Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 7, Issue 3, 2007

Type 1 diabetes (T1D) develops as a result of a complex and poorly understood self-targeting immune reaction that destroys the insulin-producing β-cells in the pancreatic islets of Langerhans. Environmental factors are thought to play a major role in this process and likely influence the success of β-cell replacement therapies. Unfortunately, the identification of these agents and the mechanisms by which they promote diabetes remain unclear. Nonetheless, data are accumulating from studies of diabetesprone animals and humans that strengthen the proposition that diet is an important determinant of diabetes outcome. These studies emphasize a key role for selected dietary constituents, defective gut barrier function, gut immune cell activation, the maintenance of glucoregulation, islet homeostasis/ regeneration and overall immune dysregulation in diabetes pathogenesis. In this issue, internationally recognized experts review recent findings that implicate dietary components in T1D, explore the role of the gastrointestinal tract, provide lessons from the role of wheat in celiac disease, and describe the effort to identify candidate dietary molecules and understand their role in pancreas biology and metabolism. The study of nutritional effects on diabetes expression is a challenging but useful paradigm for environmental modification of this complex chronic disease. As we begin to understand the integrative biology of diabetes-related dietary constituents, we move closer to understanding the origins of T1D. The upshot of these discussions is that we must learn how to modify the environment to prevent or delay the process that destroys β-cells. One of the most important sources of bioactive agents from our environment is the food we eat. We should not be surprised that the pancreas which plays a key role in digestion of food and nutrient uptake is itself strongly influenced by food constituents which may also up- or down-regulate the largest collection of immune cells in the body within the gutassociated lymphoid tissues. Understanding how diet alters diabetes outcome could lead to relatively harmless and economical interventions that delay onset or possibly prevent this disease in some individuals or even permit enhanced survival of transplanted islets. We can but hope!

The relative risk of type 2 diabetes is higher in individuals of low birth weight, and programming of the metabolic axis is influenced by the intrauterine nutritional environment. The β-cells of the pancreatic islets develop from precursor cells and islet development is controlled by the interactions of transcription factors and peptide growth factors. Both are modulated by fetal nutrition. Fetal programming of adult glucose intolerance has been studied using rodent models, including administration of a low protein (LP) diet. Long-term changes are found in insulin action within target tissues, as well as in the development and function of the endocrine pancreas. Intrauterine growth restriction in rat or man results in a reduced islet and β-cell mass at birth. A reduction of dietary protein to 8% throughout gestation caused relative growth restriction at birth with reduced β-cell mass and islet size. If LP diet is extended to weaning the changes are irreversible, and include an altered β-cell ontogeny, decreased cell replication but increased apoptosis, a reduced expression of insulin-like growth factors, and a reduction in islet vascularity and the number of endothelial precursor cells. The net result is a population of islets with limited plasticity and an inability to adapt to the associated insulin resistance. Studies with supplementation of selected amino acids in early life showed that the altered pancreatic morphology, and glucose intolerance, is reversible by taurine. Both LP diet and taurine are able to delay the onset of type 1 diabetes in the non-obese diabetic mouse.

Gluten is one of the most ubiquitous ingredients in the human diet. The unique physicochemical properties of this biomaterial are the result of its primary structure (rich in Pro and Gln residues), secondary structure (abundance of non-hydrogen bond dependent polyproline II helices), and tertiary and quarternary structures (extensive intra- and intermolecular disulfide linkages). From a biological perspective, although the nutritional characteristics of gluten are well understood, its toxicological effects in certain individuals are only just beginning to be appreciated. Celiac Sprue, a widespread disease, is perhaps the best dissected form of gluten intolerance, where dietary gluten elicits an elaborate immune response that leads to enteropathy in the upper small intestine and a wide range of gastrointestinal as well as extraintestinal symptoms. A growing body of evidence suggests that a combination of proteolytic resistance and high affinity for two human proteins - transglutaminase 2 and HLA-DQ2 (or alternately HLA-DQ8) - renders pro-inflammatory in the Celiac small intestine. Other forms of gluten sensitivity have also been recognized in the clinic and in animal models of disease, although their precise relationship to gluten structure remains to be elucidated. An enhanced understanding of gluten chemistry and toxicology is spawning the emergence of pharmacological approaches to treat gluten sensitivity, as well as sensitive and accurate methods to quantify gluten content in food products.

