Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

High dietary protein intake, reducing or eliciting insulin resistance?

Abstract

Dietary proteins have an insulinotropic effect and thus promote insulin secretion, which indeed leads to enhanced glucose clearance from the blood. In the long term, however, a high dietary protein intake is associated with an increased risk of type 2 diabetes. Moreover, branched-chain amino acids (BCAA), a prominent group of amino acids, were recently identified to be associated with diabetes. Observational data and intervention studies do not point in the same direction regarding the effect of protein intake on insulin sensitivity and diabetes risk. Therefore, the first aim of this review will be to discuss human studies addressing high dietary protein intake and insulin action, with special attention for BCAA. In the second part, we will highlight the (patho) physiological consequences of high-protein diets regarding insulin action, in particular the role of the mechanistic target of the rapamycin pathway.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481.

    Article  CAS  Google Scholar 

  2. Jacobsen ATB Investigations of the influence of different foods on the blood sugar in normal, diabetic and pregnant persons. Biochem Z 1913; 56: 471–494.

    Google Scholar 

  3. El Khoury D, Hwalla N . Metabolic and appetite hormone responses of hyperinsulinemic normoglycemic males to meals with varied macronutrient compositions. Ann Nutr Metab 2010; 57: 59–67.

    Article  CAS  Google Scholar 

  4. Ricci G, Canducci E, Pasini V, Rossi A, Bersani G, Ricci E et al. Nutrient intake in Italian obese patients: Relationships with insulin resistance and markers of non-alcoholic fatty liver disease. Nutrition 2011; 27: 672–676.

    Article  CAS  Google Scholar 

  5. Sluijs I, Beulens JWJ, Van Der A DL, AMW Spijkerman, Grobbee DE, Van Der Schouw YT . Dietary intake of total, animal, and vegetable protein and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-NL study. Diabetes Care 2010; 33: 43–48.

    Article  CAS  Google Scholar 

  6. Song Y, Manson JE, Buring JE, Liu S . A prospective study of red meat consumption and type 2 diabetes in middle-aged and elderly women: the women's health study. Diabetes Care 2004; 27: 2108–2115.

    Article  CAS  Google Scholar 

  7. Pounis GD, Tyrovolas S, Antonopoulou M, Zeimbekis A, Anastasiou F, Bountztiouka V et al. Long-term animal-protein consumption is associated with an increased prevalence of diabetes among the elderly: the Mediterranean islands (MEDIS) study. Diabetes Metab 2010; 36: 484–490.

    Article  CAS  Google Scholar 

  8. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E et al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011; 17: 448–453.

    Article  Google Scholar 

  9. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9: 565–566.

    Article  CAS  Google Scholar 

  10. Rietman A, Schwarz J, Blokker BA, Siebelink E, Kok FJ, Afman LA et al. Increasing protein intake modulates lipid metabolism in healthy young men and women consuming a high-fat hypercaloric diet. J Nutr 2014; e-pub ahead of print 4 June 2014; doi:10.3945/jn.114.191072.

    Article  CAS  Google Scholar 

  11. Walrand S, Short KR, Bigelow ML, Sweatt AJ, Hutson SM, Nair KS . Functional impact of high protein intake on healthy elderly people. Am J Physiol Endocrinol Metabol 2008; 295: E921–E928.

    Article  CAS  Google Scholar 

  12. Tura A, Conte B, Caparrotto C, Spinella P, Maestrelli P, Valerio A et al. Insulin sensitivity and secretion in young, healthy subjects are not changed by Zone and Mediterranean diets. Mediterr J Nutr Metab 2010; 3: 233–237.

    Article  Google Scholar 

  13. Harber MP, Schenk S, Barkan AL, Horowitz JF . Effects of dietary carbohydrate restriction with high protein intake on protein metabolism and the somatotropic axis. J Clin Endocrinol Metab 2005; 90: 5175–5181.

    Article  CAS  Google Scholar 

  14. Pal S, Ellis V, Dhaliwal S . Effects of whey protein isolate on body composition, lipids, insulin and glucose in overweight and obese individuals. Br J Nutr 2010; 104: 716–723.

    Article  CAS  Google Scholar 

  15. Forsythe CE, Phinney SD, Feinman RD, Volk BM, Freidenreich D, Quann E et al. Limited effect of dietary saturated fat on plasma saturated fat in the context of a low carbohydrate diet. Lipids 2010; 45: 947–962.

