The KINGS Ins2+/G32S mouse: a novel model of beta cell endoplasmic reticulum stress and human diabetes

Animal models are important tools in diabetes research as ethical and logistical constraints limit access to human tissue. Beta cell dysfunction is a common contributor to the pathogenesis of most types of diabetes. Spontaneous hyperglycaemia developed in a colony of C57BL/6J mice at King’s College London (KCL). Sequencing identified a mutation in the Ins2 gene, causing a glycine to serine substitution at position 32 on the B chain of the preproinsulin2 molecule. Mice with the Ins2^+/G32S mutation were named KCL Ins2 G32S (KINGS) mice. The same mutation in humans (rs80356664) causes dominantly inherited neonatal diabetes. Mice were characterised and beta cell function was investigated. Male mice became overtly diabetic at around 5 weeks of age whereas female mice had only slightly elevated non-fasting glycaemia. Islets showed decreased insulin content and impaired glucose-induced insulin secretion, which was more severe in males. Transmission electron microscopy and studies of gene and protein expression showed beta cell endoplasmic reticulum (ER) stress in both sexes. Despite this, beta cell numbers were only slightly reduced in older animals. In conclusion, the KINGS mouse is a novel model of a human form of diabetes that may be useful to study beta cell responses to ER stress.