Four weeks of carbohydrate overfeeding induce widespread dysmetabolic traits in men born with a low birth weight compared to matched normal birth weight controls

Background and aims: Low birth weight (LBW) is a well-known risk factor for development of type 2 diabetes (T2D) later in life. This is particularly apparent when exposed to an affluent dietary lifestyle. Data from our group has indicated that impaired subcutaneous adipose tissue expandability, associated with increased ectopic (hepatic) fat deposition, may be on the critical path of T2D development in LBW subjects. We aimed to study whether a 4-week overfeeding (+25% energy) challenge, consisting of simple carbohydrates (COF), would result in differential dysmetabolic effects, including increased hepatic fat content, in LBW men compared with normal birth weight (NBW) controls.

Materials and methods: We included 22 healthy, early middle-aged, and non-obese LBW men (mean BW 2797±175 g) as well as 21 NBW controls (mean BW 3807±176 g) matched for age and BMI. We measured body composition by DXA, hepatic fat content by magnetic resonance spectroscopy, glucose and insulin metabolism, hepatic glucose production (HGP) by deuterium glucose, energy metabolism by indirect calorimetry, selected plasma biomarkers by multiplex Mesoscale Discovery technology as well as untargeted serum metabolomics and lipidomics by mass spectrometry before and after 4 weeks COF.

Results: In response to COF LBW, but not NBW subjects, displayed increased fasting plasma levels of glucose (P=0.03), C-peptide (P=0.01), leptin (P=0.0002) and FGF21 (P=0.005), as well as increased energy expenditure (P=0.0002) and fat oxidation rates (P=0.02) compared to baseline. COF resulted in similar significant increases in body weight in both groups. Hepatic fat content increased slightly in both LBW (P=0.023) and NBW (P=0.018) subjects after COF, however, with the LBW group having significantly increased hepatic fat content before and after COF compared with NBW controls. Fasting plasma adiponectin was significantly reduced in LBW compared with NBW subjects both before and after COF. Among 65 metabolites, 8 were differentially abundant between the groups (P<0.05) after COF. Ingenuity pathway analyses (IPA) revealed accumulation and increased lipid peroxidation in LBW subjects after COF. Further, IPA showed activation of the PPARGC1A pathway in LBW subjects contrasting a minor downregulation of the pathway in NBW subjects after COF. Finally, among 279 lipids identified by lipidomics, the LBW subjects exhibited a significantly (PFisher=0.0004) higher number of lipids to be increased after COF (n=26) compared to NBW subjects (n=6). This finding was further supported by a network analysis showing a general upregulation of the lipid profile in LBW subjects opposing a slight downregulation in NBW controls after COF.

Conclusion: LBW subjects at increased risk of T2D respond to COF with differential increases in plasma glucose, C-peptide, leptin and FGF21 levels, as well as with increased fat oxidation rates and severe differential perturbations of lipid metabolism, compared to NBW controls. The findings stress the importance of LBW individuals refraining from overeating simple carbohydrates. Additional studies are needed to further understand the role of increased hepatic fat accumulation in LBW subjects in T2D development.