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L-Tryptophan Suppresses Rise in Blood Glucose and Preserves Insulin Secretion in Type-2 Diabetes Mellitus Rats

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L-Tryptophan Suppresses Rise in Blood Glucose and Preserves Insulin Secretion in Type-2 Diabetes Mellitus Rats J Nutr Sci Vitaminol, 58, 415–422, 2012 L-Tryptophan Suppresses Rise in Blood Glucose and Preserves Insulin Secretion in Type-2 Diabetes Mellitus Rats Tomoko INUBUSHI1, Norio KAMEMURA2, Masataka ODA3, Jun SAKURAI3, Yutaka NAKAYA4, Nagakatsu HARADA4, Midori SUENAGA3, Yoichi MATSUNAGA3,*, Kazumi ISHIDOH2 and Nobuhiko KATUNUMA2 1 Faculty of Life Science, 2 Institute for Health Sciences, and 3 Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-cho, Tokushima, Tokushima 770–8514, Japan 4 Department of Nutrition and Metabolism, School of Medicine, The University of Tokushima, 3–18–15 Kuramoto-cho, Tokushima, Tokushima 770–8503, Japan (Received May 24, 2012) Summary Ample evidence indicates that a high-protein/low-carbohydrate diet increases glucose energy expenditure and is beneficial in patients with type-2 diabetes mellitus (T2DM). The present study was designed to investigate the effects of L-tryptophan in T2DM. Blood glucose was measured by the glucose dehydrogenase assay and serum insulin was measured with ELISA in both normal and hereditary T2DM rats after oral glucose administration with or without L-D-tryptophan and tryptamine. The effect of tryptophan on glucose absorption was examined in the small intestine of rats using the everted-sac method. Glucose incor- poration in adipocytes was assayed with [3H]-2-deoxy-D-glucose using a liquid scintillation counter. Indirect computer-regulated respiratory gas-assay calorimetry was applied to assay energy expenditure in rats. L-Tryptophan suppressed both serum glucose and insulin levels after oral glucose administration and inhibited glucose absorption from the intestine. Trypt- amine, but not L-tryptophan, enhanced insulin-stimulated [3H]-glucose incorporation into differentiated adipocytes. L-Tryptophan increased glucose-associated energy expenditure in rats in vivo. L-Tryptophan-rich chow consumed from a young age preserved the secretion of insulin and delayed the progression of T2DM in hereditary diabetic rats. The results sug- gested that L-tryptophan suppresses the elevation of blood glucose and lessens the burden associated with insulin secretion from b-cells. Key Words L-tryptophan, OGTT, tryptamine, type-2 diabetes mellitus The main mode of action of currently available medi- amine and serotonin (5-HT) modulate insulin secretion cations for type-2 diabetes mellitus (T2DM) is stimula- (9) and glucose uptake into skeletal muscle (10), as well tion of insulin secretion from pancreatic b-cells (1). as melatonin-stimulated insulin secretion (11). Recently, However, such glucose-lowering agents could burden it was reported that oral administration of L-tryptophan b-cells and worsen prognosis. Regular muscle exercise for 15 d did not modify glycermia or insulinemia, but enhances insulin sensitivity and consequently reduces raised melatonin in T2DM model rats (12). the burden on b-cells. Clinical evidence indicates that a In the present study, we report two novel effects for high-protein and low-carbohydrate diet is beneficial in L-tryptophan: L-tryptophan itself decreases glucose the treatment of T2DM (2–4). absorption from the small intestine, and its metabo- Although the high protein in the diet reduced blood lite, tryptamine, increases glucose uptake into adipo- glucose levels, resulting in the reduction of the bur- cytes. Finally, L-tryptophan-rich-chow consumed from den of pancreatic b-cells, its constituent amino acids a young age effectively prevents exhaustion of b-cells have various effects on blood glucose level (5); it was in old T2DM rats. We speculate that L-tryptophan and reported that amino acid combinations such as isoleu- its metabolites play an important role in “the specific cine and serine increased insulin sensitivity (6), whereas dynamic action” and that L-tryptophan is potentially L-glutamine, glycine and threonine decreased maximal useful therapeutically in T2DM. insulin responsiveness of the glucose transport system EXPERIMENTS in isolated adipocytes (7). The effects of L-tryptophan on blood glucose level have been complex, because not only Experimental animals. Four-week-old male normal L-tryptophan itself upregulates gluconeogenesis in liver Sprague-Dawley (SD) rats from Japan SLC, Inc. and (8), but also its metabolites including 5-hydroxy-trypt- hereditary type-2 diabetes Sprague-Dawley Torii rats (SDT) from CLEA Japan, Inc., which develop spontane- * To whom correspondence should be addressed. ous T2DM, were used in this study. All rats were fasted E-mail: [email protected] at 17:00 for 16-h before the experiments. SDT rats were 415 416 INUBUSHI T et al. (A) (B) 250 6000 Glucose D-Tryptophan L-Trptophan(-) L-Tryptophan L-Tryptophan (ip) ) L-Trptophan (+) 200 mL ) 4000 dL * g/ 150 (m e