Abstract. Introduction. Subjects and Methods

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1 Some Aspects of Carbohydrate and Fat Metabolism in Protein Energy Malnutrition: Part I: Glycosylated Hemoglobin, Insulin and Cortisol Levels in Children with Protein-Energy Malnutrition Moustafa M. El-Saied,* Safiea El-Deep*, Ayman A. Goda* and Sharaf A. Ghanima** From the departments of Pediatrics* and Biochemistry**, Faculty of Medicine, Assiut University, Egypt. Abstract To study the state of glycemic control in children with protein-energy malnutrition (PEM), 50 cases with PEM and 10 apparently healthy controls were studied, clinically and for the following: glucose tolerance, serum levels of albumin, insulin, cortisol and level of glycosylated hemoglobin (HbA 1c ). Blood levels of HbA 1c were significantly higher in kwashiorkor compared with those of marasmus and those of control children (p<0.001, p<0.05 respectively). Serum insulin levels were significantly lower in kwashiorkor than in marasmus and controls (p<0.001for both) while serum cortisol levels were significantly higher in PEM cases than in control (p<0.005) with no statistical difference between cases of kwashiorkor and marasmus. Serum insulin showed a strong positive correlation with serum albumin,and both of them showed strong negative correlation with blood HbA 1c levels. There was a significant positive correlation between skin fold thickness (SFT) and HbA 1c levels. However, blood glucose levels, 2 hours after glucose loading, were significantly lower in PEM cases than in controls (p<0.05). In conclusion, there is evidence for glucose intolerance in PEM cases. As this sometimes may persist after recovery from PEM, long term follow up of glycemic control of these children is recommended. Introduction Worldwide, malnutrition is still one of the leading causes of morbidity and mortality in childhood (1). Significant hormonal changes have been reported in childhood malnutrition (2). These changes may act to defend the body against protein energy malnutrition (3). Deranged carbohydrate metabolism has been reported in PEM (4) through either limited supply or limited enzymatic and hormonal mechanisms. In experimental animals, PEM early in life may result in a diminished reserve for insulin production that may predispose to glucose intolerance or even diabetes in situations with an Subjects and Methods The study included 50 children with PEM, 29 males and 21 females, between ages of 6 months and 4 years, recruited from the Pediatric Department and O.P. of Assiut University Hospital. Full clinical assessment was done including measurements of weight, height, head circumference, skin fold thickness (SFT) and mid arm circumference (MAC). The type of malnutrition was classified according to Wellcome s classification (8). Twenty-five of the children were increased insulin demand (5). Blood glucose determination alone may not be adequate for assessment of glycemic control. Glycosylated hemoglobin formation depends on the prevailing blood glucose concentration and reflects the state of glycemic control of the preceding 2-3 months (6). However, the value of HbA 1c in assessment of malnourished children has not yet been established (7). The aim of the present work is to study the state of glycemic control of children with PEM utilizing assessment of glucose tolerance, HbA 1c, insulin and cortisol levels. classified as kwashiorkor with the following host characteristics: age 18±9.79 months, weight 7.62±1.57 kg, length (height) 69.96±9.09 cm, SFT 9.81±3.24 mm and MAC 8.91±2.12 cm. The remaining 25 were classified as marasmus with the following host characteristics: age 9.80±5.27 months, weight 5.9±1.85 kg, length(height) 65.49±9.90 cm, SFT 3.06±0.82 mm and MAC 6.81±1.42 cm. The controls were 10 apparently healthy children of matchable age and sex. They Alexandria Journal of Pediatrics; Volume 12, Number 1; January

