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

Abstract

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’.

Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

“…In keeping with loss of function, the mutated ALPI alleles could not inhibit LPS activity when measured in vitro by the induction of IL‐8 (Fig G). Although TNAP, another AP expressed in the human gut mucosa, was upregulated in the intestinal mucosa of both ALPI‐deficient patients, we found no evidence of its secretion in the intestinal lumen, a result consistent with previous results (Malo, ). We therefore conclude that LPS detoxification by ALPI in the intestinal lumen is severely impaired in P1 and P2.…”

“…As shown in Fig 4C, stools of non-inflamed controls displayed substantial AP activity, which was largely inhibited by L-Phe but not by L-Arg. This result was consistent with previous reports indicating that most AP activity in stools is due to ALPI with some residual AP activity of microbial origin (Malo, 2015; Fig 4C). ALPI activity was significantly reduced in stools of patients with intestinal inflammation (faecal calprotectin > 250 lg/ g; Fig 4D), a result consistent with previous studies showing decreased ALPI expression in the inflamed intestine (Molnár et al, 2012a,b).…”

“…ALPI is mainly expressed in the small intestinal brush border, from which it is released into the lumen within vesicles that transport active ALPI towards distal intestinal sites (Eliakim et al , ; Bates et al , ; Tuin et al , ; Shifrin et al , ; Malo, ). In keeping with in vitro evidence that ALPI mutations affect protein expression, immunofluorescence analysis of small intestinal biopsies showed markedly reduced ALPI staining in P1 and P2 compared with histologically normal or IBD controls (Fig A and B).…”

Dairy products and the French paradox: Could alkaline phosphatases play a role?

“…Residual IAP in stools from patients enrolled in epidemiological and intervention studies should be considered too because stool IAP may be a valuable biomarker as recently shown, e.g. for both overt and incipient diabetes [74]. In turn, these AP markers should be related to e.g.…”

Effects of intestinal alkaline phosphatase on intestinal barrier function in a cecal ligation and puncture (CLP)‐induced mouse model for sepsis

“…Although IAP is ubiquitously expressed in the gastrointestinal tract, its distribution is variable with the highest expression levels in the duodenum and IAP expression levels decreasing over the length of the intestine. Among many other functions, IAP has been documented to be involved in the regulation of duodenal bicarbonate secretion and in lipid absorption by the intestinal epithelium . However, the role of IAP seems to encompass more than just these physiological functions, and IAP has been shown to be of importance in the response to different pathological conditions as well.…”