Endotoxemia is associated with an increased risk of incident diabetes

Abstract

Objective: Diabetes is accompanied with a chronic low-grade inflammation, which may in part be mediated by endotoxins derived from Gram-negative bacteria.

Research design and methods: We investigated in a population-based cohort whether endotoxemia is associated with clinically incident diabetes. The serum endotoxin activity was measured by limulus assay from the FINRISK97 cohort comprising 7,169 subjects aged 25-74 years and followed up for 10 years.

Results: Both the subjects with prevalent diabetes (n = 537) and those with incident diabetes (n = 462) had higher endotoxin activity than the nondiabetic individuals (P < 0.001). The endotoxin activity was significantly associated with increased risk for incident diabetes with a hazard ratio 1.004 (95% CI 1.001-1.007; P = 0.019) per unit increase resulting in a 52% increased risk (P = 0.013) in the highest quartile compared with the lowest one. The association was independent of diabetes risk factors: serum lipids, γ-glutamyl transferase, C-reactive protein, BMI, and blood glucose. Furthermore, the association of endotoxemia with an increased risk of incident diabetes was independent of the metabolic syndrome as defined either by the National Cholesterol Educational Program-Adult Treatment Panel III or the International Diabetes Federation. Endotoxin activity was linearly related (P < 0.001) to the number of components of the metabolic syndrome.

Conclusions: Both prevalent and incident diabetes were associated with endotoxemia, which may link metabolic disorders to inflammation. The results suggest that microbes play a role in the pathogenesis of diabetes.

Figure 1

Cumulative survival without incident diabetes. The cumulative survival in LPS quartiles was analyzed by Cox regression model adjusted for age, sex, education, family diabetes history, free-time physical inactivity, smoking, hypertension, BMI, serum cholesterol, triglyceride, HDL cholesterol, GGT and CRP concentrations. The HR and 95% CI for the quartiles are shown in Table 2.

Figure 2

Serum endotoxin activities according to number of parameters of metabolic syndrome. Metabolic syndrome was defined according to the ATP III criteria (n = 6,273), and mean endotoxin activities with 95% CI are shown. The number of subjects in the categories is 0 = 1,203, 1 = 2,118, 2 = 1,507, 3 = 934, 4 = 459, and 5 = 52. Linear trend of endotoxin activity vs. number of positive metabolic syndrome parameters was tested using ANOVA with linear contrasts and assuming equal variances.