Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.

Department of Physiology Faculty of Medicine Charles University 500 38 Hradec Králové Czech Republic

Zobrazit více v PubMed

Krause M.P., Riddell M.C., Hawke T.J. Effects of type 1 diabetes mellitus on skeletal muscle: clinical observations and physiological mechanisms. Pediatr. Diabetes. 2011;12:345–364. doi: 10.1111/j.1399-5448.2010.00699.x. PubMed DOI

Chandramohan G., Al-Numair K.S., Veeramani C., Alsaif M.A., Almajwal A.M. Protective effect of kaempferol, a flavonoid compound, on oxidative mitochondrial damage in streptozotocin-induced diabetic rats. Prog. Nutr. 2015;17:238–244.

Karakelides H., Asmann Y.W., Bigelow M.L., Short K.R., Dhatariya K., Coenen-Schimke J., Kahl J., Mukhopadhyay D., Nair K.S. Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects. Diabetes. 2007;56:2683–2689. doi: 10.2337/db07-0378. PubMed DOI

Monaco C.M.F., Hughes M.C., Ramos S.V., Varah N.E., Lamberz C., Rahman F.A., McGlory C., Tarnopolsky M.A., Krause M.P., Laham R., et al. Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes. Diabetologia. 2018;61:1411–1423. doi: 10.1007/s00125-018-4602-6. PubMed DOI

Vinik A.I., Nevoret M.L., Casellini C., Parson H. Diabetic neuropathy. Endocrinol. Metab. Clin. North Am. 2013;42:747–787. doi: 10.1016/j.ecl.2013.06.001. PubMed DOI

Smith H.J., Mukerji P., Tisdale M.J. Attenuation of proteasome-induced proteolysis in skeletal muscle by {beta}-hydroxy-{beta}-methylbutyrate in cancer-induced muscle loss. Cancer Res. 2005;65:277–283. PubMed

Kovarik M., Muthny T., Sispera L., Holecek M. Effects of β-hydroxy-β-methylbutyrate treatment in different types of skeletal muscle of intact and septic rats. J. Physiol. Biochem. 2010;66:311–319. doi: 10.1007/s13105-010-0037-3. PubMed DOI

Hao Y., Jackson J.R., Wang Y., Edens N., Pereira S.L., Always S.E. β-Hydroxy-β-methylbutyrate reduces myonuclear apoptosis during recovery from hind limb suspension-induced muscle fiber atrophy in aged rats. Am. J. Physiol. 2011;301:R701–R715. doi: 10.1152/ajpregu.00840.2010. PubMed DOI PMC

Clark R.H., Feleke G., Din M., Yasmin T., Singh G., Khan F.A., Rathmacher J.A. Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. JPEN J. Parenter. Enteral Nutr. 2000;24:133–139. doi: 10.1177/0148607100024003133. PubMed DOI

Olveira G., Olveira C., Doña E., Palenque F.J., Porras N., Dorado A., Godoy A.M., Rubio-Martínez E., Rojo-Martínez G., Martín-Valero R. Oral supplement enriched in HMB combined with pulmonary rehabilitation improves body composition and health related quality of life in patients with bronchiectasis (Prospective, Randomised Study) Clin. Nutr. 2016;35:1015–1022. doi: 10.1016/j.clnu.2015.10.001. PubMed DOI

Ekinci O., Yanık S., Terzioğlu Bebitoğlu B., Yılmaz Akyüz E., Dokuyucu A., Erdem S. Effect of calcium β-hydroxy-β-methylbutyrate (CaHMB), vitamin D, and protein supplementation on postoperative immobilization in malnourished older adult patients with hip fracture: A randomized controlled study. Nutr. Clin. Pract. 2016;31:829–835. doi: 10.1177/0884533616629628. PubMed DOI

Holeček M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. J. Cachexia Sarcopenia Muscle. 2017;8:529–541. doi: 10.1002/jcsm.12208. PubMed DOI PMC

Duan Y., Li F., Guo Q., Wang W., Zhang L., Wen C., Chen X., Yin Y. β-Hydroxy-β-methyl butyrate is more potent than leucine in inhibiting starvation-induced protein degradation in C2C12 myotubes. J. Agric. Food Chem. 2018;66:170–176. doi: 10.1021/acs.jafc.7b04841. PubMed DOI

Sipahi S., Gungor O., Gunduz M., Cilci M., Demirci M.C., Tamer A. The effect of oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine and glutamine on wound healing: a retrospective analysis of diabetic haemodialysis patients. BMC Nephrol. 2013;14:8. doi: 10.1186/1471-2369-14-8. PubMed DOI PMC

Aftring R.P., Miller W.J., Buse M.G. Effects of diabetes and starvation on skeletal muscle branched-chain alpha-keto acid dehydrogenase activity. Am. J. Physiol. 1988;254:E292–E300. doi: 10.1152/ajpendo.1988.254.3.E292. PubMed DOI

