European Journal of Nutrition

, Volume 52, Issue 3, pp 937–948 | Cite as

Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes

  • Francesco Sartor
  • Matthew J. Jackson
  • Cesare Squillace
  • Anthony Shepherd
  • Jonathan P. Moore
  • Donald E. Ayer
  • Hans-Peter Kubis
Original Contribution



Chronic sugar-sweetened beverage (SSB) consumption is associated with obesity and type 2 diabetes mellitus (T2DM). Hyperglycaemia contributes to metabolic alterations observed in T2DM, such as reduced oxidative capacity and elevated glycolytic and lipogenic enzyme expressions in skeletal muscle tissue. We aimed to investigate the metabolic alterations induced by SSB supplementation in healthy individuals and to compare these with the effects of chronic hyperglycaemia on primary muscle cell cultures.


Lightly active, healthy, lean subjects (n = 11) with sporadic soft drink consumption underwent a 4-week SSB supplementation (140 ± 15 g/day, ~2 g glucose/kg body weight/day, glucose syrup). Before and after the intervention, body composition, respiratory exchange ratio (RER), insulin sensitivity, muscle metabolic gene and protein expression were assessed. Adaptive responses to hyperglycaemia (7 days, 15 mM) were tested in primary human myotubes.


SSB supplementation increased fat mass (+1.0 kg, P < 0.05), fasting RER (+0.12, P < 0.05), fasting glucose (+0.3 mmol/L, P < 0.05) and muscle GAPDH mRNA expressions (+0.94 AU, P < 0.05). PGC1α mRNA was reduced (−0.20 AU, P < 0.05). Trends were found for insulin resistance (+0.16 mU/L, P = 0.09), and MondoA protein levels (+1.58 AU, P = 0.08). Primary myotubes showed elevations in GAPDH, ACC, MondoA and TXNIP protein expressions (P < 0.05).


Four weeks of SSB supplementation in healthy individuals shifted substrate metabolism towards carbohydrates, increasing glycolytic and lipogenic gene expression and reducing mitochondrial markers. Glucose-sensing protein MondoA might contribute to this shift, although further in vivo evidence is needed to corroborate this.


Soft drinks Insulin resistance PGC1α MondoA TXNIP 



We would like to thank Dr Matschke for her help with the data collection and Dr Caspari for letting us use part of the NWCRF Institute facilities. We are also grateful to Dr de Morree for proofreading the manuscript. All authors read and approved the final manuscript.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

394_2012_401_MOESM1_ESM.pdf (4.4 mb)
Supplementary Figure 1. Myocytes grown on microcarriers for 14 days in culture, photographed at ×20 magnficication (B,D) and seeded in conventional culture flasks, 40X magnification (A,C). (PDF 4480 kb)
394_2012_401_MOESM2_ESM.docx (23 kb)
Supplementary material 2 (DOCX 22 kb)


