Effects of visceral adiposity on glycerol pathways in gluconeogenesis

Objective To determine the feasibility of using oral ¹³C labeled glycerol to assess effects of visceral adiposity on gluconeogenic pathways in obese humans. Research Design and Methods Obese (BMI ≥ 30 kg/m²) participants without type 2 diabetes underwent visceral adipose tissue (VAT) assessment and stratification by median VAT into high VAT-fasting (n = 3), low VAT-fasting (n = 4), and high VAT-refed (n = 2) groups. Participants ingested [U-¹³C₃] glycerol and blood samples were subsequently analyzed at multiple time points over 3 h by NMR spectroscopy. The fractions of plasma glucose (enrichment) derived from [U-¹³C₃] glycerol via hepatic gluconeogenesis, pentose phosphate pathway (PPP), and tricarboxylic acid (TCA) cycle were assessed using ¹³C NMR analysis of glucose. Mixed linear models were used to compare ¹³C enrichment in glucose between groups. Results Mean age, BMI, and baseline glucose were 49 years, 40.1 kg/m², and 98 mg/dl, respectively. Up to 20% of glycerol was metabolized in the TCA cycle prior to gluconeogenesis and PPP activity was minor (< 1% of total glucose) in all participants. There was a 21% decrease in ¹³C enrichment in plasma glucose in the high VAT-fasting compared with low VAT-fasting group (p = 0.03), suggesting dilution by endogenous glycerol. High VAT-refed participants had 37% less ¹³C enrichment in glucose compared with high VAT-fasting (p = 0.02). There was a trend toward lower [1,2-¹³C₂] (via PPP) and [5,6-¹³C₂]/[4,5,6-¹³C₃] (via TCA cycle) glucose in high VAT versus low VAT groups. Conclusions We applied a simple method to detect gluconeogenesis from glycerol in obese humans. Our findings provide preliminary evidence that excess visceral fat disrupts multiple pathways in hepatic gluconeogenesis from glycerol.