os * Insulin (pg/ 2000 uc gl 100 * ood Bl * * 0 50 15 30 45 60 Time after administration (min) 0 0306090 Time after administration (min) (C) 2500 Glucose L-tryptophan 0.1g/dL L-tryptophan 0.2g/dL L-tryptophan 0.3g/dL D-tryptophan 0.3g/dL Fig. 1. L-Tryptophan alters the uptake of glucose. SD ) 2000 rats at 5 wk of age were subjected to OGTT [oral glucose (2 g/kg BW) alone (n58), plus L-tryptophan (62.5 mg/ (mg/dL kg BW) orally (n56) or intraperitoneally (n57), or 1500 plus D-tryptophan (62.5 mg/kg BW) orally (n55)]. * Blood sugar level (A) and serum insulin level (B). Data in (A) and (B) are mean6SD. * p,0.05, by Wilcoxon- absorption 1000 Mann-Whitney’s test. Glucose uptake in everted-sac (C). Everted-small intestine isolated from 8-wk-old rat. * Glucose 500 Sac containing 1 mL of saline was incubated in 10 g/dL * ** * of glucose solution add L-tryptophan (0.1–0.3 g/dL) or D-tryptophan (0.3 g/dL) at 37˚C. Glucose concentration 0 in the saline was assayed at 30 min and 60 min. Data 30 60 Incubation period (min) are mean6SD. * p,0.05, and ** p,0.01 by ANOVA. fed normal chow (MF, Oriental Yeast Co., Ltd.), and Wiseman was used for measurement of glucose absorp- L-tryptophan-rich-chow (add 37.5 mg L-tryptophan tion (14). A 20-cm-long portion of the small intestine to 100 g chow, total 280 mg of L-tryptophan in 100 g was isolated from 8- or 9-wk-old SD rats and one end of normal-chow and 317.5 mg of that in 100 g of of the small intestine was bound to form a sac, and the L-tryptophan-rich-chow). The rats were allowed food ad sac was everted so that the serosal layer was inside and libitum. All animal experiments described in this study the mucosal layer was outside. The sac was filled with were approved by the Animal Review Committee of 1 mL of saline and incubated in glucose solution (10 g/ Tokushima Bunri University before the study. dL) at 37˚C under aeration. The saline samples (120 mL) Oral glucose tolerance test (OGTT) and insulin assay. were pumped out from the inside of the sac for 30 and The OGTT was performed after 16-h fasting in SD or 60 min, and glucose concentrations in saline were SDT rats with glucose (2 g/kg body weight (BW)), plus assayed using the Somogyi-Nelson method (15, 16). either L- or D-tryptophan (62.5 mg/kg BW) (12). Blood Preparation of differentiated adipocytes and glucose uptake samples were collected from the inferior vena cava at assay. Preadipocytes 3T3-L1 were obtained from the the indicated times after oral administration of glucose. Health Science Research Resources Bank, Japan (17). Blood-glucose levels in the samples were assayed using a They were inoculated at a concentration of 1.03104 Nipro-Free Meter (Nipro Co., Tokyo, Japan) with a hydro- cells/mL in 24 well gelatin coated plates (IWAKI, Japan) gen electrode and the glucose dehydrogenase method. and cultured for 5-d. The cells were allowed to differenti- Insulin concentration was determined after OGTT using ate in high-glucose Dulbecco’s modified Eagle medium an enzyme-linked immunosorbent assay (ELISA) kit (DMEM) containing 1 mM dexamethasone, 10 mg/mL (Shibayagi Laboratories, Gunma, Japan) according to insulin, 0.5 mM 3-isobutyl-1-methyl-xanthine and 10% the protocol provided by the manufacturer (13). fetal bovine serum (FBS) for another 2-d. The culture Assay of glucose absorption using an everted-sac of rat medium were replaced with high-glucose DMEM con- small intestine in vitro. The method of Wilson and taining 10 mg/mL insulin and 10% FBS, and cultured Beneficial Effects ofL -Tryptophan in Diabetes 417 (A) (B) cpm(x103) cpm(x103) 10 10 L-Tryptophan Insulin - Tryptamine Insulin - * Insulin + Insulin + 8 8 6 6 ucose uptake 4 4 ucose uptake Gl Gl 2 2 0 0 0110 100 0110 100 Concentration of L-Tryptophan (µM) Concentration of Tryptamine (µM) Fig. 2. Tryptamine and L-tryptophan modulate glucose uptake. Differentiated adipocytes were cultured in [3H]-2-deoxy-D- glucose plus various concentrations of L-tryptophan (A) and tryptamine (B). Uptake of 2-deoxy-D-glucose was measured by a scintillation counter (n53). for a further 10-d. Cell differentiation was confirmed by RESULTS microscopic examination after Oil Red O staining (Sup- plementary Fig. 1) and these cells were used as the differ- Per-oral-administrated L-tryptophan suppresses hyperglyce- entiated adipocytes. The differentiated adipocytes were mia with glucose load incubated in insulin-free high-glucose DMEM without L-Tryptophan was co-administrated orally in com- FBS for 4-h and washed 3 times with 5 mM potassium bination with glucose, and blood glucose levels were dihydrogen phosphate, 20 mM 4-(2-hydroxyethyl)-1-pi- assayed using tail blood samples every 30 min. L-Tryp- perazineethanesulfonic acid (HEPES) (pH 7.4), 1 mM tophan administration both via oral and intraperito- MgSO4, 1 mM CaCl2, 136 mM NaCl, and 4.7 mM KCl, neal routes suppressed the increase in blood glucose designated as Krebe’s Ringer phosphate HEPES (KRPH) level to levels similar to those after glucose load at 30 buffer (18).
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