  1. 1.
    Chopra M, Galbraith S, Darnton-Hill I (2002) A global response to a global problem: the epidemic of overnutrition. Bull World Health Organ 80:952–958Google Scholar
  2. 2.
    Kahn CR (1994) Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43:1066–1084CrossRefGoogle Scholar
  3. 3.
    Corpeleijn E, Saris WH, Blaak EE (2009) Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle. Obes Rev 10:178–193CrossRefGoogle Scholar
  4. 4.
    Kelley DE, Mandarino LJ (2000) Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49:677–683CrossRefGoogle Scholar
  5. 5.
    Kelley DE, Simoneau JA (1994) Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 94:2349–2356CrossRefGoogle Scholar
  6. 6.
    Simoneau JA, Kelley DE (1997) Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J Appl Physiol 83:166–171Google Scholar
  7. 7.
    Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387CrossRefGoogle Scholar
  8. 8.
    Gaster M, Staehr P, Beck-Nielsen H, Schroder HD, Handberg A (2001) GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes 50:1324–1329CrossRefGoogle Scholar
  9. 9.
    Tanner CJ, Barakat HA, Dohm GL, Pories WJ, MacDonald KG, Cunningham PR, Swanson MS, Houmard JA (2002) Muscle fiber type is associated with obesity and weight loss. Am J Physiol Endocrinol Metab 282:E1191–E1196Google Scholar
  10. 10.
    Ellis BA, Poynten A, Lowy AJ, Furler SM, Chisholm DJ, Kraegen EW, Cooney GJ (2000) Long-chain acyl-CoA esters as indicators of lipid metabolism and insulin sensitivity in rat and human muscle. Am J Physiol Endocrinol Metab 279:E554–E560Google Scholar
  11. 11.
    Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ, Jensen CB, Krook A, Bjornholm M, Tornqvist H, Zierath JR, Ridderstrale M, Altshuler D, Lee RT, Vaag A, Groop LC, Mootha VK (2007) TXNIP regulates peripheral glucose metabolism in humans. PLoS Med 4:e158CrossRefGoogle Scholar
  12. 12.
    Stoltzman CA, Peterson CW, Breen KT, Muoio DM, Billin AN, Ayer DE (2008) Glucose sensing by MondoA:Mlx complexes: a role for hexokinases and direct regulation of thioredoxin-interacting protein expression. Proc Natl Acad Sci USA 105:6912–6917CrossRefGoogle Scholar
  13. 13.
    Hanke N, Scheibe RJ, Manukjan G, Ewers D, Umeda PK, Chang KC, Kubis HP, Gros G, Meissner JD (2011) Gene regulation mediating fiber-type transformation in skeletal muscle cells is partly glucose- and ChREBP-dependent. Biochim Biophys Acta 1813:377–389CrossRefGoogle Scholar
  14. 14.
    Hu FB, Malik VS (2010) Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav 100:47–54CrossRefGoogle Scholar
  15. 15.
    Malik VS, Popkin BM, Bray GA, Despres JP, Hu FB (2010) Sugar-sweetened beverages, obesity, type 2 diabetes mellitus, and cardiovascular disease risk. Circulation 121:1356–1364CrossRefGoogle Scholar
  16. 16.
    Malik VS, Popkin BM, Bray GA, Despres JP, Willett WC, Hu FB (2010) Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care 33:2477–2483CrossRefGoogle Scholar
  17. 17.
    Mattes RD, Shikany JM, Kaiser KA, Allison DB (2011) Nutritively sweetened beverage consumption and body weight: a systematic review and meta-analysis of randomized experiments. Obes Rev 12:346–365CrossRefGoogle Scholar
  18. 18.
    Sans CL, Satterwhite DJ, Stoltzman CA, Breen KT, Ayer DE (2006) MondoA-Mlx heterodimers are candidate sensors of cellular energy status: mitochondrial localization and direct regulation of glycolysis. Mol Cell Biol 26:4863–4871CrossRefGoogle Scholar
  19. 19.
    Billin AN, Eilers AL, Coulter KL, Logan JS, Ayer DE (2000) MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a max-like network. Mol Cell Biol 20:8845–8854CrossRefGoogle Scholar
  20. 20.
    Gibson R (1993) Nutritional assessment. A laboratory manual. Oxford University Press, New YorkGoogle Scholar
  21. 21.
    Sartor F, Donaldson LF, Markland DA, Loveday H, Jackson MJ, Kubis HP (2011) Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation. Appetite 57:237–246CrossRefGoogle Scholar
  22. 22.
    Sartor F, de Morree HM, Matschke V, Marcora SM, Milousis A, Thom JM, Kubis HP (2010) High-intensity exercise and carbohydrate-reduced energy-restricted diet in obese individuals. Eur J Appl Physiol 110:893–903CrossRefGoogle Scholar
  23. 23.
    WHO (1999) Definition, diagnostic and classification of diabetes mellitus and its complications. In: Report of a WHO Consultation. World Health Organization, GenevaGoogle Scholar
  24. 24.
    da Rocha EE, Alves VG, da Fonseca RB (2006) Indirect calorimetry: methodology, instruments and clinical application. Curr Opin Clin Nutr Metab Care 9:247–256CrossRefGoogle Scholar
  25. 25.
    Frayn KN (1983) Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55:628–634Google Scholar
  26. 26.
    Reiser S, Bohn E, Hallfrisch J, Michaelis OEt, Keeney M, Prather ES (1981) Serum insulin and glucose in hyperinsulinemic subjects fed three different levels of sucrose. Am J Clin Nutr 34:2348–2358Google Scholar
  27. 27.
    Reiser S, Handler HB, Gardner LB, Hallfrisch JG, Michaelis OEt, Prather ES (1979) Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and glucose response to a sucrose load. Am J Clin Nutr 32:2206–2216Google Scholar
  28. 28.
    Black SE, Mitchell E, Freedson PS, Chipkin SR, Braun B (2005) Improved insulin action following short-term exercise training: role of energy and carbohydrate balance. J Appl Physiol 99:2285–2293CrossRefGoogle Scholar
  29. 29.
