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Mechanisms Behind Decreased Endogenous Glucose Production in Malnourished Children

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Mechanisms Behind Decreased Endogenous Glucose Production in Malnourished Children 0031-3998/10/6805-0423 Vol. 68, No. 5, 2010 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2010 International Pediatric Research Foundation, Inc. Mechanisms Behind Decreased Endogenous Glucose Production in Malnourished Children ROBERT H. J. BANDSMA, MARIJKE MENDEL, MARTIJN N. SPOELSTRA, DIRK-JAN REIJNGOUD, THEO BOER, FRANS STELLAARD, BERNARD BRABIN, REIJNOUT SCHELLEKENS, EDWARD SENGA, AND GEERT TOM HEIKENS Departments of Biochemistry [R.H.J.B., E.S.], and Paediatrics and Child Health [R.H.J.B., G.T.H.], University of Malawi, Blantyre 360, Malawi; Center for Liver, Digestive and Metabolic Diseases [M.M., M.S., D.-J.R., T.B., F.S.] and Department of Clinical Pharmacy [R.S.], University Medical Center Groningen, Groningen 9713 GZ, The Netherlands; Child and Reproductive Health Group [B.B.], Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; Emma Kinderziekenhuis [B.B.], Academic Medical Centre, University of Amsterdam, Amsterdam 1100 DD, The Netherlands; Division of Gastroenterology, Hepatology and Nutrition [R.H.J.B.], The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 ABSTRACT: Severe malnutrition is a major health problem in dyspigmentation. Metabolic features include hypoalbumine- developing countries and can present itself as kwashiorkor or maras- mia, hepatic steatosis, and hypoglycemia (5–7). Marasmus is mus. Although marasmus is characterized by clinical wasting, characterized by severe wasting (low weight for height) with- kwashiorkor is associated with peripheral edema, oxidative stress, out edema. hypoalbuminemia, and hypoglycemia. The etiology of the hypogly- Hypoglycemia is a common phenomenon in kwashiorkor cemia is poorly understood. We determined endogenous glucose production (EGP) in children with severe malnutrition. Children with (5,8,9), although it is also described in patients with severe kwashiorkor, marasmus, and controls received a primed constant wasting (8). Theoretically, hypoglycemia could be caused by 13 infusion of [6,6H2]glucose for 2 h. An i.v. bolus of C- impaired hepatic endogenous glucose production (EGP) or ketoisocaproic acid (KIC) was given, and breath samples were increased glucose clearance. A small study in five children obtained during 2 h. Isotope dilution was used to calculate EGP, and with malnutrition indicated normal glucose production (10), 13 12 Ϯ CO2/ CO2 production was determined. Mean EGP SEM was although data from a kwashiorkor animal model suggested Ϯ Ϯ 5.5 0.3 mg/kg/min in the kwashiorkor group and 6.9 0.4 impaired EGP (11). Ϯ mg/kg/min and 7.6 0.7 mg/kg/min in the marasmic and control Kwashiorkor has been firmly linked to hepatic steatosis and group, respectively, (p Ͻ 0.05 kwashiorkor versus marasmus and controls). EGP correlated with serum albumin concentration (r ϭ oxidative stress. The oxidative stress has been thought to be 0.67; p Ͻ 0.001) and urinary 8-hydroxydeoxyguanosine as a marker triggered by infections, decreased antioxidant status, or toxins ϭϪ Ͻ 13 (12–14). Patients with hepatic steatosis in the context of of oxidative stress (r 0.62; p 0.005). CO2 secretion as a marker of hepatic mitochondrial function was significantly higher in the obesity and insulin resistance also demonstrate increased ox- marasmic group compared with kwashiorkor and controls. We conclude idative stress (15). Although kwashiorkor is related to a state that decreased EGP in severely malnourished children is related to the of nutritional deficiency in contrast to obesity-related steato- degree of hypoalbuminemia and oxidative stress but is not associated sis, surplus tissue fatty acids have been shown to stimulate with a clear defect in hepatic mitochondrial function. (Pediatr Res 68: oxidative stress, leading to mitochondrial damage and cell 423–428, 2010) death irrespective of its cause (16,17). Steatosis can lead to impairment of mitochondrial function (18) and ATP produc- evere malnutrition presenting as kwashiorkor or marasmus tion (19). Decreased hepatic glucose production rates as found is still a significant health problem in developing coun- S in inborn errors of metabolism in the oxidative phosphoryla- tries (1,2). The HIV/AIDS epidemic has increased case fatal- tion pathway (20) or animal models of shock indicate a close ity rates of severe malnutrition, and these children often have link between mitochondrial dysfunction and impaired glu- comorbidities caused by opportunistic infections (3). Despite coneogenesis (21). Finally, signs of hepatic failure have been the high incidence and severity of severe malnutrition, basic described in patients with severe malnutrition (22), which pathophysiological differences