This review deals with the age- and diet-related metabolic and functional anomalies found in BB rats, currently considered as an animal model of type 1 diabetes mellitus. The metabolism of nutrients, the secretion of insulin, the production of NO, the effects of IL-1β and the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase in pancreatic islets are first considered. The metabolism and mitotic activity in Peyer's patch cells and both mesenteric and pancreatic lymph node cells are then evoked. The occurrence of intestinal dysfunction is mentioned, with emphasis on recent findings made in BB rats before weaning. The participation of zonulins and mucins in the perturbation of gut permeability are also discussed. Last, attention is drawn to the perturbation of the anomeric specificity of glucose-induced insulin release, considered as a manifestation of pancreatic islet beta-cell glucotoxicity.

The existence of β-cell dysfunction and insulin resistance in vitamin D-deficient individuals on top of the demonstrated presence of receptors for 1,25-dihydroxyvitamin D3, the active metabolite of vitamin D, in pancreatic islet β- cells and immune cells have lead to scientific and clinical interest in vitamin D with respect to its potential role in the pathogenesis of type 1 diabetes. Also, its therapeutic potential in the prevention of type 1 diabetes has been studied, especially since the availability of synthetic analogues of the molecule that lack its calcemic effects. Solid evidence is available on the detrimental effects of vitamin D deficiency on insulin synthesis and secretion in animal models as well as in humans. Interventions with pharmacological doses of 1,25-dihydroxyvitamin D3 are able to delay onset of autoimmune diabetes in NOD mice mainly through immune modulation.

The non obese diabetic (NOD) mouse is a very well studied model of autoimmune diabetes. NOD mice develop insulitis, an early infiltration of leukocytes into the pancreas that leads to inflammatory lesions within the islets. In NOD mice, it has been shown that diet modifies the incidence of the disease. In particular, the diabetogenic agents come from the plant protein fraction of the natural food; cereal and soy bean proteins remain the major identified diabetogenic food components. More recently, it was shown that the gluten-free diet both delayed and prevented diabetes onset in NOD mice that had never been exposed to gluten. Compelling evidences of gut immune system involvement in diabetes is also provided by this model. Lymphocytes expressing mucosal adhesion molecules have been found to infiltrate the islets, while MadCAM blockage inhibits the development of diabetes; furthermore, diabetes has been shown to be transferred with mesenteric lymph nodes cells, at the age of 3 months the most diabetogenic cells being in the GALT (Gut Associated Lymphoid Tissue). Mice fed wheat containing diet have not only a higher incidence of diabetes, but also signs of small intestinal enteropathy and higher mucosal levels of proinflammatory cytokines. They show significant levels of serum antitTG antibodies, and single-chain antibody fragments to mouse tTG have been isolated mainly from the antibody libraries made from intestinal lymphocytes. While there is little doubt about the involvement of the intestinal immune response in the pathogenesis of diabetes, it is still unclear if dietary proteins (e.g. wheat) primarily trigger the inflammatory and then the autoimmune process in genetically prone individuals. Alternatively, dietary proteins could act on an already inflamed mucosa, because structurally more leaky or because the site of an ongoing autoimmune process, causing further damage.

The descriptive epidemiology of type 1 diabetes suggests an etiology involving genetic and environmental factors that vary across populations and environmental factors that vary over time. Exposures in the infant diet, specifically cereals and/or gluten, have been associated with development of diabetes autoimmunity in prospective studies of children at increased risk of type 1 diabetes. Similar exposures have also been associated with other childhood diseases such as celiac disease and wheat allergy, which while they may share some similarities with type 1 diabetes, essentially have different pathogeneses. The data published thus far suggest that there are specific times in infancy when exposure to cereals and/or gluten increases risk for a variety of diseases. They also suggest that intervention, i.e. removal of gluten, after becoming autoantibody positive does not lessen autoimmunity nor prevent the development of the disease itself. Additional research is needed to determine whether gluten is in fact the antigen driving the risk for three different disorders, whether gluten exposure is resulting in increased gut permeability leading to increased exposure to a variety of dietary antigens, each of which is disease specific, or whether there is yet another, undiscovered factor in the infant diet that results in disease.

