The long-term impact on offspring of exposure to hyperglycaemia in utero due to maternal glucokinase gene mutations.
OBJECTIVE
There is strong evidence that maternal diabetes while offspring are in utero results in offspring beta cell dysfunction and diabetes or glucose intolerance. Offspring born to mothers with a mutation in the glucokinase gene (GCK) are a good model for studying exposure to moderate hyperglycaemia, as mutation carriers have fasting hyperglycaemia throughout life including during pregnancy. We assessed the long term effects of exposure to maternal hyperglycaemia in utero on beta cell function and glucose tolerance in adult offspring.


METHODS
We studied 86 adult offspring (mean age 40 years), 49 born to glucokinase mothers (exposed to hyperglycaemia in utero) and 37 born to glucokinase fathers (controls). We measured glucose tolerance during an OGTT and beta cell function using early insulin response (EIR); we also measured anthropometric data including birthweight.


RESULTS
Offspring of glucokinase mothers had a higher birthweight by 450 g (p<0.001), but no evidence of deterioration in glucose tolerance (2-h glucose 9.1 vs 8.6 mmol/l p=0.50) or reduced beta cell function (log EIR 1.40 vs 1.26, p=0.11) compared with offspring born to glucokinase fathers.


CONCLUSIONS
The marked increase in birthweight shows that offspring born to affected mothers were exposed to increased glycaemia in utero. Despite this, there was no evidence of altered beta cell function or glucose tolerance. As previous human examples of marked programming by hyperglycaemia in utero have been in genetically predisposed offspring, we propose that our finding reflects the lack of genetic predisposition in the offspring to progressive beta cell dysfunction.
Singh
R
R
Department of Molecular Medicine, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, and Division of Medicine and Therapeutics, Ninewells Hospital, Dundee, UK.
Pearson
E R
ER
Clark
P M
PM
Hattersley
A T
AT
D000328:Adult; D001724:Birth Weight; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology* / Q000235:genetics; D008297:Male; D009154:Mutation; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology* / Q000235:genetics
D005941:Glucokinase