Postprandial and fasting hepatic glucose fluxes in long-standing type 1 diabetes.

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; HbA(1c): 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 (13)C magnetic resonance spectroscopy. Endogenous glucose production (EGP) and gluconeogenesis (GNG) were assessed with [6,6-(2)H(2)]glucose, glycogen phosphorylase (GP) flux, and gluconeogenic fluxes with (2)H(2)O/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.

Ectopic fat and insulin resistance.

Ectopic fat is defined by the deposition of triglycerides within cells of non-adipose tissue that normally contain only small amounts of fat. Over the past decade, magnetic resonance spectroscopy has been used extensively for noninvasive quantification of intramyocellular, intrahepatocellular, and more recently myocardial and pancreatic lipids. In liver and muscle, triglyceride content usually correlates with whole-body and tissue-specific insulin sensitivity. However, fat mass and oxidative capacity influence this relationship, indicating that ectopic lipid content is not the only factor that explains insulin resistance. Ectopic lipids may rather serve as biomarkers of the balance between metabolic supply and demand in different states of insulin sensitivity. Consequently, ectopic lipid concentrations, particularly in the liver, decrease with lifestyle- or drug-induced improvement of insulin sensitivity.