Borghi L., Lugari R., Montanari A., Dall’Argine P., Elia G.F., Nicolotti V., Simoni I., Parmeggiani A., Novarini A., Gnudi A. Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects. Diabetes. 1985;34:812–815. doi: 10.2337/diab.34.8.812. PubMed DOI

Jensen-Waern M., Andersson M., Kruse R., Nilsson B., Larsson R., Korsgren O., Essén-Gustavsson B. Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism. Lab. Anim. 2009;43:249–254. doi: 10.1258/la.2008.008069. PubMed DOI

Van den Berg E.H., Flores-Guerrero J.L., Gruppen E.G., de Borst M.H., Wolak-Dinsmore J., Connelly M.A., Bakker S.J.L., Dullaart R.P.F. Non-alcoholic fatty liver disease and risk of incident type 2 diabetes: Role of circulating branched-chain amino acids. Nutrients. 2019;11:705. doi: 10.3390/nu11030705. PubMed DOI PMC

Iwasa M., Ishihara T., Mifuji-Moroka R., Fujita N., Kobayashi Y., Hasegawa H., Iwata K., Kaito M., Takei Y. Elevation of branched-chain amino acid levels in diabetes and NAFL and changes with antidiabetic drug treatment. Obes. Res. Clin. Pract. 2015;9:293–297. doi: 10.1016/j.orcp.2015.01.003. PubMed DOI

Newgard C.B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012;15:606–614. doi: 10.1016/j.cmet.2012.01.024. PubMed DOI PMC

Laferrère B., Reilly D., Arias S., Swerdlow N., Gorroochurn P., Bawa B., Bose M., Teixeira J., Stevens R.D., Wenner B.R., et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci. Ttransl. Med. 2011;3:80re2. doi: 10.1126/scitranslmed.3002043. PubMed DOI PMC

Koksal B. Effect of streptozotocin on plasma insulin levels of rats and mice: A meta-analysis study. Open Access Maced, J. Med. Sci. 2015;3:380–383. doi: 10.3889/oamjms.2015.093. PubMed DOI PMC

Armstrong R.B., Gollnick P.D., Ianuzzo C.D. Histochemical properties of skeletal muscle fibers in streptozotocin-diabetic rats. Cell Tissue Res. 1975;162:387–394. doi: 10.1007/BF00220185. PubMed DOI

Medina-Sanchez M., Rodriguez-Sanchez C., Vega-Alvarez J.A., Menedez-Pelaez A., Perez-Casas A. Proximal skeletal muscle alterations in streptozotocin-diabetic rats: a histochemical and morphometric analysis. Am. J. Anat. 1991;191:48–56. doi: 10.1002/aja.1001910105. PubMed DOI

Holeček M., Mičuda S. Amino acid concentrations and protein metabolism of two types of rat skeletal muscle in postprandial state and after brief starvation. Physiol. Res. 2017;66:959–967. doi: 10.33549/physiolres.933638. PubMed DOI

Holecek M., Sispera L. Glutamine deficiency in extracellular fluid exerts adverse effects on protein and amino acid metabolism in skeletal muscle of healthy, laparotomized, and septic rats. Amino Acids. 2014;46:1377–1384. doi: 10.1007/s00726-014-1701-7. PubMed DOI

Muthny T., Kovarik M., Sispera L., Tilser I., Holecek M. Protein metabolism in slow- and fast-twitch skeletal muscle during turpentine-induced inflammation. Int. J. Exp. Pathol. 2008;89:64–71. doi: 10.1111/j.1365-2613.2007.00553.x. PubMed DOI PMC

Rodríguez T., Alvarez B., Busquets S., Carbó N., López-Soriano F.J., Argilés J.M. The increased skeletal muscle protein turnover of the streptozotocin diabetic rat is associated with high concentrations of branched-chain amino acids. Biochem. Mol. Med. 1997;61:87–94. doi: 10.1006/bmme.1997.2585. PubMed DOI

Holecek M., Muthny T., Kovarik M., Sispera L. Effect of beta-hydroxy-beta-methylbutyrate (HMB) on protein metabolism in whole body and in selected tissues. Food Chem. Toxicol. 2009;47:255–259. doi: 10.1016/j.fct.2008.11.021. PubMed DOI

Holeček M., Vodeničarovová M. Effects of beta-hydroxy-beta-methylbutyrate in partially hepatectomized rats. Physiol. Res. 2018;67:741–751. doi: 10.33549/physiolres.933861. PubMed DOI

Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951;193:265–275. PubMed

Holeček M., Vodeničarovová M. Muscle wasting and branched-chain amino acid, alpha-ketoglutarate, and ATP depletion in a rat model of liver cirrhosis. Int. J. Exp. Pathol. 2018;99:274–281. doi: 10.1111/iep.12299. PubMed DOI PMC

Atkinson D.E. The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers. Biochemistry. 1968;7:4030–4034. doi: 10.1021/bi00851a033. PubMed DOI

