The Effect of Insulin on Blood Levels of Infused Pentoses in Man
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The Effect of Insulin on Blood Levels of Infused Pentoses in Man Stanton Segal, … , James B. Wyngaarden, Joseph Foley J Clin Invest. 1957;36(10):1383-1394. https://doi.org/10.1172/JCI103538. Research Article Find the latest version: https://jci.me/103538/pdf THE EFFECT OF INSULIN ON BLOOD LEVELS OF INFUSED PENTOSES IN MAN By STANTON SEGAL, JAMES B. WYNGAARDEN,1 AND JOSEPH FOLFY (From the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Serzice, U. S. Department of Health, Education and Welfare, Bethesda, Md.) (Submitted for publication December 17, 1956; accepted June 6, 1957) In 1931 Wierzuchowski (1) showed an influ- No reports have been noted demonstrating an ence of insulin on galactose tolerance of dogs. effect of insulin on a sugar other than glucose in More recently, Levine, Goldstein, Huddlestun, man. This paper reports studies on the effect of Klein, and Henry (2, 3) demonstrated that insu- insulin on blood levels of infused pentoses in man. lin lowers the blood levels of D-galactose, D-xylose, Pentoses were selected because their responses to and L-arabinose but not of D-arabinose or D-man- insulin in animals have been well described, they nose, following their infusion into the eviscerated are readily available, and following intravenous in- nephrectomized dog. The volume of distribution fusion they disappear from blood relatively slowly. of the responsive sugars was increased from 45 to This latter property permitted an evaluation of the 70 per cent of body weight as a result of insulin effect of insulin upon blood levels and disappear- administration. It was suggested that the insulin response represented a facilitation of transport of H H H the sugar across the cell membrane into intra- C= 0 C=O C=O cellular fluid. In all the responsive sugars the stereochemical structure of carbon atoms 1 to 3 H-C-OH H -C-OH H-C-OH was like that of D-glucose, and these authors sug- HO-C-H HO-C-H HO-C- H gested that these structural characteristics deter- H-C-OH H -C-OH HO-C-3H mined the insulin responsiveness of a sugar. H-C-OH H-C-OH H-C-OH Confirmatory evidence has appeared that insulin H -C-OH H H affects transport of D-galactose, D-xylose and H L-arabinose across the cell membrane in the rat diaphragm (4-6), eviscerate rat (7), perfused D-GIucs D-Xylo. L-Awbinose rat heart (8) and intact cat (9). However, slow penetration of a number of sugars into muscle of nephrectomized and eviscerated rats has now also H H been demonstrated, and this slow penetration is C= 0 C=0 increased by insulin for D-lyxose, D-ribose, D-man- HO-C-H nose, D-fructose and D-fucose, as well as for HO-C-H D-xylose, D-galactose and L-arabinose (10, 11). H-C-OH HO -C-H Although these results indicate that the concept H-C-OH H-C-OH of structural specificity in carbon atoms 1 to 3 for H-C-OH H -C-OH insulin responsiveness has proved to be too limited H H in scope, the lack of an effect of insulin upon in- tracellular entry of sorbitol, mannitol and raffinose is strong evidence that the action of insulin is not D-Arabinems D - Lyxos simply an acceleration of a process of physical FIG. 1. THE STEREOCHEMICAL CONFIGURATION OF THE diffusion (12). PENTOSES USED IN THE PRESENT STUDY The carbons in bold type indicate those atoms whose 1 Present address: Department of Medicine, Duke Uni- configuration is similar to that of glucose in the first three versity School of Medicine, Durham, N. C. atoms. 1383 1384 STANTON SEGAL, JAMES B. WYNGAARDEN, AND JOSEPH FOLEY ance rates, an appraisal which could not be made . O $6 with galactose (13) or fructose (14), which disap- pear from blood even more rapidly than does la glucose (15). In the present studies, we have in- vestigated the influence of insulin upon the rate of pentose disappearance from blood, and upon the urinary excretion of pentose. The stereochemical configuration of the sugars used in the present experiment is shown in Figure G r- c-o N r- 1z r co 1. Although these sugars exist in solution in a more complex pyranose ring structure, the simpli- fied formulas shown here demonstrate certain dif- - ferences in structure. D-xylose and L-arabinose N have structures exactly like glucose in the first - - Q three carbon atoms. D-arabinose differs in spatial _____ - projection of hydrogen and