    Article  CAS  Google Scholar 

  16. Claessens M, Van Baak MA, Monsheimer S, Saris WHM . The effect of a low-fat, high-protein or high-carbohydrate ad libitum diet on weight loss maintenance and metabolic risk factors. Int J Obes 2009; 33: 296–304.

    Article  CAS  Google Scholar 

  17. Weickert MO, Roden M, Isken F, Hoffmann D, Nowotny P, Osterhoff M et al. Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans. Am J Clin Nutr 2011; 94: 459–471.

    Article  CAS  Google Scholar 

  18. Gannon MC, Nuttall FQ . Effect of a high-protein, low-carbohydrate diet on blood glucose control in people with type 2 diabetes. Diabetes 2004; 53: 2375–2382.

    Article  CAS  Google Scholar 

  19. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H . An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes. Am J Clin Nutr 2003; 78: 734–741.

    Article  CAS  Google Scholar 

  20. Nuttall FQ, Schweim K, Hoover H, Gannon MC . Effect of the LoBAG30 diet on blood glucose control in people with type 2 diabetes. Br J Nutr 2008; 99: 511–519.

    Article  CAS  Google Scholar 

  21. Mann JI . Nutrition recommendations for the treatment and prevention of type 2 diabetes and the metabolic syndrome: an evidenced-based review. Nutr Rev 2006; 64: 422–427.

    Article  CAS  Google Scholar 

  22. Ratliff J, Mutungi G, Puglisi MJ, Volek JS, Fernandez ML . Carbohydrate restriction (with or without additional dietary cholesterol provided by eggs) reduces insulin resistance and plasma leptin without modifying appetite hormones in adult men. Nutr Res 2009; 29: 262–268.

    Article  CAS  Google Scholar 

  23. Abete I, Parra D, Martinez JA . Legume-, fish-, or high-protein-based hypocaloric diets: Effects on weight loss and mitochondrial oxidation in obese men. J Med Food 2009; 12: 100–108.

    Article  CAS  Google Scholar 

  24. Morenga LT, Williams S, Brown R, Mann J . Effect of a relatively high-protein, high-fiber diet on body composition and metabolic risk factors in overweight women. Eur J Clin Nutr 2010; 64: 1323–1331.

    Article  Google Scholar 

  25. Rizkalla SW, Prifti E, Cotillard A, Pelloux V, Rouault C, Allouche R et al. Differential effects of macronutrient content in 2 energy-restricted diets on cardiovascular risk factors and adipose tissue cell size in moderately obese individuals: a randomized controlled trial. Am J Clin Nutr 2012; 95: 49–63.

    Article  CAS  Google Scholar 

  26. Johnstone AM, Lobley GE, Horgan GW, Bremner DM, Fyfe CL, Morrice PC et al. Effects of a high-protein, low-carbohydrate v. high-protein, moderate-carbohydrate weight-loss diet on antioxidant status, endothelial markers and plasma indices of the cardiometabolic profile. Br J Nutr 2011; 106: 282–291.

    Article  CAS  Google Scholar 

  27. Brinkworth GD, Noakes M, Buckley JD, Keogh JB, Clifton PM . Long-term effects of a very-low-carbohydrate weight loss diet compared with an isocaloric low-fat diet after 12 mo. Am J Clin Nutr 2009; 90: 23–32.

    Article  CAS  Google Scholar 

  28. Farnsworth E, Luscombe ND, Noakes M, Wittert G, Argyiou E, Clifton PM . Effect of a high-protein, energy-restricted diet on body composition, glycemic control, and lipid concentrations in overweight and obese hyperinsulinemic men and women. Am J Clin Nutr 2003; 78: 31–39.

    Article  CAS  Google Scholar 

  29. McAuley KA, Hopkins CM, Smith KJ, McLay RT, Williams SM, Taylor RW et al. Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women. Diabetologia 2005; 48: 8–16.

    Article  CAS  Google Scholar 

  30. Ballesteros-Pomar MD, Calleja-Fernndez AR, Vidal-Casariego A, Urioste-Fondo AM, Cano-Rodrguez I . Effectiveness of energy-restricted diets with different protein:carbohydrate ratios: The relationship to insulin sensitivity. Public Health Nutr 2010; 13: 2119–2126.

