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The KINGS Ins2+/G32S Mouse: A novel model of β-cell endoplasmic reticulum stress and human diabetes

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Article numberdb200570
Pages (from-to)2667-2677
Number of pages11
JournalDiabetes
Volume69
Issue number12
Early online date29 Sep 2020
DOIs
Accepted/In press21 Sep 2020
E-pub ahead of print29 Sep 2020
PublishedDec 2020

King's Authors

Abstract

Animal models are important tools in diabetes research because ethical and logistical constraints limit access to human tissue. β-Cell dysfunction is a common contributor to the pathogenesis of most types of diabetes. Spontaneous hyperglycemia was 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 preproinsulin 2 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 characterized, and β-cell function was investigated. Male mice became overtly diabetic at ∼5 weeks of age, whereas female mice had only slightly elevated nonfasting glycemia. 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 β-cell endoplasmic reticulum (ER) stress in both sexes. Despite this, β-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 β-cell responses to ER stress.

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