The KINGS Ins2+/G32S Mouse: A Novel Model of β-Cell Endoplasmic Reticulum Stress and Human Diabetes

Author:

Austin Amazon L.F.1,Daniels Gatward Lydia F.1,Cnop Miriam23,Santos Gabriel1ORCID,Andersson David4,Sharp Sally4ORCID,Gentry Clive4,Bevan Stuart4,Jones Peter M.1,King Aileen J.F.1ORCID

Affiliation:

1. Department of Diabetes, School of Life Course Sciences, King’s College London, London, U.K.

2. ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium

3. Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium

4. Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, U.K.

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.

Funder

Medical Research Council

Fonds National de la Recherche Scientifique

Brussels Capital Region-Innoviris

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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