Summary
Selenium is a trace element that exerts certain insulin-like actions in vitro. In this study, we evaluated its in vivo effects on the glucose homeostasis of rats made diabetic and insulin-deficient by streptozotocin. Na2SeO4 was administered ad libitum in drinking water and/or food for 10 weeks. The elevated plasma glucose levels (~ 25 mmol/l) and glucosuria (~ 85 mmol/day) of untreated rats were decreased by 50 and 80%, respectively, by selenate treatment. The beneficial effect of selenate was also evident during oral and intravenous glucose tolerance tests: the integrated glucose responses were decreased by 40–50% as compared to those in untreated rats. These effects were not due to an increase in plasma insulin levels. Compared to non-diabetic rats, pancreatic insulin reserves were reduced by more than 90% in treated and untreated diabetic rats. The hepatic activities and mRNA levels of two key glycolytic enzymes, glucokinase and l-type pyruvate kinase were blunted in diabetic rats. They increased ~ two- to threefold after selenate treatment, to reach 40–75% of the values in non-diabetic rats. In contrast, elevated activity and mRNA levels of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, were reduced by 40–65% after selenate administration. Since selenate induced a moderate decrease in body weight due to an anorexigenic effect, we checked that there was no improvement of glucose homeostasis or hepatic glucose metabolism in an additional group of calorie-restricted diabetic rats, which was weight-matched with the selenate group. In addition, no obvious toxic side-effects on the kidney or liver were observed in the rats receiving selenate. In conclusion, selenate induces a sustained improvement of glucose homeostasis in streptozotocin-diabetic rats by an insulin-like action, which involves partial correction of altered pretranslational regulatory mechanisms in liver metabolism.
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Abbreviations
- GK:
-
Glucokinase
- l-PK:
-
l-type pyruvate kinase
- PEP:
-
phosphoenolpyruvate
- PEPCK:
-
phosphoenolpyruvate carboxykinase
- C:
-
non-diabetic control rats
- D:
-
untreated diabetic rats
- WM:
-
weight-matched diabetic rats
- Se:
-
selenatetreated diabetic rats
- OGTT:
-
oral glucose tolerance test
- IV-GTT:
-
intravenous glucose tolerance test
- STZ:
-
streptozotocin
- SSC:
-
sodium saline citrate
- SSPE:
-
sodium saline phosphate ethylenediamine tetraacetic acid
- GLUT2:
-
glucose transporter isoform 2
References
Wilber CG (1980) Toxicology of selenium: a review. Clin Toxicol 17: 171–230
Lederer J (1986) Selenium et vitamine E. Maloine, Paris, pp 1–376
Yang G, Chen J, Wen Z, Ge K (1984) The role of selenium in Keshan disease. In: Drapper HH (ed) Advances in nutritional research. Plenum Press, New York, pp 203–231
Van Rij AM, Thomson CD, McKenzie JM, Robinson MF (1979) Selenium deficiency in total parenteral nutrition. Am J Clin Nutr 32: 2085–2086
Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG (1973) Selenium: biochemical role as a component of the glutathione peroxidase. Science 179: 588–590
Ezaki O (1990) The insulin-like effects of selenate in rat adipocytes. J Biol Chem 265: 1124–1128
Souness JE, Stouffer JE, Chagoya de Sanchez V (1983) The effects of selenium deficiency on rat fat cell glucose oxidation. Biochem J 214: 471–477
Rasekh HR, Potmis RA, Nonavinakere VK, Early JL, Iszard MD (1991) Effect of selenium on plasma glucose of rats: the role of insulin and glucocorticoids. Toxicol Lett 58: 199–207
McNeill JH, Delgatty HLM, Battel ML (1991) Insulin-like effects of sodium selenate in STZ-induced diabetic rats. Diabetes 40: 1675–1678
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium-thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Sambrook J, Fritsch EF, Maniatis T (1989) Extraction, purification and analysis of messenger RNA from eukaryotic cells. In: Ford N, Nolan C, Fergusson M (eds) Molecular cloning. A laboratory manual Vol 1. Cold Spring Harbor Laboratory Press, New York, p 7.22
Iynedjian PB, Ucla C, Mach B (1987) Molecular cloning of glucokinase cDNA. Developmental and dietary regulation of glucokinase mRNA in rat liver. J Biol Chem 262: 6032–6038
Simon MP, Besmond C, Cottreau D et al. (1983) Molecular cloning for rat L-type pyruvate kinase and aldolase B. J Biol Chem 258: 14576–14584
Yoo-Warren H, Monahan JE, Short J et al. (1983) Isolation and characterization of the gene coding for cytosolic phosphoenolpyruvate carboxykinase (GTP) from the rat. Proc Natl Acad Sci USA 80: 3656–3660
Thorens B, Sarkar HK, Kaback HR, Lodish HF (1988) Cloning and functional expression of a novel glucose transporter present in liver, intestine, kidney and Β-pancreatic islet cells. Cell 55: 281–290