between kwashiorkor and ma- rasmus are poorly understood. Although it was historically would also be associated with decreased EGP. postulated that kwashiorkor was caused by a protein defi- Breath tests using stable isotopes have been used to deter- ciency and marasmus by a calorie deficiency, these hypotheses mine various biochemical functions. Ketoisocaproic acid have been largely abandoned (4). Kwashiorkor is character- (KIC, a branched-chain amino acid) can undergo decarboxyl- ␣ ized by irritability, hair changes, edema, hepatomegaly, and ation through a branched-chain -ketoacid dehydrogenase complex, which is located exclusively in mitochondria. The enzyme complex has been shown to be primarily active in Received March 31, 2010; accepted July 10, 2010. hepatic mitochondria (23). KIC decarboxylation activity as- Correspondence: Robert Bandsma, M.D., Ph.D., Division of Gastroenterology, Hepa- tology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8; e-mail: [email protected] Supported by an international fellowship grant from the Nutricia Research Foundation Abbreviations: EGP, endogenous glucose production; KIC, ketoisocaproic (R.H.J.B.). acid; 8-OhdG, 8-hydroxydeoxyguanosine 423 424 BANDSMA ET AL. sessed by 13C-KIC breath tests have been used to detect Systems Laboratories, Sinsheim, Germany). Intra- and interassay coefficient Ͻ Ͻ Ͻ hepatic mitochondrial dysfunction in humans (24–26). of variation were 3% and 7% for insulin and 5% and 19% for glucagon, respectively. Cortisol and growth hormone concentrations were determined In this study, we aimed to address the underlying etiology using EIA (ALPCO Diagnostics, Salem, NH) with a intra- and interassay of hypoglycemia in kwashiorkor. We hypothesized that coefficient of variation of Ͻ10% and Ͻ9% for cortisol and Ͻ3% for growth kwashiorkor was associated with decreased EGP and KIC hormone. Urinary 8-hydroxydeoxyguanosine (8-OhdG) was determined using an ELISA (Northwest, Vancouver, Canada) and corrected for creatinine decarboxylation activity. EGP and KIC decarboxylation were excretion. Intra- and interassay coefficient of variation were Ͻ3% and Ͻ8%, assessed in severely malnourished and healthy children. Lev- respectively. els of oxidative stress, gluconeogenic precursors, and hor- Stable isotope analyses. All the breath test measurements were performed by gas isotope-ratio mass spectrometry (Delta Plus, Thermo Electron, Bre- monal changes were also characterized. men, Germany). The CO2 pulse was separated from other gas components in 12 breath and then ionized and separated in the mass spectrometer into CO2 13 ␦13 (m/z 44) and CO2 (m/z 45) ions. Measured values were expressed as C METHODS versus PeeDeeBelemnite limestone (30). For the glucose analyses, a disk (6.5 mm in diameter) was punched out of a blood spot, wetted with 40 ␮L water Subjects. The study was conducted in severely malnourished children and and 400 ␮L ethanol, and shaken for 45 min at room temperature. The control subjects admitted to MOYO House (a Nutrition Rehabilitation Unit) supernatant after centrifugation was dried at 60°C under a stream of N2. or one of the pediatric wards of the Queen Elizabeth Central Hospital (QECH) Glucose was converted to its pentaacetate derivative by adding 150 ␮L in Malawi. Children with kwashiorkor and marasmus were admitted as pyridine/acetic anhydride (1:2) and incubation for 30 min at 60°C, followed recommended by the WHO (27). Sample size was calculated to be seven per by drying at 60°C. The residue was dissolved in ethylacetate. All samples group, expecting a difference of EGP between kwashiorkor and the other were analyzed by gas chromatography quadrupole mass spectrometry groups of 20%, a power of 80%, and ␣ of 0.05. We choose to recruit (SSQ7000; ThermoFinnigan, San Jose, CA). For all calculations of mass additional children to account for potential loss of sample or technical isotopomer distribution, Excaliber software (ThermoFinnigan) was used. difficulties. Information about the study was provided verbally and through a Derivatives were separated on an AT-5MS 30 m ϫ 0.25 mm ID (0.25-␮m detailed written information sheet. Informed consent was obtained from film thickness) capillary column (Alltech, Breda, the Netherlands). The gas parents of all participants in accordance with the College of Medicine, chromatography oven temperature was started at 80°C for 1 min, increased to University of Malawi, Ethical Committee guidelines. Kwashiorkor was de- 280°C at a rate of 20°C for 1 min after which the oven was held at 280°C for fined as edema, not related to cardiac or renal disease and dyspigmentation of 3 min. Mass spectrometric analyses were performed by positive ion chemical skin or hair. Marasmus was defined as a weight/age ratio Ͻ70%, i.e. Ͼ3 SDs ionization with methane. Ions monitored for glucose pentaacetate were m/z
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