    Nilsson A, Granfeldt Y, Ostman E, Preston T, Bjorck I (2006) Effects of GI and content of indigestible carbohydrates of cereal-based evening meals on glucose tolerance at a subsequent standardised breakfast. Eur J Clin Nutr 60:1092–1099CrossRefGoogle Scholar
  30. 30.
    Stevenson E, Williams C, Nute M (2005) The influence of the glycaemic index of breakfast and lunch on substrate utilisation during the postprandial periods and subsequent exercise. Br J Nutr 93:885–893CrossRefGoogle Scholar
  31. 31.
    Wolever TM, Jenkins DJ, Ocana AM, Rao VA, Collier GR (1988) Second-meal effect: low-glycemic-index foods eaten at dinner improve subsequent breakfast glycemic response. Am J Clin Nutr 48:1041–1047Google Scholar
  32. 32.
    Acheson KJ, Schutz Y, Bessard T, Anantharaman K, Flatt JP, Jequier E (1988) Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr 48:240–247Google Scholar
  33. 33.
    Aitken JC, Thompson J (1989) The effects of dietary manipulation upon the respiratory exchange ratio as a predictor of maximum oxygen uptake during fixed term maximal incremental exercise in man. Eur J Appl Physiol Occup Physiol 58:722–727CrossRefGoogle Scholar
  34. 34.
    Horowitz JF, Mora-Rodriguez R, Byerley LO, Coyle EF (1997) Lipolytic suppression following carbohydrate ingestion limits fat oxidation during exercise. Am J Physiol 273:E768–E775Google Scholar
  35. 35.
    Trenell MI, Stevenson E, Stockmann K, Brand-Miller J (2008) Effect of high and low glycaemic index recovery diets on intramuscular lipid oxidation during aerobic exercise. Br J Nutr 99:326–332CrossRefGoogle Scholar
  36. 36.
    Stevenson E, Williams C, Nute M, Humphrey L, Witard O (2008) Influence of the glycaemic index of an evening meal on substrate oxidation following breakfast and during exercise the next day in healthy women. Eur J Clin Nutr 62:608–616CrossRefGoogle Scholar
  37. 37.
    Isken F, Klaus S, Petzke KJ, Loddenkemper C, Pfeiffer AF, Weickert MO (2010) Impairment of fat oxidation under high- vs. low-glycemic index diet occurs before the development of an obese phenotype. Am J Physiol Endocrinol Metab 298:E287–E295CrossRefGoogle Scholar
  38. 38.
    Roberts R, Bickerton AS, Fielding BA, Blaak EE, Wagenmakers AJ, Chong MF, Gilbert M, Karpe F, Frayn KN (2008) Reduced oxidation of dietary fat after a short term high-carbohydrate diet. Am J Clin Nutr 87:824–831Google Scholar
  39. 39.
    He J, Kelley DE (2004) Muscle glycogen content in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 287:E1002–E1007CrossRefGoogle Scholar
  40. 40.
    Merla G, Howald C, Antonarakis SE, Reymond A (2004) The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14–3-3. Hum Mol Genet 13:1505–1514CrossRefGoogle Scholar
  41. 41.
    Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K (2003) Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc Natl Acad Sci USA 100:5107–5112CrossRefGoogle Scholar
  42. 42.
    Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90CrossRefGoogle Scholar
  43. 43.
    Kubis HP, Hanke N, Scheibe RJ, Meissner JD, Gros G (2003) Ca2 + transients activate calcineurin/NFATc1 and initiate fast-to-slow transformation in a primary skeletal muscle culture. Am J Physiol Cell Physiol 285:C56–C63Google Scholar
  44. 44.
    Hanke N, Meissner JD, Scheibe RJ, Endeward V, Gros G, Kubis HP (2008) Metabolic transformation of rabbit skeletal muscle cells in primary culture in response to low glucose. Biochim Biophys Acta 1783:813–825CrossRefGoogle Scholar
  45. 45.
    Pilegaard H, Keller C, Steensberg A, Helge JW, Pedersen BK, Saltin B, Neufer PD (2002) Influence of pre-exercise muscle glycogen content on exercise-induced transcriptional regulation of metabolic genes. J Physiol 541:261–271CrossRefGoogle Scholar
  46. 46.
    Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S, Polonsky KS (1998) Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 47:358–364CrossRefGoogle Scholar
  47. 47.
    Arner P (2005) Insulin resistance in type 2 diabetes—role of the adipokines. Curr Mol Med 5:333–339CrossRefGoogle Scholar
  48. 48.
    Chutkow WA, Patwari P, Yoshioka J, Lee RT (2008) Thioredoxin-interacting protein (Txnip) is a critical regulator of hepatic glucose production. J Biol Chem 283:2397–2406CrossRefGoogle Scholar
  49. 49.
    Muoio DM (2007) TXNIP links redox circuitry to glucose control. Cell Metab 5:412–414CrossRefGoogle Scholar
  50. 50.
    Kaadige MR, Looper RE, Kamalanaadhan S, Ayer DE (2009) Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity. Proc Natl Acad Sci USA 106:14878–14883CrossRefGoogle Scholar
  51. 51.
    Rennie MJ, Ahmed A, Khogali SE, Low SY, Hundal HS, Taylor PM (1996) Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance. J Nutr 126:1142S–1149SGoogle Scholar
  52. 52.
    Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470CrossRefGoogle Scholar
  53. 53.
    Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C (2006) Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 295:1681–1687CrossRefGoogle Scholar
  54. 54.
    BSDA (2011) The 2011 UK soft drinks report: by popular demand. In: British Soft Drinks Association.

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Francesco Sartor
    • 1
  • Matthew J. Jackson
    • 1
  • Cesare Squillace
    • 2
  • Anthony Shepherd
    • 1
  • Jonathan P. Moore
    • 1
  • Donald E. Ayer
    • 3
  • Hans-Peter Kubis
    • 1
  1. 1.College of Health and Behavioural SciencesBangor UniversityBangorUK
  2. 2.DiSUANUniversity of Urbino “Carlo Bo”UrbinoItaly
  3. 3.Department of Oncological Sciences, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

Personalised recommendations