Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms

In recent studies, we showed a marked increase in the prevalence of the metabolic syndrome, a constellation of cardiovascular risk factors that includes central obesity, dyslipidemia, hypertension, and disturbed glucose metabolism, in patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (1,2). Insulin resistance is a key component of the World Health Organization–defined metabolic syndrome that is increased in patients with RA or SLE (3,4). Insulin resistance is an important contributor to the increased cardiovascular risk attributed to the metabolic syndrome (5,6), and therefore, it is important to understand its pathogenesis. There are several mechanisms that could contribute to altered insulin sensitivity that may be important in patients with RA or SLE, and they provide insights into the pathogenesis of insulin resistance associated with inflammation. These include obesity (7), the medications used to treat inflammatory diseases (8,9), and inflammatory mediators (3). Obesity is a highly prevalent and modifiable risk factor associated with insulin resistance and the metabolic syndrome (10). In addition, adipose tissue functions as an endocrine organ and produces several inflammatory mediators, thus contributing to a proinflammatory state and increased cardiovascular risk (10). Glucocorticoids modulate appetite, metabolism and energy partitioning, exacerbate obesity (11), and induce insulin resistance and redistribution of fat, features of the metabolic syndrome (12,13). Inflammation, acting through cytokines such as tumor necrosis factor α (TNFα), facilitates the development of insulin resistance (14). The concentrations of TNFα and other mediators are elevated in patients with inflammatory diseases, but their role in the mechanisms underlying insulin resistance associated with inflammation is unknown. Thus, we examined the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, SLE and RA.