OBJECTIVE:To study the relation of fibrinogen and C-reactive protein (CRP) to various measures of body fat and body fat distribution and to investigate whether these relations were explained by differences in insulin sensitivity. DESIGN AND SUBJECTS: Cross-sectional analysis of the IRAS (Insulin Resistance Atherosclerosis Study), a large (n ¼ 1559) triethnic population (non-Hispanic whites, African-Americans and Mexican-Americans) across different states of glucose tolerance. MEASUREMENTS: Glucose tolerance (oral glucose tolerance test), insulin sensitivity (frequently sampled intravenous glucose tolerance test and minimal model analysis), assessment of body fat mass and distribution (weight, girths, bioelectrical impedance), subclinical atherosclerosis (B-mode ultrasonography of carotid artery intima-media thickness, IMT), CRP (highly sensitive immunoassay), fibrinogen (standard assay). RESULTS: Both CRP and fibrinogen were related to all measures of body fat. Strong correlations (correlation coefficient r ! 0.35) were found between CRP and body mass index (BMI), waist circumference and adipose body mass, respectively. The associations were consistent in non-diabetic and type-2 diabetic subjects, were generally stronger in women, and were only moderately attenuated by the prevailing insulin sensitivity (S I ). In a multivariate linear regression model waist circumference explained 14.5% of the variability of circulating CRP levels (P ¼ 0.0001), BMI 0.4% (P ¼ 0.0067), and S I 1.7% (P ¼ 0.0001). Common carotid artery IMT was related to CRP and fibrinogen in men, but not in women, and was attenuated after adjusting for BMI or waist. CONCLUSION: Our findings show that measures of body fat are strongly associated with circulating levels of CRP and fibrinogen. These associations were not explained by lower S I in obese subjects. Chronic, subclinical inflammation may be one pathophysiological mechanism explaining the increased risk of atherosclerotic disease associated with adiposity.

We observed considerably greater IMT among persons with established diabetes but no significant increase in persons with IGT. These data suggest that the increased risk of CHD observed in persons with diabetes may largely develop after the onset of overt diabetes.

Patients with NIDDM are at increased risk for coronary heart disease (CHD). However, information on the predictive value of cardiovascular risk factors and the degree of hyperglycemia with respect to the risk for CHD in diabetic patients is still limited. Therefore, we carried out a prospective study on risk factors for CHD, including a large number of NIDDM patients. At baseline, risk factor levels of CHD were determined in 1,059 NIDDM patients (581 men and 478 women), aged from 45 to 64 years. These patients were followed up to 7 years with respect to CHD events. Altogether, 158 NIDDM patients (97 men [16.7%] and 61 women [12.8%]) died of CHD and 256 NIDDM patients (156 men [26.8%] and 100 women [20.9%]) had a serious CHD event (death from CHD or nonfatal myocardial infarction). A previous history of myocardial infarction, low HDL cholesterol level (<1.0 mmol/l), high non-HDL cholesterol (> or =5.2 mmol/l), high total triglyceride level (>2.3 mmol/l), and high fasting plasma glucose (>13.4 mmol/l) were associated with a twofold increase in the risk of CHD mortality or morbidity, independently of other cardiovascular risk factors. High calculated LDL cholesterol level (> or =4.1 mmol/l) was significantly associated with all CHD events. The simultaneous presence of high fasting glucose (>13.4 mmol/l) with low HDL cholesterol, low HDL-to-total cholesterol ratio, or high total triglycerides further increased the risk for CHD events up to threefold. Our 7-year follow-up study provides evidence that dyslipidemia and poor glycemic control predict CHD mortality and morbidity in patients with NIDDM.

The relative importance of insulin resistance and abnormal insulin secretion as risk factors for the development of impaired glucose tolerance (IGT) is controversial. Few prospective data are available on metabolic precursors of IGT. We examined the relation of fasting serum insulin level (as a marker of insulin resistance) and change in insulin/glucose ratio (delta I30/ delta G30) over the first 30 min after glucose ingestion (as a marker of insulin secretion) as predictors of the 7-year development of IGT in 839 Mexican Americans and non-Hispanic whites with normal glucose tolerance at baseline from the San Antonio Heart Study. IGT eventually developed in 148 subjects. When modelled separately, fasting serum insulin (odds ratio (OR) = 2.60, 95% confidence interval (CI) = 1.58, 4.28, p < 0.005), but not delta I30/ delta G30 (OR = 0.80, 95% CI = 0.50, 1.27, p = 0.339) predicted the development of IGT. However, when both variables were included in the same logistic regression model, fasting serum insulin (OR = 3.50, 95% CI = 1.97, 6.21, p < 0.001) and low delta I30/ delta G30 (OR = 0.48, 95% CI = 0.28, 0.82, p = 0.008) both predicted IGT. These results were basically unchanged after further adjustment for obesity, body fat distribution and fasting plasma glucose level. We conclude that both decreased insulin secretion (as assessed by low delta I30/ delta G30) and increased insulin resistance (as assessed by fasting serum insulin) predict the development of IGT and are thus early precursors of non-insulin-dependent diabetes mellitus; further studies of insulin secretion should take into account the level of basal insulin resistance.

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