Effect of a Gluten Free Diet on Ameliorating New Onset Type 1 Diabetes Mellitus in Children and Adolescents

Research Strategy A. SPECIFIC AIMS

The continuing rise in incidence of type 1 diabetes mellitus (T1DM) globally has not been matched by successful efforts for prevention or amelioration of the disease. Additionally, a huge gap exists in our understanding of the adjacent gastrointestinal milieu in which the pancreatic islet destructive process occurs and leads to insulin-dependence in T1DM. The largest increase in incidence of type 1 diabetes over the past decade has occurred in children under 5 years of age, a group particularly susceptible to diabetes related morbidity and mortality. Invasive methodologies via finger pricking for glucose monitoring and subcutaneous insulin injection remain the standard of care required for patient survival. Many intervention studies have been conducted based on inadequately substantiated knowledge of the mechanisms (presumed to be exclusively autoimmune) causing permanent beta-cell destruction in type 1 diabetes. Almost all intervention trials in new-onset type 1 diabetes show only transient improvement of insulin production (up to 6 months) with subsequent decline to levels similar to the control arms. Moreover, there are scientific arguments and data which suggest that non autoimmune pathogenic mechanisms may be involved, perhaps in a more toxic and generalized affliction of the pancreas. Recent evidence that beta-cells continue to regenerate in the pancreas of patients with long-standing type 1 diabetes offers hope that the disease process leading to insulin-dependence may be reversed if islet destruction is arrested at a critical window of time.

The link between type 1 diabetes and the gut microbiome is actively being explored. Emerging evidence suggests a role of the gut microbiome in the destruction and protection of islets in type 1 diabetes-prone experimental models. In addition, type 1 diabetes was prevented in genetically established murine models of the disease when these animals were restricted to a gluten-free diet. The specific hypothesis addressed in this application is that a gluten-free diet introduced shortly after diagnosis can reverse or halt the progression of type 1 diabetes in children and adolescents. Our proposed mechanism is that a gluten-free diet preserves endogenous insulin production via altering the gut microbiota towards strains that are inherently less toxic to islets. The study is designed for a comprehensive assessment of the role of a gluten-free diet in children with T1DM. A specific objective is to reduce or modify patients' gut microbiota early in the disease process as a possible means of arresting islet destruction. The specific measurable aims of the current application outline an innovative approach to begin the identification of beta-cell protective effects of specific changes in gut flora that can be therapeutically developed to ameliorate type 1 diabetes.

Specific Aim 1: To determine the effect of a gluten-free diet on endogenous insulin secretion and pancreatic morphology in children and adolescents with new-onset type 1 diabetes.

Specific Aim 2: To determine the effect of a gluten-free diet on the gut flora of patients with new-onset type 1 diabetes.