Intestinal Alkaline Phosphatase at the Crossroad of Intestinal Health and Disease – Putative Role in Type 1 Diabetes

Based on both national and international collaboration, the FinnDiane Study Group has recently found that many patients with uncomplicated type 1 diabetes exhibited early signs of gastrointestinal inflammation. In patients with type 1 diabetes, early identification of gut related diseases will be warranted in order to prevent the development of other inflammation driven complications such as cardiovascular disease and diabetic nephropathy.

It is evident that both genetic and environmental factors play a role in the development of late diabetic complications. Poor glycemic control, significantly associated with the development of micro- and macrovascular complications, increases also the risk of infections and gastrointestinal problems in patients with diabetes. Based on the recent observations, it seems probable that gastrointestinal inflammation, increased gut permeability, changes in microbial composition, and translocation of bacterial compounds may have a significant impact on the development of diabetic kidney disease. It can be also hypothesized that problems related to gastrointestinal tract could be much more common in adult patients with type 1 diabetes than previously anticipated.

The human gut contains about 1.0-1.5 kg of bacteria. Brush-border enzyme intestinal alkaline phosphatase (IAP) plays an important role in gut mucosal defense 7 suppressing inflammatory mediators – including microbial compounds (endotoxins, polyphosphates), and luminal ATP by dephosphorylation. IAP has also been shown to be involved in the regulation of duodenal bicarbonate secretion and fatty acid absorption. Decrease in luminal IAP activity could increase the risk of gastrointestinal disease through changes in the microbial composition, intestinal inflammation, and gut permeability.

It is a good question whether the intestinal IAP deficiency is linked to inflammatory condition of the gut in patients with type 1 diabetes. Clinical parameters and fecal biomarkers were investigated in 41 non-diabetic controls and 46 patients with type 1 diabetes. Interrelationships between fecal IAP activity and other gut related inflammatory markers were examined. Decreased fecal IAP activity in patients with type 1 diabetes was accompanied by lower fecal butyrate, and IgA antibody concentrations (see figure). Of note, subjects with uncomplicated type 1 diabetes also exhibited higher fecal calprotectin concentrations compared to non-diabetic controls. Mucosal IgA secretion modulates host immunity and colonization of commensal bacteria in the gut. The study also showed for the first time that oral IAP supplementation could increase intestinal IgA levels in mice, which will open new avenues for prevention and treatment of diabetic complications.

Figure: Alterations in gut homeostasis in patients with type 1 diabetes

 

Original Study: Lassenius MI, Fogarty CL, Blaut M, Haimila K, Riittinen L, Paju A, Kirveskari J Järvelä J, Ahola AJ, Gordin D, Härma M-A, Kumar A, Hamarneh SR, Hodin RA, Sorsa T, Tervahartiala T, Hörkkö S, Pussinen PJ, Forsblom C, Jauhiainen M, Taskinen M-R, Groop P-H, Lehto M. Intestinal alkaline phosphatase at the crossroad of intestinal health and disease – a putative role in type 1 diabetes. J Intern Med 281(6): 586-600, 2017