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

Abstract

OBJECTIVEIntravenous 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 METHODST1D 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.RESULTSWhen 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.CONCLUSIONSPoorly 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.

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

“…This finding extends our previous results on the effects of parenteral administration of polyunsaturated lipids (29). The present study also provides a comprehensive analysis of in vivo hepatic glucose and glycogen fluxes in humans that includes an assessment of glycogen cycling, which ensured correct estimation of GLY and GNG contributions to EGP (30). In chronic insulin-resistant states, such as occurs in T2DM or type 1 diabetes mellitus (T1DM), elevation of GNG and EGP coexists with enhanced glycogen cycling (30).…”

“…In chronic insulin-resistant states, such as occurs in T2DM or type 1 diabetes mellitus (T1DM), elevation of GNG and EGP coexists with enhanced glycogen cycling (30). Surprisingly, oral lipid loading stimulated GNG and hepatic insulin resistance without affecting glycogen cycling, which remained negligible, as was reported for healthy humans in the fasted state (30,31). This indicates that healthy humans can rapidly downregulate GLY under conditions of elevated GNG to avoid futile cycling.…”

“…The present study also provides a comprehensive analysis of in vivo hepatic glucose and glycogen fluxes in humans that includes an assessment of glycogen cycling, which ensured correct estimation of GLY and GNG contributions to EGP (30). In chronic insulin-resistant states, such as occurs in T2DM or type 1 diabetes mellitus (T1DM), elevation of GNG and EGP coexists with enhanced glycogen cycling (30). Surprisingly, oral lipid loading stimulated GNG and hepatic insulin resistance without affecting glycogen cycling, which remained negligible, as was reported for healthy humans in the fasted state (30,31).…”

“…At 8:00 pm, 10:00 pm, and 12:00 am, volunteers drank 1.6 g/kg body water of 2 H 2 O (99.9%; Sigma-Aldrich), up to a total dose of 5 g/kg body water in order to assess GNG (19) ( Figure 9). Body water was assumed to be 60% in all of our male study cohort participants (30 (19). Urine was sampled from -120 to 0 minutes, from 270 to 375 minutes, and from 390 to 510 minutes for the quantification of GNG and GLY.…”

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

“…This is an important finding in light of the known reduction in glycogen stores with type 2 diabetes, suggesting that the metabolic defects of type 2 diabetes may be responsible and that it may be reversible. Indeed, insulin-resistant states, including poorly controlled diabetes, have been associated with impaired insulin-stimulated glycogen synthesis [36][37][38][39][40]. Defects in glycogen synthesis may be the result of dysregulation of the enzymes glycogen phosphorylase and/or glycogen synthase.…”