It is unknown why patients with type II insulin resistant (IR) diabetes mellitus have an increased incidence of atherosclerosis when compared to non-diabetics. Our goal is to develop porcine models of IR and a mixed model of IR plus familial hypercholesterolemia that will be useful in studies to define the role of IR in atherosclerosis. The pigs will be used to determine if the presence of IR causes an increased burden of atherosclerosis compared to control animals without IR and to determine if markers of atherosclerosis that are present in these animals will correlate with disease progression in IR animals. Two unique strains of pigs will be used, one from Chapel Hill (CH) with increased total body fat and a second with familial hypercholesterolemia (FH) that are lean. Both the CH and FH strains have subpopulations with and without increased insulin resistance (IR).
In Aim I, CH-IR and FH-IR pigs will be bred for increased severity of IR.
In Aim II, the effect of IR on the extent of coronary, aortic, and carotid artery atherosclerosis and the changes in serum and tissue markers of atherosclerosis will be determined in CH-IR pigs and compared to CH pigs without IR, both groups being fed a high fat atherogenic diet. A second study will compare these same variables in FH-IR and FH-nonIR pigs fed normal (low fat) pig chow. Intravascular ultrasound (IVUS) will be used during the study to monitor disease progression in vivo. Both IVUS and morphometry of fixed vessels will be used to measure atherosclerosis at termination.
In Aim III, insulin like growth factor-I (IGF-1) will be given to the CH-IR pigs to reduce IR, and the pigs will be fed a high fat atherogenic diet. The extent of atherosclerosis and the changes in markers in these IGF-I treated pigs will be compared to controls.
In Aim I V, the FH-IR pigs will be fed normal (low fat) pig chow and an aVb3 inhibitor that we have shown reduces atherosclerosis in non-IR pigs and its effect on lesion development determined. Our overall objective is to develop a useful, relevant, available model of IR and atherosclerosis that can be used to identify mechanisms that lead to accelerated atherosclerosis in insulin resistant humans and to develop and test potential new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069364-05
Application #
6946463
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2001-09-30
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2007-08-31
Support Year
5
Fiscal Year
2005
Total Cost
$464,190
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Nichols, Timothy C; Merricks, Elizabeth P; Bellinger, Dwight A et al. (2015) Oxidized LDL and Fructosamine Associated with Severity of Coronary Artery Atherosclerosis in Insulin Resistant Pigs Fed a High Fat/High NaCl Diet. PLoS One 10:e0132302
Cannon, Coralie Zegre; Godfrey, Virginia L; King-Herbert, Angela et al. (2009) Metastatic uterine adenocarcinoma in an 8-year-old gilt. J Am Assoc Lab Anim Sci 48:795-800
Behler, Russell H; Nichols, Timothy C; Zhu, Hongtu et al. (2009) ARFI imaging for noninvasive material characterization of atherosclerosis. Part II: toward in vivo characterization. Ultrasound Med Biol 35:278-95
Bellinger, Dwight A; Merricks, Elizabeth P; Nichols, Timothy C (2006) Swine models of type 2 diabetes mellitus: insulin resistance, glucose tolerance, and cardiovascular complications. ILAR J 47:243-58
Dumont, Douglas; Behler, Russell H; Nichols, Timothy C et al. (2006) ARFI imaging for noninvasive material characterization of atherosclerosis. Ultrasound Med Biol 32:1703-11