Intrauterine Hyperglycemia Modifying the Development of (Monogenic) Diabetes?

• HNF, hepatic nuclear factor
• MODY, maturity-onset diabetes of the young
• OGTT, oral glucose tolerance test

During the last decade, mutations in the glucokinase and hepatic nuclear factor (HNF) genes were found to cause maturity-onset diabetes of the young (MODY), which is characterized by a dominant autosomal mode of inheritance, high penetrance, lack of cardiovascular morbidity, and defective insulin response to glucose stimulus combined with normal, or even supranormal, insulin sensitivity (1,2). Most forms of MODY are caused by mutations in transcription factors such as HNF-1α (MODY3), HNF-4α (MODY1), insulin promoter factor (IPF)-1 (MODY4), HNF-1β (MODY5), or glukokinase (MODY2) (1). Although the precise mechanisms by which mutations in these transcription factors cause diabetes are not known, they are thought to involve transcription of a number of β-cell genes (3). Despite the fact that the defects are already present at birth, diabetes is rarely manifested at birth. Instead, the monogenic forms of diabetes are in fact heterogeneous with respect to age at diabetes diagnosis and severity of the insulin secretory defect (1). It has been hypothesized that high insulin sensitivity could maintain normoglycemia, despite minimal insulin secretory capacity, and that any deterioration in insulin sensitivity could result in hyperglycemia. This is supported by frequent deterioration of glucose tolerance during puberty or pregnancy.

The age at diagnosis of diabetes …