Abstract

BackgroundInsulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown.Research ObjectiveTo determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet.Key MethodsThe primary endpoint was severity of coronary atherosclerosis in adult pigs (Sus scrofa, n = 37) fed a high fat diet that also contained high NaCl (56% above recommended levels) for 1 year.Principal FindingsTwenty pigs developed severe and diffuse distal coronary artery atherosclerosis (i.e., severe = intimal area as a percent medial area > 200% in at least 2 coronary artery cross sections and diffuse distal = intimal area as a percent medial area ≥ 150% over 3 sections separated by 2 cm in the distal half of the coronary artery). The other 17 pigs had substantially less coronary artery atherosclerosis. All 37 pigs had blood pressure in a range that would be considered hypertensive in humans and developed elevations in total and LDL and HDL cholesterol, weight gain, increased backfat, and increased insulin resistance (Bergman Si) without overt diabetes. Insulin resistance was not associated with atherosclerosis severity. Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis. Most importantly, the 20 high fat/high NaCl diet -fed pigs with severe and diffuse distal coronary artery atherosclerosis had substantially greater increases (p< 0.05) in oxidized LDL (oxLDL) and fructosamine consistent with increased protein glycation.ConclusionIn pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.

Highlights

  • The increasing prevalence of insulin resistance and type 2 diabetes is likely to be attended by a substantial increase in cardiovascular disease (CVD).[1,2,3] Insulin resistance (IR) is defined as a decreased biological response to normal concentrations of serum insulin that over time leads to compensatory hyperinsulinemia.[2]

  • In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis

  • Even the most aggressive medical treatment regimens do not lower the risk for CVD to the non-diabetic level. [9, 11,12,13,14,15] These findings strongly suggest that factors other than absolute glucose concentrations may be activating pathophysiological mechanisms that augment the development of atherosclerosis

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Summary

Introduction

The increasing prevalence of insulin resistance and type 2 diabetes is likely to be attended by a substantial increase in cardiovascular disease (CVD).[1,2,3] Insulin resistance (IR) is defined as a decreased biological response to normal concentrations of serum insulin that over time leads to compensatory hyperinsulinemia.[2]. [9, 11,12,13,14,15] These findings strongly suggest that factors other than absolute glucose concentrations may be activating pathophysiological mechanisms that augment the development of atherosclerosis. There is a need for a relevant animal model of insulin resistance and/or type 2 diabetes that exhibits severe and diffuse coronary and aortic atherosclerosis which are associated with identifiable biochemical abnormalities. Insulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown. To determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet

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