[ Diabetes Type 2 ]

Hepatic Glycogen Metabolism in Type 1 Diabetes After Long-Term Near Normoglycemia

Eight normal controls and nine non-insulin-dependent diabetes mellitus diabetics were, after an overnight fast, infused for 3 h with [6-3H]- and with [U-13C]glucose with six 13C carbons at rates from 0.03 to 0.15 mg.kg-1.min-1. Increased gluconeogenesis was an early pathological finding in newly diagnosed youth with type 2 diabetes despite mild fasting hyperglycaemia (~7 mmol/l). Patterns of liver gluconeogenic intermediates after 3-mercaptopicolinate infusion suggested inhibition at the level of phosphoenolpyruvate carboxykinase. Vanadate caused a significant reduction in blood glucose but failed to normalize it, despite effective serum vanadate concentrations (26.2 +/- 1.6 micromol/L). This Review critically discusses the role of the adenosine–adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications. Levels of the gluconeogenic precursors alanine and lactate were increased during pregnancy in both the women without IDDM (from 0.18 [SEM 0.02] mmol/L and 0.64 [SEM 0.09] mmol/L, respectively, to 0.25 [SEM 0.02] mmol/L and 1.15 [SEM 0.17] mmol/L, respectively, p < 0.01) and in those with IDDM (from 0.15 [SEM 0.01] mmol/L and 0.47 [SEM 0.04] mmol/L, respectively, to 0.19 [SEM 0.02] mmol/L and 0.70 [SEM 0.01] mmol/L, respectively, p < 0.05). Additionally, increased L-lactate production from pyruvate and pyruvate production from L-lactate were observed.
Accepted September 1, 2015. We also observed that between 18 and 42 h of fasting, 1) the relative contribution of protein breakdown to glutamine production was enhanced, while that of de novo synthesis declined; 2) the apparent contribution of glutamine to glucose production rose from 8 ± 1 to 16 ± 3% of overall glucose Ra; and 3) the relative apparent contribution of glutamine to gluconeogenesis remained constant. Thus, the hormonal stimulation of gluconeogenesis from dihydroxyacetone is decreased by diabetes, probably because of decreased pyruvate kinase activity, but the interaction of glucagon and norepinephrine with hepatocytes and the subsequent stimulation of gluconeogenesis from physiologic substrates is not impaired. Blood lactate concentrations and lactate turnover were unchanged despite decreased conversion of glucose to lactate. All the steps of Gluconeogenesis are the same as that of glycolysis with the same enzymes except in 3 steps. ∼50%; P < 0.05. In conclusion, combined long- and short-term intensified insulin substitution normalizes rates of hepatic glycogen synthesis but not the contribution of gluconeogenesis to glycogen synthesis in type 1 diabetes. Early studies on glycogen metabolism in type 1 diabetic patients using liver biopsies revealed controversial results, reporting either increased or decreased liver glycogen concentrations (1,2,3,4). Here, Lee et al. This could be secondary to basement membrane thickening, but there is also evidence that the cyclic AMP mechanism may be defective. We recently found that type 1 diabetic subjects with poor metabolic control, as evidenced by an HbA1c of ∼9%, also present with reduced glycogen breakdown during the night after mixed meal ingestion (7). Short-term intensified insulin treatment for 24 h, resulting in near-normal plasma glucose concentrations, improved both defects in glycogen synthesis and breakdown that, however, were still ∼52 and ∼26% lower, respectively, compared with nondiabetic subjects. At present, even advanced insulin substitution regimens do not resemble the physiologic insulin secretion pattern, since peripheral administration of insulin distorts the portal-to-peripheral insulin gradient and thereby affects hepatic glycogen turnover (8). In the present study we investigated the mechanisms underlying hyperglycemia and hypertriglyceridemia in gestational diabetes using a rat model of GDM. Even a small increase in this ratio would dramatically reduce hepatic glycogen accumulation (10,11,12). Finally, a defect in the “portal signal,” which stimulates hepatic uptake of glucose on its enteral or portal vein delivery (13,14,15), could be present in diabetic patients. Such defects likely contribute to the excessive fasting endogenous glucose production (EGP) and plasma glucose concentrations that are found in poorly controlled type 1 diabetic patients (16,17). Long- and short-term near normoglycemia exerts an additive effect to decrease EGP and fasting hyperglycemia in those patients (18,19). It is conceivable that long- and short-term near normoglycemia could further improve hepatic glycogen metabolism and glucose production.

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