Newgard CB, Hirsch LJ, Foster DW, McGarry JD (1983) Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. J Biol Chem 258: 8046–8052
Blair JB, Cimbala MA, Foster JL, Morgan RA (1976) Hepatic pyruvate kinase. Regulation by glucagon, cyclic adenosine 3′∶5′-monophosphate, and insulin in the perfused rat liver. J Biol Chem 251: 3756–3762
Chang HC, Lane MD (1966) The enzymatic carboxylation of phosphoenolpyruvate. II. Purification and properties of liver mitochondrial phosphoenolpyruvate carboxykinase. J Biol Chem 241: 2413–2420
Bradford M (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254
Alfthan G, Kumpulainen J (1982) Determination of selenium in small volumes of blood plasma and serum by electrothermal atomic absorption spectrometry. Anal Chim Acta 140: 221–227
Welz B, Melcher M, Nève J (1984) Determination of selenium in human body fluids by hybride-generation atomic absorption spectrometry. Optimization of sample composition. Anal Chim Acta 165: 131–140
Robberecht HJ, Deelstra HA (1984) Selenium in human urine. Determination, speciation and concentration levels. Talanta 31: 497–508
Sokal RR, Rohlf FJ (1969) Biometry. The principles and practice of statistics in biological research. Freeman, San Francisco, pp 1–776
Oka Y, Asano T, Shibasaki Y et al. (1990) Increased liver glucose-transporter protein and mRNA in STZ-induced diabetic rats. Diabetes 39: 441–446
Burcelin R, Kande J, Eddouks M, Assan R, Girard J (1992) Evidence that GLUT2 mRNA and protein concentrations are decreased by hyperinsulinemia and increased by hyperglycemia in liver of diabetic rats. Biochem J 288: 675–679
Brichard SM, Desbuquois B, Girard J (1993) Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism. Effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2. Mol Cell Endocrinol 91: 91–97
Brichard SM, Henquin JC, Girard J (1993) Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism. Diabetologia 36: 292–298
Granner D, Pilkis S (1990) The genes of hepatic glucose metabolism. J Biol Chem 265: 10173–10176
Jensen PK, Christiansen JS, Steven K, Parving HH (1981) Renal function in streptozotocin-diabetic rats. Diabetologia 21: 409–414
Brichard SM, Okitolonda W, Henquin JC (1988) Long term improvement of glucose homeostasis by vanadate treatment in diabetic rats. Endocrinology 123: 2048–2053
Malabu UH, Dryden S, McCarthy HD, Kilpatrick A, Williams G (1994) Effects of chronic vanadate administration in the STZ-induced diabetic rat: the antihyperglycemic action of vanadate is entirely attributable to its suppression of feeding. Diabetes 43: 9–15
Wolffram S, Arduser F, Scarrer E (1985) In vivo intestinal absorption of selenate and selenite by rats. J Nutr 115: 454–459
Starke A, Grundy S, McGarry JD, Unger RH (1985) Correction of hyperglycemia with phlorizin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes. Proc Natl Acad Sci USA 82: 1544–1546
Heyliger CE, Tahiliani AG, McNeill JH (1985) Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227: 1474–1477
Meyerovitch J, Farfel Z, Sack J, Shechter Y (1987) Oral administration of vanadate normalizes blood glucose levels in streptozotocin-treated rats. J Biol Chem 262: 6658–6662
Gil J, Miralpeix M, Carreras J, Bartrons R (1988) Insulinlike effects of vanadate on glucokinase activity and fructose 2,6-bisphosphate levels in the liver of diabetic rats. J Biol Chem 263: 1868–1871
Valera A, Rodriguez-Gil JE, Bosch F (1993) Vanadate treatment restores the expression of genes for key enzymes in the glucose and ketone bodies metabolism in the liver of diabetic rats. J Clin Invest 92: 4–11
Rossetti L, Giaccari A, Klein-Robbenhaar E, Vogel LR (1990) Insulinomimetic properties of trace elements and characterization of their in vivo mode of action. Diabetes 39: 1243–1250
Swarup G, Speeg KV, Cohen S, Garbers DL (1982) Phosphotyrosyl-protein phosphatase of TCRC-2 cells. J Biol Chem 257: 7298–7301
Nechay BR (1984) Mechanisms of action of vanadium. Ann Rev Pharmacol Toxicol 24: 501–524
Bollen M, Miralpeix M, Ventura F, Toth B, Bartrons R, Stalmans W (1990) Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase. Biochem J 267: 269–271
Pugazhenthi S, Khandelwal RL (1990) Insulinlike effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozotocin-induced diabetic rats. Diabetes 39: 821–827
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Becker, D.J., Reul, B., Ozcelikay, A.T. et al. Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats. Diabetologia 39, 3–11 (1996). https://doi.org/10.1007/BF00400407
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DOI: https://doi.org/10.1007/BF00400407