression as hepatocytes defi cient in SIRT1 show reduced PPARa induced
FGF21 expression while modest overexpression of SIRT1 increases FGF21
expression in hepatocytes. However, the mechanism of SIRT1-mediated
regulation of FGF21 secretion in mice has not been fully explored.
To further understand the role of SIRT1 in mice, we analyzed the effect of
genetic and pharmacological manipulation of SIRT1 activity on the induction
of FGF21 by fasting as well as by two specifi c ligands of PPARa. A 24 hour fast
increased FGF21 expression in liver as well as serum FGF21 levels by 8-10 fold.
Oral administration of a specifi c small molecule SIRT1 activator during fasting
further enhanced FGF21 serum levels by about two-fold. Administration of
PPARa ligands WY14643 or GW7647 to ad lib fed mice also resulted in a dose
dependent increase in hepatic FGF21 expression as well as serum FGF21 levels
of up to 60 fold over vehicle treated ad lib fed mice. Concomitant administration
of a sub-maximal dose of PPARa agonists WY14643 or GW7647 and a SIRT1
activator to ad lib fed mice signifi cantly increased serum FGF21 levels beyond
those induced by the PPARa agonist alone.
We also analyzed the effects of fasting or PPARa agonists on FGF-21
induction in SIRT1 conditional knockout mice. In contrast to the positive
action of SIRT1 activator on FGF-21 induction, genetic deletion of SIRT1
signifi cantly muted induction of FGF21 expression in liver as well as serum
FGF-21 levels. Taken together these observations suggest a key role for
SIRT1 in the regulation of FGF-21 levels. In addition, these observations
suggest that regulation of FGF-21 levels may contribute to the metabolic
benefi ts of genetic or pharmacological SIRT1 activation.
1800-P
Sitagliptin Suppresses Ghrelin Hormone in Patients with Diabetes
BERHANE SEYOUM, ALEMU FITE, ABDUL B. ABOU-SAMRA, Detroit, MI
Ghrelin is an appetite-stimulating hormone mainly produced by the stomach.
Circulating levels of ghrelin concentration increase in fasting states and fall
following meal. Sitagliptin is an orally available new class of anti-diabetic
drug that inhibits dipeptidyl peptidase-4 (DPP-4) enzyme leading to 2-3 fold
increase in the serum concentration of endogenous glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This study
was performed to determine the effects of sitagliptin on circulating levels
of ghrelin. Control subjects (N=15) and 46 diabetic patients were recruited
for the study. The diabetic patients were treated with sitagliptin (N=15),
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INTEGRATED PHYSIOLOGY—OTHER CATEGORY HORMONES
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metformin (N=16) or combination of sitagliptin and metformin (N=15) for one
week. Serum concentrations of total and active ghrelin were determined
in all subjects immediately before and 2 hours after meal challenge. Same
testes were repeated among patients with diabetes after receiving drug
therapy for a week. Results demonstrated that postprandial active ghrelin
was more signifi cantly suppressed in patients with diabetes than in nondiabetic
controls. Maximum suppression was seen after patients were put
on treatment and after meal challenge. Active ghrelin was more signifi cantly
decreased than total ghrelin in diabetic patients (by 36%, p0.05) whereas active ghrelin decreased
from 140±26 pg/ml to 85±12 pg/ml (p