Phenotype of insulin-dependent diabetes in chronic undernutrition: beta cell stress and immune dysfunction—a rural sub-Saharan perspective on type 5 diabetes – Published online 29/09/2025

Elisabeth R. Trimble, David I. W. Phillips, Shitaye A. Balcha

In low- and middle-income countries (LMICs), people presenting with clinical features of insulin-dependent type 1 diabetes have a phenotype that differs from that of type 1 diabetes in economically developed countries. In this issue, Trimble et al (https://doi.org/10.1007/s00125-025-06553-w) provide a framework of possible pathophysiological mechanisms underlying the observed phenotypic differences. The authors discuss how chronic undernutrition, including undernutrition in utero, in LMICs is associated with altered thymic function and an altered autoimmune profile, which can lead to (auto)immune dysfunction. The authors also highlight how chronic undernutrition is associated with beta cell stress. The intermediary metabolism of beta cells, which includes the folding of proinsulin and the insertion of three disulphide bonds, involves many oxidative processes. Compared with other pancreatic cells, beta cells have a relatively low antioxidant capacity, and this is reduced further in chronic undernutrition. The cells develop oxidative stress, leading to neoantigen formation and apoptosis, which may account for 50% or more of all cases of insulin-dependent diabetes in conditions of chronic undernutrition. The authors conclude that there is a need for clinical recognition of the altered phenotype of insulin-dependent diabetes resulting from chronic undernutrition in LMICs. The figure from this review is available as a downloadable slide

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