Individuals with rheumatoid arthritis (RA) experience a more than 2-fold increased risk of myocardial infarction (1). Both traditional and nontraditional risk factors contribute to atherogenesis in RA (2, 3). Among these risk factors is insulin resistance, which is reported to be associated with inflammation and glucocorticoid therapy in RA (2, 4–6). In addition, RA patients experience a diabetes prevalence of 10–20% (7–9), and diabetes predicts increased rates of cardiovascular events in this disease (8, 9).
In the general population, insulin resistance is an established risk factor for cardiovascular disease and type 2 diabetes mellitus (DM) (10) and constitutes a central mechanism in the metabolic syndrome, wherein it clusters particularly with dyslipidemia and impaired glucose metabolism (11). In the general population, the main determinant of insulin resistance is abdominal obesity (11). Other contributing factors include age and hypertension (12, 13). In our experience, 50% of RA patients have hypertension (4). Furthermore, among the antihypertensive agents, β-blockers and diuretics have been reported to impair insulin sensitivity and to have the propensity to provoke the onset of type 2 DM, whereas angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) have favorable effects on glucose metabolism (14–16).
In normal subjects, decreased insulin sensitivity results in increased insulin secretion by pancreatic beta cells (12, 17). In contrast, in individuals predisposed to type 2 DM, this ability to compensate for insulin resistance is impaired (12, 17). Although type 2 DM is often (but not always) preceded by insulin resistance, impaired insulin secretion plays a more pivotal role than insulin resistance in the progression from normal glucose tolerance to type 2 DM (17).
In the Insulin Resistance Atherosclerosis Study, age and abdominal fat content were found to be main determinants of the presence of impaired insulin secretion (12). Enlarged fat cells release excess nonesterified fatty acids and adipokines that, in the long term, impair beta cell function (17). This process has been referred to as lipotoxicity (17–19). To our knowledge, insulin secretion has not been studied in RA. High-grade inflammation and glucocorticoid therapy, both of which are relevant in the context of RA, have the potential to adversely affect beta cell function (20–25).
In this study, we determined the relative contribution of characteristics known to affect glucose metabolism in the general population (age, abdominal obesity, hypertension, and antihypertensive agents) as well as characteristics of RA (disease activity and glucocorticoid therapy) to impaired insulin sensitivity and beta cell function in RA.
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- PATIENTS AND METHODS
In the present study, patients with high-grade inflammation had increased insulin resistance and reduced beta cell function as compared with patients with low-grade inflammation. Furthermore, patients with high-grade inflammation also had lower HDL cholesterol and higher ratios of triglycerides to HDL cholesterol and total cholesterol to HDL cholesterol, characteristics that form part of the metabolic/insulin resistance syndrome (10, 11, 36). Also, all 8 patients with impaired fasting glucose or diabetes had high-grade inflammation, although this association was not statistically significant. Impaired fasting glucose and diabetes are clinical hallmarks of impaired beta cell function (17). An unanticipated finding, however, was the higher body mass index and waist circumference in RA patients with high-grade inflammation, whereas in the general population, obesity contributes to both insulin resistance and reduced beta cell function (12). Adjustment for waist circumference in the logistic regression models indicated that abdominal obesity may explain differences in lipids, insulin resistance, and beta cell function between patients with high-grade inflammation and patients with low-grade inflammation.
In population studies, adiposity is closely correlated with circulating levels of cytokines and accounts for as much as 30% of the (low-grade) systemic inflammatory burden (2). The association of waist circumference with hsCRP concentrations in the present cohort therefore suggests that enlarged abdominal fat cell–derived adipokines, such as interleukin-6 (in addition to inflamed joint derived interleukin-6), also contribute to CRP concentrations in RA. We recently observed an increased waist circumference in RA patients as compared with healthy controls (P = 0.01), whereas the body mass index was similar in both groups (P = 0.1) (31). Westhovens et al (37) previously reported a decreased fat content in the legs, an increased abdominal fat content, and a generalized reduction in lean body mass in patients with RA. These characteristics form part of the so-called “rheumatoid cachexia” that affects more than 50% of RA patients and is related to cytokine production and use of glucocorticoids (37, 38). The contribution of abdominal obesity to CRP concentrations in RA may complicate the interpretation of this acute-phase response when used as a disease activity marker in these patients.
We found that insulin resistance was associated with waist circumference, hsCRP level, DAS28, ESR, patient's assessment of disease activity, presence of hypertension, and use of antihypertensive agents (a marker of hypertension in univariate analysis). Such associations between acute-phase responses and insulin resistance are well documented in RA (4, 5). In mixed regression models, waist circumference was the main contributor to insulin resistance, and among the RA characteristics, only the patient's assessment of disease activity made a significant, but small (5%), contribution to the model R2 of HOMA-IR. Previous studies of insulin resistance in RA did not report on the relative role of excess weight.
Obesity is the main determinant of insulin resistance in the general population (10–12). Our findings therefore suggest that the interventions that are increasingly recommended for the treatment of insulin resistance in the general population may be equally important in RA patients with insulin resistance (39–41). However, the present investigation was of a cross-sectional design, and longitudinal studies have clearly shown a marked improvement in insulin sensitivity upon suppression of disease activity with short-term glucocorticoid therapy and DMARDs in RA (5, 6). The relative importance of weight control and disease activity suppression in enhancing insulin sensitivity in RA deserves further study.