Odedra B.R., Dalal S.S., Millward D.J. Muscle protein synthesis in the streptozotocin-diabetic rat. A possible role for corticosterone in the insensitivity to insulin infusion in vivo. Biochem. J. 1982;202:363–368. doi: 10.1042/bj2020363. PubMed DOI PMC

Millward D.J., Garlick P.J., Nnanyelugo D.O., Waterlow J.C. The relative importance of muscle protein synthesis and breakdown in the regulation of muscle mass. Biochem. J. 1976;156:185–188. doi: 10.1042/bj1560185. PubMed DOI PMC

Harper A.E., Miller R.H., Block K.P. Branched-chain amino acid metabolism. Ann. Rev. Nutr. 1984;4:409–454. doi: 10.1146/annurev.nu.04.070184.002205. PubMed DOI

Holeček M. Why are branched-chain amino acids increased in starvation and diabetes? Nutrients. 2020;12:3087. doi: 10.3390/nu12103087. PubMed DOI PMC

May M.E., Mancusi V.J., Aftring R.P., Buse M.G. Effects of diabetes on oxidative decarboxylation of branched-chain keto acids. Am. J. Physiol. 1980;239:E215–E222. doi: 10.1152/ajpendo.1980.239.3.E215. PubMed DOI

Lombardo Y.B., Thamotharan M., Bawani S.Z., Paul H.S., Adibi S.A. Posttranscriptional alterations in protein masses of hepatic branched-chain keto acid dehydrogenase and its associated kinase in diabetes. Proc. Assoc. Am. Physicians. 1998;110:40–49. PubMed

Holeček M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr. Metab. 2018;15:33. doi: 10.1186/s12986-018-0271-1. PubMed DOI PMC

Bervoets L., Massa G., Guedens W., Louis E., Noben J.P., Adriaensens P. Metabolic profiling of type 1 diabetes mellitus in children and adolescents: a case-control study. Diabetol. Metab. Syndr. 2017;9:48. doi: 10.1186/s13098-017-0246-9. PubMed DOI PMC

Drábková P., Šanderová J., Kovařík J., Kanďár R. An assay of selected serum amino acids in patients with type 2 diabetes mellitus. Adv. Clin. Exp. Med. 2015;24:447–451. doi: 10.17219/acem/29223. PubMed DOI

Holm L.J., Buschard K. L-serine: a neglected amino acid with a potential therapeutic role in diabetes. APMIS. 2019;127:655–659. doi: 10.1111/apm.12987. PubMed DOI PMC

Sharawy M.H., El-Awady M.S., Megahed N., Gameil N.M. The ergogenic supplement β-hydroxy-β-methylbutyrate (HMB) attenuates insulin resistance through suppressing GLUT-2 in rat liver. Can. J. Physiol. Pharmacol. 2016;94:488–497. doi: 10.1139/cjpp-2015-0385. PubMed DOI

Yonamine C.Y., Teixeira S.S., Campello R.S., Gerlinger-Romero F., Rodrigues C.F., Guimarães-Ferreira L., Machado U.F., Nunes M.T. Beta hydroxy beta methylbutyrate supplementation impairs peripheral insulin sensitivity in healthy sedentary Wistar rats. Acta Physiol. 2014;212:62–74. doi: 10.1111/apha.12336. PubMed DOI

Zhang Y., Yang M., Zhou P., Yan H., Zhang Z., Zhang H., Qi R., Liu J. β-Hydroxy-β-methylbutyrate-induced upregulation of miR-199a-3p contributes to slow-to-fast muscle fiber type conversion in mice and C2C12 cells. J. Agric. Food Chem. 2020;68:530–540. doi: 10.1021/acs.jafc.9b05104. PubMed DOI

Solon-Biet S.M., Cogger V.C., Pulpitel T., Wahl D., Clark X., Bagley E., Gregoriou G.C., Senior A.M., Wang Q.P., Brandon A.E., et al. Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nat. Metab. 2019;1:532–545. doi: 10.1038/s42255-019-0059-2. PubMed DOI PMC

Desikan V., Mileva I., Garlick J., Lane A.H., Wilson T.A., McNurlan M.A. The effect of oral leucine on protein metabolism in adolescents with type 1 diabetes mellitus. Int. J. Pediatr. Endocrinol. 2010;2010:493258. doi: 10.1186/1687-9856-2010-493258. PubMed DOI PMC

Hoppeler H., Hudlicka O., Uhlmann E. Relationship between mitochondria and oxygen consumption in isolated cat muscles. J. Physiol. 1987;385:661–675. doi: 10.1113/jphysiol.1987.sp016513. PubMed DOI PMC

Hamm R. Transaminases of skeletal muscle. 2. Transaminase activities in white and red muscles of pigs and cows. J. Food Sci. 1969;34:449–452. doi: 10.1111/j.1365-2621.1969.tb12802.x. DOI

Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions

Aspartic Acid in Health and Disease

Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus

Serine Metabolism in Health and Disease and as a Conditionally Essential Amino Acid

Side effects of amino acid supplements

The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases