Abstract
AIMS/HYPOTHESIS: The role of increased gluconeogenesis as an important contributor to fasting hyperglycaemia at diabetes onset is not known. We evaluated the contribution of gluconeogenesis and glycogenolysis to fasting hyperglycaemia in newly diagnosed youths with type 2 diabetes following an overnight fast. METHODS: Basal rates (μmol kg(FFM) (-1) min(-1)) of gluconeogenesis ((2)H2O), glycogenolysis and glycerol production ([(2)H5] glycerol) were measured in 18 adolescents (nine treatment naive diabetic and nine normal-glucose-tolerant obese adolescents). RESULTS: Type 2 diabetes was associated with higher gluconeogenesis (9.2 ± 0.6 vs 7.0 ± 0.3 μmol kg(FFM) (-1) min(-1), p < 0.01), plasma fasting glucose (7.0 ± 0.6 vs 5.0 ± 0.2 mmol/l, p = 0.004) and insulin (300 ± 30 vs 126 ± 31 pmol/l, p = 0.001). Glucose production and glycogenolysis were similar between the groups (15.4 ± 0.3 vs 12.4 ± 1.4 μmol kg(FFM) (-1) min(-1), p = 0.06; and 6.2 ± 0.8 vs 5.3 ± 0.7 μmol kg(FFM) (-1) min(-1), p = 0.5, respectively). After controlling for differences in adiposity, gluconeogenesis, glycogenolysis and glucose production were higher in diabetic youth (p ≤ 0.02). Glycerol concentration (84 ± 6 vs 57 ± 6 μmol/l, p = 0.01) and glycerol production (5.0 ± 0.3 vs 3.6 ± 0.5 μmol kg(FFM) (-1) min(-1), p = 0.03) were 40% higher in youth with diabetes. The increased glycerol production could account for only ~1/3 of substrate needed for the increased gluconeogenesis in diabetic youth. CONCLUSION/INTERPRETATIONS: Increased gluconeogenesis was a major contributor to fasting hyperglycaemia and hepatic insulin resistance in newly diagnosed untreated adolescents and was an early pathological feature of type 2 diabetes. Increased glycerol availability may represent a significant source of new carbon substrates for increased gluconeogenesis but would not account for all the carbons required to sustain the increased rates.