It is noteworthy that the patient's assessment of disease activity constituted the only disease activity variable that was independently associated with insulin resistance. As opposed to the other disease activity parameters that were recorded, the patient's assessment of disease activity is a self reported variable, and such characteristics are prone to be influenced by psychological status (42). This may be relevant in the present context, since depression is common in RA (43) and is related to insulin resistance (44).
We have previously reported an independent association between glucocorticoid use and insulin resistance in RA (7). This finding, together with other reported limitations of glucocorticoid therapy in RA (45–47), led to a radical reduction in glucocorticoid use in our clinics. Although the mean disease duration in this cohort (5 years) was shorter that that in our previous investigation (11 years) (7), the most relevant difference between the 2 cohorts was the extent of glucocorticoid therapy. The mean cumulative dose of glucocorticoids in the present study was <0.5 gm, as compared with 7.3 gm in our previous investigation (7). Short-term use of glucocorticoids in RA patients with insulin resistance and active disease was also reported to enhance insulin sensitivity (5). Taken together, the findings indicate that when glucocorticoids are used sparingly and tailored to disease activity, they may not adversely affect insulin sensitivity in RA. This may be most easily achieved by using low-dose intraarticular pulse glucocorticoid therapy (in combination with DMARD initiation or intensification), as was frequently done in the current cohort.
The DAS28, tender joint count, and patient's assessment of disease activity were independent negative predictors of beta cell function. Joint-derived cytokines induce the production of CRP and fibrinogen by the liver (2), whereas fibrinogen is the main determinant of the ESR (48), and certain cytokines adversely affect beta cell function (20–23). However, in contrast to the clinical disease activity variables, the CRP and ESR were not related to beta cell function in the present investigation. Mediators of altered beta cell function other than cytokines include adipocyte-derived nonesterified fatty acids and hormones such as adiponectin and leptin (17). Bokarewa et al (49) recently described increased circulating concentrations of leptin that were not related to the CRP concentrations in RA. The cross-sectional design of the present study precludes a determination of causality between RA disease activity and beta cell function. The interactions between adipocyte-derived substances, disease activity characteristics, and beta cell function in RA require further investigation.
Cumulative doses of glucocorticoids were strongly associated with enhanced beta cell function in the present cohort. In a longitudinal investigation, glucocorticoid therapy accounted for the increased incidence of diabetes in RA (8). These apparently contrasting findings may again relate to differences in glucocorticoid use. In the latter study (8), 33% of the patients were taking prednisone, as compared with 13% in the present investigation. In our 15 patients who were taking prednisone, the dosage was ≤4 mg/day in 8 of them. Although our results need to be confirmed longitudinally, when glucocorticoids are used sparingly in RA, they may improve beta cell function through their antiinflammatory effects, which outweigh their known adverse effects on glucose metabolism (7, 25).
In patients with high-grade inflammation, age was further associated with decreased beta cell function in the mixed regression models. Age was found to be the most important determinant of impaired beta cell function in a large population study (12). Also, the use of ACE inhibitors and/or ARBs was associated with enhanced beta cell function. Recent clinical trials have revealed that the use of these agents lowers the risk of type 2 DM in patients with hypertension (16). There is also evidence that blockade of the renin–angiotensin system may promote the differentiation of adipocytes, which may result in improved insulin sensitivity and decreased storage of excess calories in the pancreas, thereby reducing lipotoxicity and improving insulin secretion (50). Our results may further support the use of the latter agents as first-line therapy for hypertension in RA.
As mentioned above, a limitation of this study is its cross-sectional design, and our findings need to be confirmed in a longitudinal investigation. We evaluated only 94 patients. An analysis of a larger data set may reveal a greater number of significant associations between the independent variables assessed in the current study and insulin resistance and impaired beta cell function. Also, we used the HOMA-IR and HOMA-B (29) to evaluate insulin resistance and beta cell function, respectively. Alternative methods include dynamic tests, such as the hyperinsulinemic euglycemic clamp for insulin resistance and the hyperglycemic clamp for beta cell function. However, the latter techniques are not necessarily superior to the HOMA-IR and the HOMA-B (29). Rather, they give information about different aspects of insulin resistance and beta cell function. Each of these different investigations has its own limitations. Furthermore, there is a good correlation between estimates of insulin resistance derived from the HOMA-IR and from the euglycemic clamp, and between estimates of beta cell function derived from the HOMA-B and from the hyperglycemic clamp (29). Finally and as alluded to previously, in view of the sparing use of glucocorticoids, our results may not apply to RA patients treated with higher doses of the corticosteroids.
In conclusion, abdominal obesity and RA disease activity were determinants of insulin resistance in this cohort of patients with RA. Age and disease activity were associated with reduced beta cell function, whereas treatment of hypertension with ACE inhibitors and/or ARBs and the sparing use of glucocorticoids were associated with enhanced beta cell function. Since abdominal obesity, antihypertensive therapy, disease activity, and glucocorticoid use constitute factors that are modifiable, our findings may have implications for the prevention and treatment of cardiovascular disease and diabetes in RA.