Background. We have previously shown that the deficiency of the gut enzyme intestinal alkaline phosphatase (IAP) is associated with type 2 diabetes mellitus (T2DM) in humans, and mice deficient in IAP develop the metabolic syndrome, a precipitant of T2DM and ischemic heart disease (IHD). We hypothesized that IAP deficiency might also be associated with IHD in humans. We aimed to determine the correlation between the IAP level and IHD in humans. Methods and Results. The IHD patients were recruited from the National Institute of Cardiovascular Diseases (NICVD), Dhaka, Bangladesh, and the control healthy participants were recruited from a suburban community of Dhaka. We determined the IAP level in the stools of 292 IHD patients (187 males, 105 females) and 331 healthy control people (84 males, 247 females). We found that compared to controls, IHD patients have approx. 30% less IAP (mean±SEM: 63.7±3.5 vs. 44.9±2.1 U/g stool, respectively; p<0.000001), which indicates that IAP deficiency is associated with IHD, and a high level of IAP is probably protective against IHD in humans. The adjusted generalized linear model (GLM) of regression analysis predicted a strong association of IAP with IHD (p=0.0035). Multiple logistic regression analysis showed an independent inverse relationship between the IAP level and the IHD status (odds ratio, OR=0.993 with 95% CI 0.987-0.998; p<0.01). Conclusions. IAP deficiency is associated with IHD, and a high level of IAP might be protective against IHD.

IntroductionOur previous case–control study demonstrated that a high level of intestinal alkaline phosphatase (IAP), an endotoxin-detoxifying anti-inflammatory enzyme secreted by villus-associated enterocytes and excreted with stool, plays a protective role against type 2 diabetes mellitus (T2DM) irrespective of obesity. In the current study, we investigated the long-term effect of IAP deficiency (IAPD) on the pathogenesis of T2DM.Research design and methodsA healthy cohort of participants without diabetes (30–60 years old), comprising 188 without IAPD (IAP level: ≥65 U/g stool) and 386 with IAPD (IAP level: <65 U/g stool), were followed up for 5 years. We measured stool IAP (STAP) and fasting plasma glucose, and calculated the risk ratio (RR) using log-binomial regression model.ResultsT2DM incidence rates were 8.0%, 11.7%, 25.6%, and 33.3% in participants with ‘persistent no IAPD’ (IAP level: always ≥65 U/g stool), ‘remittent IAPD’ (IAP level: increased from <65 U/g stool to ≥65 U/g stool), ‘persistent IAPD’ (IAP level: always <65 U/g stool), and ‘incident IAPD’ (IAP level: decreased from ≥65 U/g stool to <65 U/g stool), respectively. Compared with ‘persistent no IAPD’ the risk of developing T2DM with ‘incident IAPD’ was 270% higher (RR: 3.69 (95% CI 1.76 to 7.71), χ2 p<0.001). With ‘persistent IAPD’ the risk was 230% higher (RR: 3.27 (95% CI 1.64 to 6.50), p<0.001). ‘Remittent IAPD’ showed insignificant risk (RR: 2.24 (95% CI 0.99 to 5.11), p=0.0541). Sensitivity analyses of persistent IAP levels revealed that, compared with participants of the highest persistent IAP pentile (always >115 U/g stool), the rate of increase of fasting glycemia was double and the risk of developing T2DM was 1280% higher (RR: 13.80 (95% CI 1.87 to 101.3), p=0.0099) in participants of the lowest persistent IAP pentile (always <15 U/g stool). A diabetes pathogenesis model is presented.ConclusionsIAPD increases the risk of developing T2DM, and regular STAP tests would predict individual vulnerability to T2DM. Oral IAP supplementation might prevent T2DM.