2 were nutritionally normal and not acutely ill coming for minor surgical operations. Oral consent was obtained from the parents of the subjects and controls before they were recruited into the study. Venous blood samples were taken from patients and controls, within 24 hours of admission, following an overnight fasting. Venous blood sample was divided into 3 aliquots, 1 ml for glucose estimation, 1 ml in a heparinized bottle for HbA 1c determination and 2 ml for separation of serum for determination of sodium, potassium, albumin, insulin and cortisol. For glucose tolerance test, every subject was given glucose 1.75 g/kg of ideal weight by mouth (9) ; and after 2 hours blood glucose estimation was done. Levels of glycosylated hemoglobin in whole blood samples were estimated by the use of 'Glycated hemoglobin (HbA 1c ) kits' (Sigma Diagnostics, St. Louis, USA), procedure No Immunoassay kits for quantitative determination of cortisol in human serum (Immunotech. Corp., Boston, USA, Catalog number 107) were used. Serum insulin was estimated by immunoenzymatic assay for quantitative measurement of human Insulin. Results Table I shows diarrhea, hepatomegaly, death rate and some routine laboratory data of PEM cases and controls. Table II shows levels of serum albumin, insulin, cortisol and blood glucose fasting, glucose after 2 hours, and HbA 1c in PEM cases and controls. Table III shows levels of serum albumin, insulin, cortisol and blood glucose fasting, glucose after 2 hours and HbA 1c in kwashiorkor and marasmic cases. HbA 1 c level was significantly higher,while serum insulin was significantly lower in cases of kwashiorkor than in control (p< 0.05,p<0.001 respectively). Figure 1 shows the correlation between HbA 1c and each of SFT and serum albumin. HbA 1c shows a significant positive correlation with SFT on one hand (r=0.451, p<0.001), and a significant negative correlation with serum albumin on the other hand (r=-0.362, p<0.01). Figure 2 shows the correlation between serum insulin and each of serum albumin and blood glucose levels, 2 hours after glucose loading. Serum insulin levels shows positive correlation with serum albumin on one hand (r=0.47, p<0.001) and a significant negative correlation with the 2 hours glucose levels on the other hand (r=-0.57, p<0.001). Figure 3 shows the significant negative correlation between serum insulin and HbA 1c (r=-0.456, p<0.001). Table I : Some clinical and routine laboratory data of PEM patients and controls Diarrhea Hepatomegaly Serum Serum Death rate Sodium meq/l potassium meq/l Kwashiorkor 36% 64% ±1.63* 3.76±0.35* 20% Marasmus 44% 8% ± ±0.39 8% Controls (n=10) ±4.13* 4.77±0.39* - * p <0.001 I vs III Alex. J. Pediar. 12 (1), Jan

3 Patients (n=50) Control (n=10) Table II: Levels of serum albumin, insulin, cortisol and blood glucose fasting, glucose after 2 hours and HbA 1c in PEM cases and controls Albumin g/dl fasting mmol/l after 2h mmol/l HbA 1c (% of total Hemoglobin) Insulin µu/ml Cortisol µg/dl 31.30± 3.24± 4.79± 9.01± 8.3± ± ± 3.37± 5.16± 7.46± 10.54± 13.97± P<0.001 Insignificant P<0.05 P<0.05 P<0.005 P<0.005 Table III: Levels of serum albumin, insulin, cortisol and blood glucose fasting, glucose after 2 hours and HbA 1c in kwashiorkor and marasmus. Kwashiorkor Marasmus Albumin g/dl fasting mmol/l after 2h mmol/l HbA 1c (% of total Hemoglobin) Insulin µu/ml Cortisol µg/dl 28.04± 3.23± 4.81± 10.11± 6.62± 24.73± ± 3.24± 4.77± 7.92± 9.98± 24.57± P<0.001 Insignificant Insignificant P<0.001 P<0.001 Insignificant Fig. 1: Correlation between HbA 1c and each of S.F.T. and serum albumin inside patients group (r = 0.451, p<0.001) (r = , p<0.01) Fig. 2: Correlation between serum insulin and both of serum 113 Alex. J. Pediatr. 12 (1), Jan 1998

4 albumin and Gl. 2 hrs. inside patients group Albumin (r = 0.47, p<0.001) Gl. 2 hrs. (r = -0.57, p<0.001) Fig. 3: Correlation between serum insulin and HbA 1c inside patients group ( r = , p<0.001) Discussion Alex. J. Pediar. 12 (1), Jan

