From the Department of Medicine, University of Texas Health Science
Center at San Antonio, Texas (S.M.H.); the Department of Public Health
Sciences, Winston-Salem, NC (R.D'A.); the Department of Clinical
Biochemistry, University of Cambridge, Cambridge, UK (C.N.H.); the National
Heart, Lung and Blood Institute, Division of Epidemiology and Clinical
Applications, Bethesda, Md (P.J.S.); the Department of Physiology and
Biophysics, University of Southern California School of Medicine, Los Angeles,
Calif (R.N.B.); the Department of Radiology, Tufts University School of
Medicine, Boston, Mass (D.O'L.); the Department of Preventive Medicine
and Biometrics, University of Colorado Medical School, Denver, Colo (M.R.);
Kaiser Permanente, Division of Research, Oakland, Calif (J.S.); the Department
of Pathology, University of Vermont School of Medicine, Burlington, Vt (R.T.);
and the Department of Medicine, University of California at Los Angeles School
of Medicine, Los Angeles, Calif (M.F.S.).
Background and Purpose—Insulin
resistance and hyperinsulinemia have been
associated with atherosclerosis. Recent attention has
focused on the possible role of proinsulin because most
radioimmunoassays for insulin cross-react with proinsulin. Therefore,
it is not known which of the two, insulin per se or
proinsulin, is more strongly related to atherosclerosis.
Methods—We examined the relation between fasting proinsulin,
fasting split proinsulin, fasting and 2-hour insulin (after oral
glucose load), and intima-media wall thickness (IMT) in the common
carotid artery (CCA) and internal carotid artery (ICA) in 985
nondiabetic subjects from the Insulin Resistance
Atherosclerosis Study, a multiethnic study of insulin
resistance and atherosclerosis.
Results—In the overall population, a weak but significant
relation between proinsulin and CCA IMT was observed
(r=0.07, P=0.029). However, the relation
between proinsulin and IMT was stronger in Hispanics and non-Hispanic
whites than in African Americans. In non-Hispanic whites and Hispanics,
significant correlations between CCA and proinsulin
(r=0.087) and between ICA and proinsulin
(r=0.101), split proinsulin (r=0.092),
and fasting insulin (r=0.087) were observed. The
significant correlations became more attenuated (and nonsignificant)
after adjustment for cardiovascular risk factors,
especially plasminogen activator
inhibitor-1 (PAI-1).
Conclusions—The association between proinsulin and IMT, while
weak, appears to be stronger than the association between insulin and
IMT. Adjustment for PAI-1 markedly attenuated the association between
proinsulin and IMT, suggesting a possible mediating role for PAI-1 in
this association. It is possible that proinsulin may represent
a marker of atherosclerosis rather than a causal factor
for atherosclerosis. Studies of the insulin resistance
syndrome and atherosclerosis that use insulin as a
surrogate for insulin resistance should consider the use of specific
insulin assays as well as determination of proinsulin concentrations.
© 1998 American Heart Association, Inc.
Original Contributions
Proinsulin and Insulin Concentrations in Relation to Carotid Wall Thickness
Insulin Resistance Atherosclerosis Study
Key Words: atherosclerosis • insulin • plasminogen activator inhibitor-1 • proinsulin
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