Type 1 Diabetes
Insulin-dependent diabetes is an auto-immune disease resulting in the progressive destruction of insulin-producing beta cells in the pancreas.
The pathogenesis entails a genetic predisposition and environmental factors. Many genes confer susceptibility to Type I diabetes and most of them are involved in the immune response. These include local determinants of the major histocompatibility complex (MHC) designated by IDDM1 (major genetic risk factor) and the insulin gene region (Chowdhury et al., 1999; Nerup et al., 2001).
Other largely unknown genes are also involved in the pathogenesis of the disease, and because of its complexity, it is difficult to identify them. Mutations of these genes may be involved in the autoimmune responses caused by the immune system’s inappropriate response to certain stimuli. Recently a new IDDM18-susceptible gene, located near the IL-2 gene, was characterized. A simple substitution of nucleotides in the uncoded 3’UTR region may affect the production of IL-12 (Morahan et al., 2001).
An important role may be played by the intestinal immune system in triggering anti-b-cell autoimmunity in the pancreas in Type 1 diabetes (Vaarala, 1999; 2002).
The reasons are as follows:
Diet modifies the incidence of diabetes and the phenotype of T-cells infiltrating the islets of Langerhans in animal models of human Type 1 diabetes.
T-cells infiltrating the islets of Langerhans in Type 1 diabetics and in experimental models of autoimmune diabetes are intestinal in origin since they exhibit the b7-integrin receptor (gut associated homing receptor).
Mesenteric lymphocytes of non-obese diabetic (NOD) mice are likely to transfer of diabetes to healthy recipients. NOD mice spontaneously develop insulin-dependent diabetes and are used as a model for human Type 1 diabetes.
Administration of autoantigens by the oral route influences the development of the disease in animal models.
Role of Diet
If an infant is exposed to milk protein by feeding before the age of three months, this may increase its risk of developing Type 1 diabetes through various mechanisms:
Primary immunization against autoantigens of b cells is observed if the intestine is exposed to cow milk formulas containing immunogenic bovine insulin. The antibodies and induced T-cells show a cross reaction with human insulin. Activity of bovine anti-insulin antibodies increases over time in children at genetic risk who develop anti-b-cell autoimmunity. This phenomenon is not observed in control subjects who are autoantibody negative. The intestinal immune system plays a key role in controlling anti-insulin immunity induced by the insulin present in food. Disruption of intestinal integrity both at the level of permeability and of the immune response may lead to disturbance of this equilibrium.
Another effect of consuming cow’s milk at an early age may be induction of an anti-b-casein specific response exhibiting cross-reactivity with the b cells in the pancreas (Cavallo et al., 1996).
The deleterious effect of cow’s milk may also be due to destabilization of oral tolerance by the biologically active peptides (Wasmuth and Kolb, 2000). Other food antigens besides milk proteins (e.g., ovalbumin) may be involved in the development of diabetes. Among the dietary factors that can play a role are vitamin D deficiency and exposure to toxins such as nitrosamines (Akerblom et al., 2002).
The Autoimmune Response Mechanism
Macrophages or dendritic cells are the first cells to infiltrate the islets of Langerhans. They appear to be involved in the early stage of the pathogenesis of Type 1 diabetes because their inactivation results in quasi-complete diabetes prevention in NOD mice (Yoon et al., 1998). Presentation of b-cell autoantigens to CD4+ cells by macrophages or dendritic cells in association with MHC II molecules is considered the initial stage in the development of autoimmune diabetes. Activated macrophages secrete IL-12, which stimulates TH1-type CD4+ cells. CD4+ cells secrete IFN g and IL-2. IFN g activates quiescent macrophages, which then release IL1b, TNFa and free radicals toxic to b-cells. IL-2 and other cytokines induce the migration of CD8+ peripheral T-lymphocytes towards inflammatory foci in the Langerhans islets. The CD8+ cells specific to b-cell autoantigens differentiate into cytotoxic lymphocytes through recognition of these autoantigens bound to MHC I molecules in the presence of CD4+ cells. Cytotoxic cells destroy cells by releasing perforin and granzyme and by apoptosis mediated by Fas (CD95).
Like other pathologies related to food intolerance, TNFa plays a major role in the pathogenesis of Type 1 diabetes. TNFa is directly involved in the destruction of b-cells and the profound inflammatory effects by acting directly on the APC and autoresponsive T-lymphocytes. (Christen et al., 2001). The effect of cytokines varies, however. A given cytokine may slow down or accelerate the development of diabetes, based on dose, frequency and the age and nature of the animal model studied (Rabinovitch, 1998). TNFa therefore accelerates the progress of the disease at an early stage; at advanced stages, the induction of TNFa expression reverses the autoimmune process by reducing the lytic activity of CD8+ cells (Christen et al., 2001). Apart from the specificity of antigen recognition, the quality of the immune response to b-cells is a determining factor in the destruction of these cells.
Oral Tolerance
Regulation of the intestinal immune response plays an essential role in the pathogenesis since many observations show that it is disrupted in Type 1 diabetes (Akerblom et al., 2002).
Oral tolerance depends on immunological homeostasis and normal maturity of the intestine. These two elements are influenced by growth factors and the cytokines of maternal milk, colonization by physiological bacterial flora, infections and diet (Wasmuth and Kolb, 2000). Rotavirus or enterovirus infections are observed before the diabetes is triggered and the anti-b-cell autoimmunity is developed (Couper, 2001). Apart from their harmful action on intestinal permeability, enterovirus infections may accelerate the triggering of diabetes by catalyzing the development of T-cell autoimmunity (Serreze et al., 2000).
An increase in intestinal permeability may therefore eliminate oral tolerance and induce an exaggerated immune response to autoantigens or food antigens that may exhibit cross reactions with cellular components (Vahasalo et al., 1996). Elevated concentrations of IgG and IgA antibodies against milk proteins (bovine albumin, beta-lactoglobulin) and ovalbumin are observed in children and adolescents with Type 1 diabetes compared to healthy subjects (Kohno et al., 2002; Savilathi et al., 1993).
Administering bacterial immunostimulants by mouth to BB rats, which, like the NOD mice, spontaneously develop insulin-dependent diabetes, reduces the TH1 response of the intestinal immune system and subsequently plays a beneficial role in oral tolerance (Bellmann et al., 1997).
In conclusion, food intolerance plays a major role in the pathogenesis of Type 1 diabetes. This is why several measurements of specific food anti-antigen IgG would be beneficial from a preventive or therapeutic (prognostic) perspective for patients with this pathology.
Preventive goal:
Subjects at risk: Siblings and direct descendants of Type 1 diabetics in order to re-establish intestinal permeability and oral tolerance. Currently there is no genetic test available to precisely assess the risk for developing Type 1 diabetes given the significant number of genes implicated.
Therapeutic goal:
Patients with recently diagnosed Type 1 diabetes: Reduction of the immune response, which is the basis for the destruction of b-cells, with the goal of prolonging the interval of time without insulin therapy and reducing the insulin dose in the mid- and long-term and the risk of developing insulin resistance.
Subjects with long-standing diabetes: Elimination from the diet foods responsible for allergies resulting in a reduced inflammatory response and associated effects linked to glucose metabolism, which consequently allow for reduced insulin dosage and insulin resistance.
