Insights from maturity-onset diabetes of the young into impaired insulin secretion in type 2 diabetes.

Monogenic diabetes arises from pathogenic variants in a single gene that are sufficient to cause disease predisposition. In general, a greater functional impact of genetic abnormalities is associated with an earlier age of onset. Accordingly, monogenic diabetes encompasses a wide clinical spectrum, including neonatal diabetes mellitus presenting within the first six months of life, and maturity-onset diabetes of the young (MODY) typically manifesting from childhood to early adulthood; both diabetic types exhibit impaired insulin secretory capacity. Although MODY is currently classified as diabetes of monogenic defect with impaired insulin secretion, it has become evident that mutations in rare MODY subtypes exhibit reduced pathogenic effects and low penetrance. In addition, observed differences in the clinical phenotypes caused by the same mutation, even in the same family, might be caused by other phenotypic modifying factors. Furthermore, their clinical expression is influenced, at least in part, by environmental factors, such as the intrauterine environment. Nevertheless, identification of the causative genes underlying monogenic diabetes has elucidated previously unrecognized molecular mechanisms responsible for the impaired insulin secretion. These findings have not only revealed novel therapeutic targets but have also provided important insights into the pathophysiology of common type 2 diabetes mellitus in the Japanese population, a multifactorial disease in which defective insulin secretion plays a central role.