A mutation in the insulin 2 gene induces diabetes with severe pancreatic β-cell dysfunction in the Mody mouse

Diabetes is a major public issue due to its high prevalence and long-term complications (1). The molecular pathogenesis of diabetes, however, remains largely unknown. The common forms of diabetes are syndromes with heterogeneous etiologies, each of which is influenced by polygenic and multiple environmental factors. Therefore, genetic and pathophysiologic analysis of diabetes remains a major challenge. On the other hand, recent progress in the identification of genetic alterations in monogenic disorders has provided clues for understanding the molecular pathogenesis of the common forms with similar phenotypes. There are several rare monogenic forms of diabetic syndromes, both in humans and in rodent models. In humans, there is a syndrome called maturity-onset diabetes of the young (MODY), which is inherited in an autosomal dominant mode (2). The primary lesions in these diseases are in the pancreatic β cells, resulting in decreased insulin secretion. The causal genes of some types of MODY were recently identified (3). In contrast, most of the monogenic diabetic syndromes in rodent models such as ob, db, agouti, tubby, and fat mice accompany obesity (4). The responsible genes are involved in the regulation of body weight, and their alterations result in increased insulin resistance in peripheral tissues, except in fat mice. Very recently, Yoshioka and colleagues established a monogenic diabetic model, called the Akita mouse (5). This model does not accompany either obesity or insulitis, but is accompanied by a notable pancreatic β-cell dysfunction, which distinguishes this mouse from the other well-characterized animal models. Diabetes in this mouse resembles that of human MODY in terms of early onset, an autosomal dominant mode of inheritance, and primary dysfunction of the β cells. The gene locus is named murine Mody and has been determined to be located on a distal end of Chromosome 7 by linkage analysis (5) and quantitative trait locus analysis (6). In this study, we demonstrate that the Mody mouse has a missense mutation of the insulin 2 gene (Ins2), which lies on a corresponding area of the Mody locus identified by the genetic analysis. This mutation completely cosegregates with the qualitative phenotype of diabetes in the Mody congenic lines, and it is therefore concluded to be responsible for diabetes in this mouse. The Mody mutation codes insulin 2, whose cysteine residue at the seventh amino acid of the A chain is replaced with tyrosine. This cysteine is involved in the formation of one of the