5 The estimation of glycemic control based on blood glucose determination alone may be misleading because blood glucose levels are dependent upon many factors (7). Glycosylated hemoglobin is formed at a rate dependent on the glucose concentration to which erythrocytes are exposed, and HbA 1c measurement reflects the average blood glucose concentration during the preceding 2-3 months (6). The significantly higher HbA 1c values observed in kwashiorkor patients compared with those of marasmus and with those of control children is in keeping with the existence of glucose intolerance, which has been previously documented in kwashiorkor patients (7). Serum insulin was lower in PEM cases in general and in kwashiorkor cases in particular than in controls and there was a strong negative correlation between serum insulin and HbA 1c level. Low insulin levels have been previously demonstrated in children with kwashiorkor (3) and was suggested to further perpetuate the state of protein deficiency (10). Insulin deficiency in PEM cases has been attributed to some damage to the cells of Islets of Langerhans (2) and, is probably related to protein rather than to calorie deficiency (11). This is supported by finding; in the present series; of a strong positive correlation between serum albumin and serum insulin, and a strong negative correlation between both and blood HbA 1c. In the present study there is a significant positive correlation between each of SFT and MAC on one hand and HbA 1c on the References 1. Barness LA, Curran JA: Malnutrition. In: Nelson WE, Behrman RE, Kliegman RM and Arvin AM (eds.), Nelson Textbook of Pediatrics (15 th ed.), W.B. Saunders Company, 1996, P Brooks SR, Golden MH, Payne-Robinson HM: Ultrastructure of the islets of Langerhans in proteinenergy malnutrition. West-Ind Med J 1993; 42(3): Soliman AT, Aref MK, Hassan AEI: Hormonal changes in protein energy malnutrition. Indian Pediatr 1988; 55: Dhatt PS, Gupta SG, Saini AS, Mingh S, Mehta HC: Intravenous glucose utilization in marasmus. Ind J Pediatr 1981; 47: other hand. This indicates that cases with better SFT have protein depletion with relatively less energy depletion resulting in preservation of subcutaneous fat on one hand and presence of elevated blood glucose secondary to insulin deficiency over long time producing increased formation of HbA 1c on the other hand. Some paradox exists between the finding of lower insulin level and higher HbA 1c level on one hand, and lower blood glucose level, 2 hours after glucose loading on the other hand in PEM cases than in controls. This may be explained by suggesting that, in PEM pancreatic damage with decreased insulin production occurs early when the still available energy may exposes the red cells to high blood glucose and increases the level of HbA 1c. With progression of PEM and more profound energy depletion, blood glucose levels tends to drop in spite of low insulin level and some mechanisms to maintain it, as increased glucagon (12) and cortisol (13) may be working. Serum cortisol levels were significantly higher in PEM cases than in controls in the present series. On glucose loading these mechanisms may be partially checked resulting in a modest rise of blood glucose in spite of insulin deficiency. In conclusion, there is glucose intolerance in PEM children supported by the finding of lower serum insulin and elevated HbA 1c levels. As permanent glucose intolerance has been described in a minority of children up to 10 years after recovery from kwashiorkor (14) long term follow up of these patients is necessary. 5. Swenne I, Borg LA, Crace CI and Landstron SA: Persistent reduction of pancreatic mass after a limited period of PEM in the young rat. Diabetologia 1992; 35(10): Sperling MA: Diabetes Mellitus. In: Nelson WE, Behrman RE, Kliegman RM and Arvin AM (eds.), Nelson Textbook of Pediatrics (15 th ed.), W.B. Saunders Company, 1996; P Adegberno SA, Dada OA, Olanrewaju IU, Fafunso: Glycosylated haemoglobin levels in children with protein-energy malnutrition. Ann Trop Pediatr 1991; 11: Wellcome Trust Working Party: Classification of protein-energy malnutrition. Lancet 1970; 2: Alex. J. Pediatr. 12 (1), Jan 1998

6 9. Nicholson JE and Pesce MA: Laboratory testing and reference values (Table 670-2) in infatns and children. In Nelson WE, Behrman RE, Kliegman RM and Arvin AM (eds.), Nelson Textbook of Pediatrics (15 th ed.), W.B. Saunders Company 1996; P Soliman AT, Alsalmi I, Asfour M: Hypoinsulinaemia has an importent role in the development of oedema and hepatomegaly during malnutrition. J Trop Pediatr 1996; 42(5): Claeyssens S, Lavoinne A, Vaillant C, Rakotomanga J A, Joyeux B B, Peret J: Metabolic changes during earyl starvation in rats fed a low protein diet in the postweaning growth period. Metabolism 1992; 41(7): Aref MK, Zaky K, El-Ashwash A: Insulin and glucagon in protein calorie malnutrition. MS Thesis, Faculty of Medicine, Alexandria University, Egypt, Soliman AT, Hassan AEH, Aref KM, Hintz LR, Rosenfold GR, Rogol DA: Serum insulin like growth factors I and II concentrations and growth hormone and insulin response to arginine infusion in children with protein energy malnutrition before and after nutritional rehabilitation. Pediatr Res 1986; 20: Becker DJ, Pimstone BL, Hamsen JDL, Hendrickse S: Insulin secretion in protein-calorie malnutrition. Quantitative abnormalities and response to treatment. Diabetes 1971; 20: Alex. J. Pediar. 12 (1), Jan

Serum Cortisol Concentrations in Children with Protein-Energy Malnutrition

Original Articles Serum Cortisol Concentrations in Children with Protein-Energy Malnutrition Ashraf T. M. Soliman, MD; Abd El-Hadi I. Hassan, MD; Mohamed K. Aref, MD; Alan D. Rogol, MD, PhD From the Department