Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus

Abstract

Maturity-onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β-cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.

Keywords: Maturity-onset diabetes of the young; Penetrance; Type 2 diabetes mellitus.

Figure 1

Distribution of onset‐age of maturity‐onset diabetes of the young type 1 (MODY 1), MODY 2, MODY 3, MODY 5 and MODY 6. Onset age of MODY 1–3, 5 and 6 is dotted with black circles. *P‐values < 0.01 and **P‐values < 0.05 by the Kruskal–Wallis test followed by the Steel–Dwass test, respectively.

Figure 2

Abdominal computed tomography scan at the pancreas head levels of patients, (a) the daughter and (b) the mother, with maturity‐onset diabetes of the young type 5. (a) The uncinate process and the posteroinferior part of the pancreas head are shown by arrows in the computed tomography. (b) Overall atrophy of the pancreas is shown by arrows. Although both patients have the same nonsense mutation (p.Q477X), (a) body and tail loss are observed in the daughter's pancreas and (b) overall atrophy in the mother's. A renal cyst was found in the left kidney of the mother.

Figure 3

The age of onset or diagnosis of maturity‐onset diabetes of the young type 3 is dependent on the pattern of inheritance of the mutation (paternal or maternal) and also maternal affected status (diabetic or non‐diabetic) when the mutation is of maternal inheritance. DM+, diabetes mellitus‐positive; DM−, diabetes mellitus‐negative.

Figure 4

Birthweight of maturity‐onset diabetes of the young type 2 (MODY2) and MODY3 is dependent on the pattern of inheritance of the mutation (paternal or maternal). *P < 0.05. NS, not significant.