Phenotype of insulin-dependent diabetes in chronic undernutrition: beta cell stress and immune dysfunction—a rural sub-Saharan perspective on type 5 diabetes

In economically developed countries most lean individuals presenting with insulin-dependent diabetes have autoimmune type 1 diabetes. However, in many rural areas of low- and middle-income countries (LMIC), 40-50% of individuals with a similar clinical presentation are negative for diabetes-associated autoantibodies at initial clinical presentation. The phenotype differs from the classical presentation of type 1 diabetes even in those with evidence of an autoimmune process: altered autoantibody profile; later peak age of onset; and, in those with post-pubertal clinical presentation, more marked male predominance. The incidence of insulin-dependent diabetes in LMIC is low, even when assessing those with and without autoantibodies together. A framework of possible pathophysiological mechanisms underlying the observed phenotypic differences is presented to explain how chronic undernutrition and micronutrient deficiencies might alter the presentation of insulin-dependent diabetes. Inhabitants of rural sub-Saharan Africa (SSA) depend almost entirely on staple foods grown locally in nutrient-deficient soil. The resulting chronic undernutrition, often intergenerational, affects linear growth and body morphology, and has direct immune and non-immune effects on beta cell development and function. Undernutrition directly affects thymic function, alters the autoimmune profile and is often associated with social deprivation and parasitic infection, both of which can delay and modify the (auto)immune response. Non-immune effects of undernutrition include beta cell stress, associated with apoptosis and formation of neoantigens. That environmental effects of undernutrition and social deprivation affect the altered insulin-dependent diabetes phenotype is shown by the movement back towards a classical type 1 diabetes phenotype in offspring of emigrants from SSA who are born in and develop insulin-dependent diabetes in an economically developed country. The degree of phenotype change depends on how long the parents have lived in their adopted country. It has recently been proposed that insulin-dependent diabetes in those who are mal/undernourished be called type 5 diabetes. There is need for clinician recognition of the altered phenotype(s) of insulin-dependent diabetes resulting from chronic undernutrition in rural LMIC. Additionally, changes in agricultural practice are needed to improve the nutrient content of food consumed by the rural population.