AIMS/HYPOTHESIS: Being born small for gestational age (SGA) is associated with an increased risk of type 2 diabetes in an affluent society, but could confer an improved chance of survival during sparse living conditions. We studied whether insulin action and other metabolic responses to prolonged fasting differed between 21 young adults born SGA and 18 matched controls born appropriate for gestational age (AGA).

METHODS: A frequently sampled IVGTT and indirect calorimetry measurements were performed after a 36 h fast. Endogenous glucose production, insulin sensitivity (SI), first-phase insulin secretion and glucose effectiveness were estimated by stable isotope tracer techniques and minimal modelling. Muscle and fat biopsies were obtained after 35 h of fasting.

RESULTS: During fasting, SGA individuals experienced a more pronounced decrease in serum insulin and lower plasma triacylglycerol levels compared with AGA individuals. In addition, energy expenditure decreased in SGA but increased in AGA individuals. After fasting, SGA individuals displayed lower fat oxidation than AGA individuals. SG was reduced in SGA compared with AGA individuals, whereas hepatic or whole body insulin action (SI) did not differ between groups. SGA individuals had increased muscle PPARGC1A DNA methylation. We found no differences in adipose tissue PPARGC1A DNA methylation, muscle and adipose tissue PPARGC1A mRNA expression, or muscle glycogen levels between the groups.

CONCLUSION: Compared with AGA individuals, SGA individuals displayed a more energy-conserving and energy-conserving cardiometabolic response to 36 h fasting. The role of increased muscle PPARGC1A DNA methylation in mediating this response requires further study.