2011 ADA Posters 1261-2041.indd - Diabetes

Integrated Physiology/
Obesity
POSTERS
prevented the THAP- and TUNI-induced decreases in insulin-stimulated
IRS1 Y 612 phosphorylation and glucose uptake. These data suggest a novel
paradigm where ER stress enhances TRB3 expression leading to insulin
resistance in skeletal muscle. ADA-Funded Research
& 1715-P
Effects of Muscle Specifi c Deletion of Carnitine Palmitoyltransferase
and Carnitine Acetyltransferase on Fuel Selection
JINGYING ZHANG, ROBERT C. NOLAN, SARAH E. SEILER, TIMOTHY R. KOVES,
INDU KHETERPAL, ROBERT D. STEVENS, OLGA R. ILKAYEVA, DEBORAH M.
MUOIO, RANDALL L. MYNATT, Baton Rouge, LA, Durham, NC
Mitochondrial fatty acid import and oxidation is initiated by carnitine
palmitoyltransferase-I (CPTI). CPTI is located in the outer mitochondrial
membrane and catalyzes the formation of long chain acyl-carnitines from
carnitine and acyl-CoA. Short chain acyl-carnitines are formed via the
activity of carnitine acetyltransferase (CrAT) in the mitochondrial matrix.
Even though CrAT’s role is not completely understood, it is thought to buffer
acetyl-CoA/CoA in the mitochondria. To understand the role of each enzyme
in energy homeostasis, substrate utilization and insulin sensitivity; mice
were generated with muscle specifi c deletion of CPT-I m-/- and CrAT m-/- . CPT-
I m-/- and CrAT m-/- mice have normal body weight, fat mass, fat free mass,
energy expenditure and food intake. However, long chain fatty acid oxidation
is greatly reduced in muscle homogenates and isolated mitochondria
from CPT-I m-/- mice. Given the popular hypothesis that impaired fatty acid
oxidation in skeletal muscle causes the accumulation of lipid intermediates
leading to insulin resistance, we paradoxically observed improved GTT
and ITT in CPT-I m-/- mice relative to control mice. Metabolic chamber data
demonstrated that CPT-I m-/- mice oxidize more carbohydrate than control
mice. Conversely, CrAT m-/- mice had impaired GTT and ITT relative to control
mice. Metabolic chamber data revealed no difference in 24 hour RER
between CrAT m-/- and control mice, but there is impaired switching from
fatty acid oxidation to carbohydrate oxidation during the transition from a
fasted to fed state. In vitro studies in muscle homogenates and isolated
mitochondria demonstrated that the addition of carnitine increased PDH
activity and the complete oxidation of pyruvate in control mice but not CrAT
m-/- mice. In addition, the ability of pyruvate to suppress fatty acid oxidation
was blunted in mitochondria from CrAT m-/- mice. Together our data indicate
that, the loss of skeletal muscle CPTI results in reduced oxidization of long
chain fatty acids and stimulates glucose oxidation, whereas the loss of CrAT
in muscle predominately affects metabolic fl exibility.
Supported by: NIH ADA-Funded Research
& 1716-P
Diabetes Mellitus Impact on Left Ventricular Myocardial Structure
and Function in Aortic Stenosis before Valve Replacement
INÊS FALCÃO-PIRES, NAZHA HAMDANI, CRISTINA GAVINA, JOLANDA VAN DER
VELDEN, ATTILA BORBÉLY, HANS NIESSEN, GER STIENEN, ADELINO F. LEITE-
MOREIRA, WALTER J. PAULUS, Porto, Portugal, Amsterdam, The Netherlands,
Debrecen, Hungary, Amsterdam, Portugal
Diabetes mellitus (DM) is an independent risk factor for progression of
aortic valve stenosis (AS) and signifi cantly impacts longterm outcome after
valve replacement. High incidence of residual heart failure may account
for this prognosis. We aimed to assess the impact of DM on diastolic (dys)
function of AS patients.
Patients with severe isolated AS (n=46) and AS plus type-II diabetes
(AS-DM + ,n=16) with preserved left ventricular (LV) ejection fraction and
no clinical or angiographic signs of coronary artery disease were studied.
Doppler echocardiographic data was used to compare in vivo LV function.
Biopsies were used to assess fi brosis, cardiomyocyte hypertrophy
(MyD), advanced glycation endproducts (AGEs) and phosphorylation of
myofi lamentary proteins. Isolated and permeabilized cardiomyocytes were
used to measure active force (F active ), resting force (F passive ) and myofi lament
calcium sensitivity(pCa 50 ).
In isolated AS, LV deceleration time and end-diastolic pressure were
augmented (239±19ms; 21.4±1.4mmHg, respectively) and the latter
signifi cantly correlated with increased fi brosis (12.9±1.1%; r=0.40,p=0.04)
and MyD (22.9±0.5μm; r=0.60, p