Environmental modulators of type 1 diabetes mellitus

Abstract

In genetically susceptible subjects, type 1 diabetes (T1D) appears to be a chronic immune- mediated disease with a subclinical prodromal period characterized by selective loss of insulin-releasing pancreatic beta cells. However, only a relatively small proportion of genetically susceptible subjects progress to clinical disease, which indicates that environmental factors are needed to trigger and drive the disease process in genetically predisposed subjects. In this article we provide a selective review on environmental factors involved in the pathogenesis of T1D. Accumulating evidence suggests that the proportion of subjects with high-risk human leukocyte antigen (HLA) genotypes has decreased over the last decades among patients with newly diagnosed T1D, whereas the proportion of those with low-risk or even protective HLA genotypes has increased. These findings indicate that increased environmental pressure is responsible for progression to clinical diabetes in patients with less genetic predisposition. The birth cohort studies indicate that the first signs of beta cell autoimmunity may be induced during infancy before age 3, which implies that dietary factors for beta cell autoimmunity and T1D may be active in that time period, during which early nutrition provides essential exogenous exposure. Progression to clinical T1D typically needs the combination of genetic disease susceptibility, a diabetogenic trigger, and a high exposure to a driving antigen. The triggers appear to be enteroviruses and rotaviruses as well as components of the infant diet including cows milk and gluten, while the Mediterranean diet appears protective. The only definite enterovirus responsible for T1D is congenital rubella, which may be complicated by late development of T1D. There is a temporal association between enteroviral infection and future development of antibodies resulting in T1D. Clinical studies indicate that islet cell antibodies develop 3 months after birth and seroconversion of enterovirus RNA in serum to antibodies occurs more significantly in subjects with T1D compared to controls. Omega-3 fatty acids, cocoa flavonoids, sour milk and cottage cheese have been found to be protective against autoimmunity in T1D. These foods likely promote the gut microbiome, which is deteriorated by the Western diet resulting in an increased production of lipid mediators; protectin, and resolving lipoxins, which are anti-inflammatory