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      Assessment of Hepatic Glucose Metabolism by Indirect Calorimetry in Combination with a Non-Invasive Technique Using Naturally Enriched 13C Glucose in Healthy Children and Adolescents

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          The metabolic fate of hepatic glucose can be best studied using invasive techniques such as tracer infusions and frequent blood sampling which have been revealed to be impractical in the pediatric age group. The aim of this study was to develop a non-invasive method based on indirect calorimetry and expired <sup>13</sup>CO<sub>2</sub> monitoring in order to gain insight into the mechanisms leading to impaired glucose tolerance in children and teenagers. As a first step, net glucose oxidation (NGO) and energy expenditure (EE) were measured in 47 subjects (range 7.5–17.3 years) of whom 18 were prepubertal (P1), 11 in early puberty (P2–P3) and 18 in late puberty (P4–P5) after 3-hourly loads of 180 mg/kg of oral maize glucose containing naturally enriched <sup>13</sup>C. Isotope analysis allowed to calculate exogenous and endogenous glucose oxidation (EXGO, ENGO) and, hence, to derive TGS and NGS, that is glycogen turnover. NGO and EE decreased significantly with pubertal progression, reflecting higher metabolism at younger ages, whereas EXGO remained constant. TGS did not change significantly whereas NGS showed a significant negative correlation with pubertal progression: this can be explained by the fact that glycogenolysis exceeded glycogen synthesis in this experimental setting. This non-invasive method appears to be a promising tool to study the fate of hepatic glucose and therefore glycogen turnover in children at risk of developing glucose intolerance and/or type 2 diabetes.

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          Most cited references 17

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          Prevalence of impaired glucose tolerance among children and adolescents with marked obesity.

          Childhood obesity, epidemic in the United States, has been accompanied by an increase in the prevalence of type 2 diabetes among children and adolescents. We determined the prevalence of impaired glucose tolerance in a multiethnic cohort of 167 obese children and adolescents. All subjects underwent a two-hour oral glucose-tolerance test (1.75 g [DOSAGE ERROR CORRECTED] of glucose per kilogram of body weight), and glucose, insulin, and C-peptide levels were measured. Fasting levels of proinsulin were obtained, and the ratio of proinsulin to insulin was calculated. Insulin resistance was estimated by homeostatic model assessment, and beta-cell function was estimated by calculating the ratio between the changes in the insulin level and the glucose level during the first 30 minutes after the ingestion of glucose. Impaired glucose tolerance was detected in 25 percent of the 55 obese children (4 to 10 years of age) and 21 percent of the 112 obese adolescents (11 to 18 years of age); silent type 2 diabetes was identified in 4 percent of the obese adolescents. Insulin and C-peptide levels were markedly elevated after the glucose-tolerance test in subjects with impaired glucose tolerance but not in adolescents with diabetes, who had a reduced ratio of the 30-minute change in the insulin level to the 30-minute change in the glucose level. After the body-mass index had been controlled for, insulin resistance was greater in the affected cohort and was the best predictor of impaired glucose tolerance. Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group. Impaired oral glucose tolerance was associated with insulin resistance while beta-cell function was still relatively preserved. Overt type 2 diabetes was linked to beta-cell failure.
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            Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.

            Insulin resistance and impaired insulin secretion both occur in non-insulin-dependent diabetes (NIDDM), but their relative importance is unclear. Hyperglycemia itself has adverse effects on tissue insulin sensitivity and insulin secretion that make it difficult to distinguish between primary and secondary abnormalities. To avoid this problem we studied subjects with postprandial glucose intolerance but not sustained hyperglycemia. We compared the rate of systemic appearance and disappearance of glucose, the output of endogenous hepatic glucose, splanchnic and muscle uptake of glucose, and plasma insulin and glucagon responses after the ingestion of 1 g of glucose per kilogram of body weight in 15 subjects with impaired glucose tolerance (8 of them nonobese and 7 obese) and in 16 normal subjects (9 nonobese and 7 obese) who were matched for age and weight. After glucose ingestion the mean (+/- SE) rate of total systemic appearance of glucose was significantly higher in both the nonobese subjects (455 +/- 12 mmol per five hours) and the obese subjects (486 +/- 17 mmol per five hours) with impaired glucose tolerance than in the respective normal subjects (411 +/- 11 and 436 +/- 7 mmol per five hours). This difference was fully accounted for by the reduced suppression of endogenous hepatic glucose in the subjects with impaired glucose tolerance (a reduction of about 28 percent, vs. 48 percent in the normal subjects; P less than 0.01). Despite late hyperinsulinemia, at 30 minutes the subjects with impaired glucose tolerance had smaller increases in plasma insulin and smaller reductions in plasma glucagon (both P less than 0.01). Molar ratios of plasma insulin to plasma glucagon levels correlated inversely (r = -0.62, P less than 0.001) with the rates of systemic glucose appearance; the latter correlated positively (r = 0.72, P less than 0.0001) with peak plasma glucose concentrations. Impaired glucose tolerance, the precursor of NIDDM, results primarily from reduced suppression of hepatic glucose output due to abnormal pancreatic islet-cell function. The late hyperinsulinemia may be the consequence of an inadequate early beta-cell response rather than of insulin resistance.
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              Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans.

              13C NMR spectroscopy was used to assess flux rates of hepatic glycogen synthase and phosphorylase in overnight-fasted subjects under one of four hypoglucagonemic conditions: protocol I, hyperglycemic (approximately 10 mM) -hypoinsulinemia (approximately 40 pM); protocol II, euglycemic (approximately 5 mM) -hyperinsulinemia (approximately 400 pM); protocol III, hyperglycemic (approximately 10 mM) -hyperinsulinemia (approximately 400 pM); and protocol IV; euglycemic (approximately 5 mM) -hypoinsulinemia (approximately 40 pM). Inhibition of net hepatic glycogenolysis occurred in both protocols I and II compared to protocol IV but via a different mechanism. Inhibition of net hepatic glycogenolysis occurred in protocol I mostly due to decreased glycogen phosphorylase flux, whereas in protocol II inhibition of net hepatic glycogenolysis occurred exclusively through the activation of glycogen synthase flux. Phosphorylase flux was unaltered, resulting in extensive glycogen cycling. Relatively high rates of net hepatic glycogen synthesis were observed in protocol III due to combined stimulation of glycogen synthase flux and inhibition of glycogen phosphorylase flux. In conclusion, under hypoglucagonemic conditions: (a) hyperglycemia, per se, inhibits net hepatic glycogenolysis primarily through inhibition of glycogen phosphorylase flux; (b) hyperinsulinemia, per se, inhibits net hepatic glycogenolysis primarily through stimulation of glycogen synthase flux; (c) inhibition of glycogen phosphorylase and the activation of glycogen synthase are not necessarily coupled and coordinated in a reciprocal fashion; and (d) promotion of hepatic glycogen cycling may be the principal mechanism by which insulin inhibits net hepatic glycogenolysis and endogenous glucose production in humans under euglycemic conditions.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                September 2004
                10 September 2004
                : 62
                : 3
                : 142-148
                aEndocrinology and Diabetology Unit, Department of Pediatrics, University Hospital Center; bInstitute of Physiology, University of Lausanne Medical School, and cDepartment of Public Education, School Health Services, Lausanne, Switzerland
                80070 Horm Res 2004;62:142–148
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 37, Pages: 7
                Original Paper


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