Diabetes causes marked changes in lymphocyte metabolism R Otton, J R Mendonça and R Curi Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, 05508-900 Butantan, São Paulo, São Paulo, Brazil (Requests for offprints should be addressed to R Otton; Email: rose@fisio.icb.usp.br) Abstract An enhanced susceptibility to infections is well known to occur in a poorly controlled diabetic state. Since glucose and glutamine are essential for lymphocyte function, we investigated whether their metabolism is changed in lymphocytes obtained from mesenteric lymph nodes of alloxan-induced diabetic rats (40 mg/kg body weight). The activities of hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase (G6PDH), citrate synthase and phosphate-dependent glutaminase were determined. Decarboxylation of metabolites [U- 14 C]-, [1- 14 C]- and [6- 14 C]-glucose, [1- 14 C]- and [2- 14 C]-pyru- vic acid, [U- 14 C]-palmitic acid and [U- 14 C]-glutamine was evaluated in incubated lymphocytes isolated from mesenteric lymph nodes. The measurements were carried out in cells following three experimental protocols: (1) lymphocytes freshly obtained from control and alloxan- induced diabetic rats, (2) lymphocytes from insulin-treated (2 U/rat per day) diabetic rats and (3) lymphocytes ob- tained from control and diabetic rats and cultured in the presence of insulin (1 mU/ml) for 6 h. The activities of hexokinase, G6PDH and citrate synthase were decreased by the diabetic state, whereas that of phosphofructokinase was raised. Decarboxylation of [U- 14 C]- and [6- 14 C]- glucose, [1- 14 C]- and [2- 14 C]-pyruvate and [U- 14 C]- glutamine were also decreased in lymphocytes from dia- betic rats, whereas [U- 14 C]-palmitic acid decarboxylation was increased. Insulin administration in vivo or added to the culture medium reversed the changes observed in freshly obtained lymphocytes. Alloxan-induced diabetes did change lymphocyte metabolism and this may be an important mechanism leading to impairment of lym- phocyte function. Journal of Endocrinology (2002) 174, 55–61 Introduction An enhanced susceptibility to infections is well known to occur in a poorly controlled diabetic state (Kraine & Tisch 1999). The incidence of a recognized group of rare infections is definitely high in diabetes mellitus or confined almost entirely to diabetic patients (Larkin et al. 1985). Infectious diseases, particularly tuberculosis, were a major cause of death among diabetic patients before the advent of insulin therapy (Eliopoulos 1995). Critical evaluations of the topic suggest that infections in general are more difficult to eliminate in the diabetic host (Garcia-Leme 1989). The reasons why diabetic patients present an increased susceptibility to frequent and prolonged infections, however, remain to be fully determined. Mature lymphocytes recirculate via blood and lymph through lymphoid tissues in a relatively quiescent state until stimulated to proliferate during, for example, a bacterial or viral infection. T-cell blastic transformation stimulated by phytohaemagglutin (Korfel et al. 1990) and plasma levels of immunoglobulins (Muller et al. 1989) are markedly reduced in patients with diabetes mellitus type 1, an effect reversed by insulin administration. In diabetic mice, the secretion of interleukin (IL)-4 is markedly reduced, in contrast to the secretion of IL-2 and interferon-, which is not affected (Wood et al. 1999). Type 2 diabetic patients show reduced thymidine uptake by lymphocytes, a reduced percentage of IL-2 receptor- positive cells and increased plasma levels of tumour necrosis factor- when compared with controls (Pavelic et al. 1987, Chang & Shaio 1995, Pickup et al. 2000). On the other hand, production of IL-2, IL-6 and IL-10 is dose- and time-dependently suppressed by elevation in glucose concentrations. High glucose levels also inhibit proliferation of peripheral mononuclear cells (Reinhold et al. 1996). Despite these changes in immune function, the effect of the diabetic state on lymphocyte metabolism has not been addressed. The metabolism of glucose and glutamine in lym- phocytes obtained from alloxan-induced diabetic rats was investigated. These metabolites are well known major fuels for lymphocytes and play a key role in the bio- synthesis of ATP, DNA, RNA and phospholipids (Newsholme et al. 1999). Key enzyme activities of glyco- lysis (hexokinase and phosphofructokinase), pentose- phosphate pathway (glucose-6-phosphate dehydrogenase; 55 Journal of Endocrinology (2002) 174, 55–61 0022–0795/02/0174–055  2002 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology.org Downloaded from Bioscientifica.com at 06/28/2022 09:36:49AM via free access