Type 1 diabetes (T1D) results when an immune attack destroys most of the insulin-producing β-cells in the pancreas, overwhelming the capacity of the organ to preserve normoglycemia. Islet homeostasis is maintained by a physiological balance of β-cell neogenesis, replication and death. This balance is affected by various challenges such as food consumption, nutrient uptake, hormonal status, obesity and pregnancy. It is the susceptibility to develop T1D that is inherited and disease expression is strongly influenced by exposure to common environmental factors. It is well accepted that diabetes incidence can be altered in diabetes-prone animals by modification of dietary components. This raises the possibility that diet-associated changes in islet function or mass play a role in T1D. In this review, we discuss the effect of diet on islet β-cell homeostasis, with particular emphasis on islet neogenesis and replication in healthy and diabetes-prone animals with a brief discussion of human studies. A better understanding of the role of diet on islet homeostasis in susceptible individuals may help develop strategies for prevention and treatment of diabetes by dietary intervention.

The link between the gut immune system and type 1 diabetes (T1D) has been suggested by studies which have demonstrated that dietary factors modify the disease in animal models of autoimmune diabetes. In humans, some studies suggest that autoreactive T-cells may originate from the gut immune system. For example, T-cells derived from pancreas of a patient with type 1 diabetes adhered to mucosal and pancreatic endothelium. Also autoreactive T-cells from patients with T1D expressed the gut-associated homing receptor, alpha4beta7-integrin. When intestinal biopsy samples from children with T1D but without signs of celiac disease were studied, markers of inflammation are up-regulated. Intestinal immune activation is seen as increased expression of HLA class II molecule and ICAM-1 throughout the epithelial cells. The densities of IL-4 and IL-1alpha positive cells are increased in the lamina propria. Intestinal biopsy samples from patients with T1D show aberrant reaction of immune activation seen as expansion of CD3 and CD25 cells when stimulated with wheat gliadin in vitro. This suggests that wheat gliadin could be a trigger of intestinal inflammation not associated with celiac disease but present in children with T1D. Another dietary candidate for the trigger of intestinal inflammation in T1D is dietary insulin present in cow milk, a dietary risk factor linked to T1D. Enterovirus and rotavirus infections associated with the risk of beta-cell autoimmunity are known to change the permeability of the gut as well as cytokine environment and could stimulate the intestinal immune system by these mechanisms. The composition of intestinal microflora is important for the development of balance between tolerance and immunity in the gut immune system. The changes in the intestinal microflora are discussed as a cause of sub-clinical intestinal inflammation associated with T1D. The gut hypothesis suggests that the underlying sub-clinical intestinal inflammation allows the development of destructive beta-cell autoimmunity in genetically susceptible individuals who are not able to control the immune response to dietary antigens such as insulin due to interference of environmental factors which break oral tolerance.

In the following we briefly update the information on the study which tests our hypothesized role of the weaning diet in the etiology of type 1 diabetes (T1D), and describe the ongoing Trial to Reduce IDDM in the Genetically at Risk (TRIGR). The study will determine whether weaning to a formula in which cow milk (CM) proteins (the most common intact foreign weaning protein in humans) have been extensively hydrolyzed, reduces risk for T1D in genetically susceptible children. This double blind, randomized controlled trial in subjects with affected first-degree relatives and riskassociated HLA genotypes, requires 2032 eligible infants: 4516 newborn babies need to be recruited, 45% of which are predicted to have eligible HLA genotypes. An international, multicenter consortium has been established comprising 78 centers in 15 countries. By the end of November 2005 we had achieved 81% of the recruitment target with 4396 infants registered, 3896 randomized and 1644 eligible infants entered into the intervention. The 6-8 month intervention is designed to compare the effects of either hydrolyzed casein or standard CM based weaning formula. Duration of breastfeeding is at the mothers' discretion. All subjects are observed for 10 years with measurements of serological markers of intact CM exposure, diabetes predictive autoantibodies (endpoint at age 6 years) and progression to clinical T1D (endpoint at age 10 years). If the intervention is effective in delaying autoimmunity or its progression to diabetes, this first ever primary prevention study of T1D, will have farreaching impact for families with members at risk.