hydroxI groups on carbons 2 and 3, and D-lyxose on carbon 2 alone. |v D-lyxose is the pentose whose structure in carbon _ atoms to 4 resembles that of the hexose D-man-a 1 m" O OOe c 0 C4 nose. Because of the unusual kinetics of disap- __ pearance of D-ribose from blood, the effects of in- . l|S 0N0| o sulin on D-ribose blood levels will be reported in a i E e|°440 | |M C t- subsequent communication. t .1g s | | N Ne ] 4 _ ) METHODS it d Eleven studies were performed on five normal males 8 N b3O > _ en ohe -C4 m6 0 0 and one female ranging in age from 18 to 28. All were o M to maintained on a 250-Gm. carbohydrate diet and were 5 in 00c fasted overnight prior to any study. An indwelling plastic ° "' catheter was placed in an antecubital vein, and control N X V i blood specimens taken. A three-way stopcock was then at- - tached and with a infusion of saline. N kept open very slow 0 Ten- or 20-Gm. quantities of pentose, as a 10 per cent m-In Jo _ 0 N solution, were then infused into a vein of the opposite % arm. A blood sample was drawn from the indwelling e N N N catheter at the end of the infusion and a period of 25 to i 0 0' 30 minutes was then permitted to elapse in order to in- sure adequate mixing of the sugars in body fluids. At N CO 4orO the end of this period blood samples were drawn at 5- ors o . - 10-minute intervals for 25 to 30 minutes. At this time 0 ' _ (50 to 60 minutes after the end of the pentose infusion), . when enough blood values had been obtained to establish v -0 a 0 C N o E a curve of the falling blood levels, 0.1 unit of regular in- a QW * N .__4N sulin was injected intravenously per Kg. of body weight. t Blood specimens were drawn at 5- to 15-minute intervals _ 0 0 for another 90 to 110 minutes. In some experiments in- NN- N N* 0 travenous glucose (10 per cent solution) was given after |2 insulin injection. In three of the studies sugars were 0 0 0 X. 4J infused at a constant rate after administration of a 0.,,00~0.0 0 00 priming dose and the effect of insulin on the constant 04~d ~d ~ ~ ~ ~ - pentose level obtained was evaluated. Urine was collected at various intervals over a 24-hour * period.3 ci EFFECT OF INSULIN ON INFUSED PENTOSES IN MAN 1385 All of the pentoses initially employed were obtained L-arabinose were obtained from Pfanstiehl Laboratories, from Dr. Hewitt G. Fletcher, Jr., of the Section on Carbo- Incorporated, Waukegan, Illinois. The sugars were pre- hydrates, Laboratory of Chemistry of this Institute, and pared for intravenous use by autoclaving as 10 per cent recrystallized before use. All had specific optical rota- solutions, and were found sterile and pyrogen-free prior tions corresponding with those of the pure sugars re- to use. ported in the literature (16). Subsequently, D-xylose and Blood glucose and pentose levels were determined by 20gms D-XYLOSE IV 100 - 7u INSULIN IV 50 40 mgm % 30 XYLOSE 20 10 100 mgm 1 75 GLUCOSE 50 25 'I. I .. Ie 0 0 20 40 60 80 100 120 140 160 180 TIME IN MINUTES FIG. 2. THE EFFECT OF INSULIN ADMINISTRATION ON BLOOD LEVELS OF D-XYLOSE (SUBJECr W. R.) Blood xylose levels are plotted hemilogarithmically versus time. Blood glucose values are plotted on normal ordinates. 100 BLOOD 50 A RABI NOSE 40 mgm % 30 20 10 100 BLOOD GLUCOSE 75 mgm % 50 25 0 0 20 40 60 80 100 120 140 160 TIME IN MINUTES FIG. 3. THE EFFECT OF INSULIN ON THE BLOOD LEVELS OF L-ARABINOSE (SUBJECT W. W.) 1386 STANTON SEGAL, JAMES B. WYNGAARDEN, AND JOSEPH FOLEY I I I I* I I lOgms D-ARABINOSE IV 6S INSULN IV GLUCOSE o50ms IV 100 - I mgm % 50 ARABINOSE 40 30 20 150 125 /.7 . mgm % 100 GLUCOSE 75 _.**@ _- /~~~~ 50 25 0 0 20 40 60 80 100 120 140 160 180 TIME IN MINUTES FIG. 4. THE LACK OF RESPONSE OF THE BLOOD LEVELS OF D-ARABINOSE TO INJECTED INSULIN (SUBJECT C. C.) Glucose was administered to alleviate hypoglycemia. II I I 20gms D-LYXOSE IV 7u INSULIN IV GLUCOSEgms 100 I mgm % 50 LYXOSE 40 30 20 10 150 125 0\ 0---- 0 mgm % 100 . /~~~~~~~~~~~ GLUCOSE 75 50 | @ | \/ I I~~~~1111 25 0 0 20 40 60 80 100 120 140 160 180 TIME IN MINUTES FIG. 5. THE LACK OF RESPONSE OF BLOOD LEVELS OF D-LYXOSE TO INTRA- VENOUS INSULIN (SUBJECT W. R.) methods devised in this laboratory (17). The pentose RESULTS values were determined by the orcinol method using blood filtrates in which glucose had been destroyed by treatment Effect of insulin upon rates of disappearance of with the enzyme glucose oxidase.