The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.
Low birthweight is associated with insulin resistance, hypertension, coronary-artery disease, and non-insulin-dependent diabetes (NIDDM). A suggested explanation for this association is intrauterine programming in response to maternal malnutrition. We propose, however, that genetically determined insulin resistance results in impaired insulin-mediated growth in the fetus as well as insulin resistance in adult life. Low birthweight, measures of insulin resistance in life, and ultimately glucose intolerance, diabetes, and hypertension could all be phenotypes of the same insulin-resistant genotype. There is evidence to support this hypothesis. Insulin secreted by the fetal pancreas in response to maternal glucose concentrations is a key growth factor. Monogenic diseases that impair sensing of glucose, lower insulin secretion, or increase insulin resistance are associated with impaired fetal growth. Polygenic influences resulting in insulin resistance in the normal population are therefore likely to result in lower birthweight. Abnormal vascular development during fetal life and early childhood, as a result of genetic insulin resistance, could also explain the increased risk of hypertension and vascular disease. The predisposition to NIDDM and vascular disease is likely to be the result of both genetic and fetal environmental factors.
Hattersley
A T
AT
Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, Exeter, UK. A.T.Hattersley@exeter.ac.uk
Tooke
J E
JE
D000328:Adult; D002318:Cardiovascular Diseases / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D004198:Disease Susceptibility; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D005941:Glucokinase / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000209:etiology; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D009154:Mutation; D010641:Phenotype
D007328:Insulin; D005941:Glucokinase