A High Level of Intestinal Alkaline Phosphatase Is Protective Against Type 2 Diabetes Mellitus Irrespective of Obesity

EBioMedicine. 2015 Dec 1;2(12):2016-23. doi: 10.1016/j.ebiom.2015.11.027. eCollection 2015 Dec.


Mice deficient in intestinal alkaline phosphatase (IAP) develop type 2 diabetes mellitus (T2DM). We hypothesized that a high level of IAP might be protective against T2DM in humans. We determined IAP levels in the stools of 202 diabetic patients and 445 healthy non-diabetic control people. We found that compared to controls, T2DM patients have approx. 50% less IAP (mean +/- SEM: 67.4 +/- 3.2 vs 35.3 +/- 2.5 U/g stool, respectively; p < 0.000001) indicating a protective role of IAP against T2DM. Multiple logistic regression analyses showed an independent association between the IAP level and diabetes status. With each 25 U/g decrease in stool IAP, there is a 35% increased risk of diabetes. The study revealed that obese people with high IAP (approx. 65 U/g stool) do not develop T2DM. Approx. 65% of the healthy population have < 65.0 U/g stool IAP, and predictably, these people might have 'the incipient metabolic syndrome', including 'incipient diabetes', and might develop T2DM and other metabolic disorders in the near future. In conclusion, high IAP levels appear to be protective against diabetes irrespective of obesity, and a 'temporal IAP profile' might be a valuable tool for predicting 'the incipient metabolic syndrome', including 'incipient diabetes'.

Keywords: AP, alkaline phosphatase; BMI, body mass index; FPG, fasting plasma glucose; Fatty liver; Glucose intolerance; Hypertension; IAP, intestinal alkaline phosphatase; IAP-KO, IAP knockout; Incipient diabetes; Insulin resistance; L-Arg, L-homoarginine; LPS, lipopolysaccharides; Obesity; TNAP, tissue non-specific alkaline phosphatase; The metabolic syndrome; l-Phe, l-phenylalanine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alkaline Phosphatase / deficiency
  • Alkaline Phosphatase / metabolism*
  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / etiology*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Enzyme Activation
  • Feces / enzymology
  • Female
  • Humans
  • Intestines / enzymology*
  • Male
  • Middle Aged
  • Obesity / epidemiology
  • Obesity / etiology*
  • Obesity / metabolism*
  • Risk Factors


  • Alkaline Phosphatase