Postprandial and Fasting Hepatic Glucose Fluxes in Long-Standing Type 1 Diabetes

Abstract

OBJECTIVE Intravenous insulin infusion partly improves liver glucose fluxes in type 1 diabetes (T1D). This study tests the hypothesis that continuous subcutaneous insulin infusion (CSII) normalizes hepatic glycogen metabolism. RESEARCH DESIGN AND METHODS T1D with poor glycemic control (T1Dp; HbA1c: 8.5 ± 0.4%), T1D with improved glycemic control on CSII (T1Di; 7.0 ± 0.3%), and healthy humans (control subjects [CON]; 5.2 ± 0.4%) were studied. Net hepatic glycogen synthesis and glycogenolysis were measured with in vivo 13C magnetic resonance spectroscopy. Endogenous glucose production (EGP) and gluconeogenesis (GNG) were assessed with [6,6-2H2]glucose, glycogen phosphorylase (GP) flux, and gluconeogenic fluxes with 2H2O/paracetamol. RESULTS When compared with CON, net glycogen synthesis was 70% lower in T1Dp (P = 0.038) but not different in T1Di. During fasting, T1Dp had 25 and 42% higher EGP than T1Di (P = 0.004) and CON (P < 0.001; T1Di vs. CON: P = NS). GNG was 74 and 67% higher in T1Dp than in T1Di (P = 0.002) and CON (P = 0.001). In T1Dp, GP flux (7.0 ± 1.6 μmol ⋅ kg−1 ⋅ min−1) was twofold higher than net glycogenolysis, but comparable in T1Di and CON (3.7 ± 0.8 and 4.9 ± 1.0 μmol ⋅ kg−1 ⋅ min−1). Thus T1Dp exhibited glycogen cycling (3.5 ± 2.0 μmol ⋅ kg−1 ⋅ min−1), which accounted for 47% of GP flux. CONCLUSIONS Poorly controlled T1D not only exhibits augmented fasting gluconeogenesis but also increased glycogen cycling. Intensified subcutaneous insulin treatment restores these abnormalities, indicating that hepatic glucose metabolism is not irreversibly altered even in long-standing T1D.