High White Blood Cell Count Is Associated With a Worsening of Insulin Sensitivity and Predicts the Development of Type 2 Diabetes

Chronic low-grade inflammation may be involved in the pathogenesis of insulin resistance and type 2 diabetes. We examined whether a high white blood cell count (WBC), a marker of inflammation, predicts a worsening of insulin action, insulin secretory function, and the development of type 2 diabetes in Pima Indians. We measured WBC in 352 nondiabetic Pima Indians (215 men and 137 women, aged 27 6 years [means SD], body fat 32 8%, WBC 8,107 2,022 cells/mm 3 ) who were characterized for body composition (by hydrodensitometry or dual-energy X-ray absorptiometry), glucose tolerance (by 75-g oral glucose tolerance test), insulin action (M; by hyperinsulinemic clamp), and acute insulin secretory response (AIR; by 25-g intravenous glucose challenge). Among 272 subjects who were normal glucose tolerant (NGT) at baseline, 54 developed diabetes over an average follow-up of 5.5 4.4 years. Among those who remained nondiabetic, 81 subjects had follow-up measurements of M and AIR. Crosssectionally, WBC was related to percent body fat (r 0.32, P < 0.0001) and M (r 0.24, P < 0.0001), but not to AIR (r 0.06, P 0.4). In a multivariate analysis, when adjusted for age and sex, both percent body fat (P < 0.0001) and M (P 0.03) were independently associated with WBC. A high WBC value predicted diabetes (relative hazard 90th vs. 10th percentiles [95%CI] of 2.7 [1.3‐5.4], P 0.007) when adjusted for age and sex. The predictive effect of WBC persisted after additional adjustment for established predictors of diabetes, i.e., percent body fat, M, and AIR (relative hazard 2.6 [1.1‐ 6.2], P 0.03). After adjustment for follow-up duration, a high WBC at baseline was associated with a subsequent worsening of M (P 0.003), but not a worsening of AIR. A high WBC predicts a worsening of insulin action and the development of type 2 diabetes in Pima Indians. These findings are consistent with the hypothesis that a chronic activation of the immune system may play a role in the pathogenesis of type 2 diabetes. Diabetes 51:455‐ 461, 2002 A ctivation of the immune system and inflammation may be detected by an increase in a number of markers, including white blood cell count (WBC) and cytokine and plasminogen activator inhibitor-1 (PAI-1) concentrations. Because of the cross-sectional relationship between markers of inflammation and insulin resistance and/or type 2 diabetes (1‐ 4), it has been suggested that a chronic low-grade activation of the immune system may play a role in the pathogenesis of type 2 diabetes. To date, there is some evidence from prospective studies in Pima Indians and other populations to support the hypothesis that altered markers of inflammation, such as a high WBC, plasma fibrinogen, PAI-1, gamma globulin, and lower albumin concentrations, are associated with the later development of type 2 diabetes (5‐ 8). However, the mechanisms by which these markers of inflammation contribute to the development of type 2 diabetes are largely unknown. In the present study, we examined the pathophysiological role of an activated immune system, as assessed by elevated WBC, in the development of type 2 diabetes in Pima Indians, a population with marked insulin resistance and one of the highest reported prevalence rates of type 2 diabetes in the world (9). Our aim was to examine 1) whether a high WBC was associated with later development of type 2 diabetes; 2) if so, whether these associations were independent of adiposity, insulin action, and insulin secretion; and 3) whether a high WBC was associated with a subsequent decrease in insulin sensitivity and/or insulin secretion.