Early delivery is needed if the fetus inherits an HNF4A mutation from either parent because increased insulin secretion results in ~800-g weight gain in utero, and prolonged severe neonatal hypoglycaemia can occur post-delivery.
K(ATP) channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%).
We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes.
Obesity and hyperinsulinemia have been observed occasionally in other subtypes of MODY, which suggests that hyperinsulinemia may be a general phenomenon when obesity occurs in MODY subjects.
This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.
These data indicate that hyperinsulinemia down-regulates HNF4alpha in the liver through the up-regulation of SREBPs, thereby establishing a link between these two critical transcription factor pathways that regulate lipid and glucose metabolism in the liver.