Leaky gut and diabetes mellitus: what is the link?

Abstract

Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide, and a rapidly rising incidence, diabetes mellitus poses a great burden on healthcare systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dys-regulation of the intestinal barrier. Via alterations in the intestinal permeability, intestinal barrier function becomes compromised whereby access of infectious agents and dietary antigens to mucosal immune elements is facilitated, which may eventually lead to immune reactions with damage to pancreatic beta cells and can lead to increased cytokine production with consequent insulin resistance. Understanding the factors regulating the intestinal barrier function will provide important insight into the interactions between luminal antigens and immune response elements. This review analyses recent advances in the mechanistic understanding of the role of the intestinal epithelial barrier function in the development of type 1 and type 2 diabetes. Given our current knowledge, we may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of type 1 and type 2 diabetes.

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice

“…The 'leaky gut' theory has been suggested as a potential mechanism by which increased exposure of the immune system to luminal microbial antigens could result in the stimulation of autoimmune responses leading to T1D (de Kort et al, 2011). However, we did not find that antibiotic-induced diabetes was associated with barrier dysfunction (Supplementary data Figure 3).…”

“…The 'hygiene hypothesis' proposes that insufficient microbial exposure during infancy drives autoimmunity, and certain intestinal microbes and their antigens are hypothesized to induce autoimmune responses. Increased exposure to intestinal microbial antigens or metabolites through the gut could be involved in triggering diabetogenic immune responses (reviewed in (de Kort et al, 2011)). …”

Butyrate reduces high-fat diet-induced metabolic alterations, hepatic steatosis and pancreatic beta cell and intestinal barrier dysfunctions in prediabetic mice

“…Comparatively, islets from mice receiving supplementation with butyrate (CB and HFB groups) displayed a tendency of an increase, although not statistically significant, in insulin secretion at the supraliminal concentration of glucose (16.7 mM) (Figure 2(b)). This change resulted in a significantly higher (P ¼ 0.012) fold increase in glucose-induced insulin secretion in HFB islets (56.5 AE 18.8 (10) fold as compared to basal secretion) than HF islets (10.5 AE 3.4 (13) fold as compared to basal secretion), which, in turn, displayed a significant lower (P ¼ 0.02) secretory response to glucose as compared to control (C) islets (32.4 AE 7.9 (14) fold as compared to basal secretion).…”

“…22,25,45,59,60 Based on clinical and experimental evidence, the current hypothesis postulates that a disruption of the intestinal epithelial barrier induced by a modified microbiota or altered luminal content would lead to an increased intestinal permeability to antigens from dietary, viral or bacterial origin, that in turn could activate autoimmune reactions against insulin-producing beta cells (in T1DM) and/or elicit secretion of pro-inflammatory cytokines, locally and systemically, leading to insulin resistance (in T2DM). 14,48,61,62 Given our current knowledge, one may assume that reinforcing the intestinal barrier can offer and open new therapeutic horizons in the treatment of these two types of diabetes. Taken all into consideration, we went to investigate the effect of butyrate supplementation on intestinal barrier function in our animal model of T2DM, ....................................................................................................................... focusing on the structure and function of the intestinal TJ, an essential element of this barrier.…”

“…4,6,9,10 In addition, it has been recently proposed that microbiota-derived lipopolysaccharides, crossing a leaky intestinal epithelium, may also play a role in the long-term development of insulin resistance in T2DM. [11][12][13][14] In order to compensate the permanent state of insulin resistance, pancreatic beta cells are capable of an adaptive response that involves changes in their secretory function and mass in the endocrine pancreas. [15][16][17][18] At initial stages, beta cells increase insulin biosynthesis and release but, subsequently, due to the continuous resistance of biological tissues to insulin, beta cell mass expands to promote a further increase in secretion of this hormone necessary for the maintenance of normoglycemia.…”