Premature Atherosclerosis Associated With Monogenic Insulin Resistance

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Abstract
Background —The common insulin resistance syndrome, with obesity, dyslipidemia, hyperglycemia, and hypertension, is associated with increased risk of atherosclerosis. Early atherosclerosis in rare monogenic forms of insulin resistance, however, has not been extensively documented. Cardiovascular end points were thus evaluated in subjects with Dunnigan-type familial partial lipodystrophy (FPLD) due to mutations at LMNA codon 482. Methods and Results —FPLD subjects ≥35 years old were stratified by genotype for either the LMNA R482Q or R482W mutation. Twenty-three subjects were heterozygous mutation carriers, and 17 were R482/R482 homozygous family control subjects. All LMNA mutation carriers had FPLD with insulin resistance. In addition, LMNA mutation carriers had significantly more type 2 diabetes, hypertension, and dyslipidemia than normal family control subjects. Eight LMNA mutation carriers had coronary heart disease (CHD), compared with 1 normal control subject (OR 5.9, 95% CI 1.2 to 30.2). Six LMNA mutation carriers had CHD end points before age 55 years, and 4 of these, all women, had been hospitalized for CABG surgery between the ages of 35 and 54 years. Conclusions —Rare LMNA mutations that underlie FPLD with insulin resistance and hyperinsulinemia are also associated with early CHD, notably in women. This suggests that abnormalities of the nuclear envelope can result in a phenotype that recapitulates most of the important attributes of the common insulin resistance syndrome, including accelerated cardiovascular disease. FPLD thus appears to be an appropriate human monogenic model for the common insulin resistance syndrome.