    Article  Google Scholar 

  31. Sargrad KR, Homko C, Mozzoli M, Boden G . Effect of high protein vs high carbohydrate intake on insulin sensitivity, body weight, hemoglobin A1c, and blood pressure in patients with type 2 diabetes mellitus. J Am Diet Assoc 2005; 105: 573–580.

    Article  CAS  Google Scholar 

  32. Wycherley TP, Moran LJ, Clifton PM, Noakes M, Brinkworth GD . Effects of energy-restricted high-protein, low-fat compared with standard-protein, low-fat diets: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2012; 96: 1281–1298.

    Article  CAS  Google Scholar 

  33. Linn T, Santosa B, Grönemeyer D, Aygen S, Scholz N, Busch M et al. Effect of long-term dietary protein intake on glucose metabolism in humans. Diabetologia 2000; 43: 1257–1265.

    Article  CAS  Google Scholar 

  34. Halton TL, Liu S, Manson JE, Hu FB . Low-carbohydrate-diet score and risk of type 2 diabetes in women. Am J Clin Nutr 2008; 87: 339–346.

    Article  CAS  Google Scholar 

  35. Tai ES, Tan MLS, Stevens RD, Low YL, Muehlbauer MJ, Goh DLM et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010; 53: 757–767.

    Article  CAS  Google Scholar 

  36. Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D et al. Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 2012; 125: 2222–2231.

    Article  CAS  Google Scholar 

  37. Layman DK, Baum JI . Dietary protein impact on glycemic control during weight loss. J Nutr 2004; 134: 4.

    Article  Google Scholar 

  38. Nilsson M, Stenberg M, Frid AH, Holst JJ, Björck IME . Glycemia and insulinemia in healthy subjects after lactose-equivalent meals of milk and other food proteins: the role of plasma amino acids and incretins. Am J Clin Nutr 2004; 80: 1246–1253.

    Article  CAS  Google Scholar 

  39. Biolo G, Tessari P, Inchiostro S, Bruttomesso D, Fongher C, Sabadin L et al. Leucine and phenylalanine kinetics during mixed meal ingestion: a multiple tracer approach. Am J Physiol Endocrinol Metab 1992; 262: E455–E463.

    Article  CAS  Google Scholar 

  40. Hoerr RA, Matthews DE, Bier DM, Young VR . Effects of protein restriction and acute refeeding on leucine and lysine kinetics in young men. Am J Physiol Endocrinol Metab 1993; 264: E567–E575.

    Article  CAS  Google Scholar 

  41. Jakobsen LH, Kondrup J, Zellner M, Tetens I, Roth E . Effect of a high protein meat diet on muscle and cognitive functions: a randomised controlled dietary intervention trial in healthy men. Clin Nutr 2011; 30: 303–311.

    Article  CAS  Google Scholar 

  42. Takeshita Y, Takamura T, Kita Y, Ando H, Ueda T, Kato K et al. Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance: implications for type 2 diabetes. Metab Clin Exp 2012; 61: 1388–1394.

    Article  CAS  Google Scholar 

  43. Shah SH, Crosslin DR, Haynes CS, Nelson S, Turer CB, Stevens RD et al. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia 2012; 55: 321–330.

    Article  CAS  Google Scholar 

  44. Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI . Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc Natl Acad Sci USA 2012; 109: 8236–8240.

    Article  CAS  Google Scholar 

  45. Würtz P, Mäkinen VP, Soininen P, Kangas AJ, Tukiainen T, Kettunen J et al. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes 2012; 61: 1372–1380.

    Article  Google Scholar 

  46. Adams SH . Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state. Adv Nutr 2011; 2: 445–456.

    Article  CAS  Google Scholar 

  47. Schwingshackl L, Hoffmann G . Long-term effects of low-fat diets either low or high in protein on cardiovascular and metabolic risk factors: a systematic review and meta-analysis. Nutr J 2013; 12: 48.

    Article  CAS  Google Scholar 

  48. Krebs M, Brehm A, Krssak M, Anderwald C, Bernroider E, Nowotny P et al. Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia 2003; 46: 917–925.

    Article  CAS  Google Scholar 

  49. Carr RD, Larsen MO, Winzell MS, Jelic K, Lindgren O, Deacon CF et al. Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab 2008; 295: E779–E784.

    Article  CAS  Google Scholar 

  50. Acheson KJ, Blondel-Lubrano A, Oguey-Araymon S, Beaumont M, Emady-Azar S, Ammon-Zufferey C et al. Protein choices targeting thermogenesis and metabolism. Am J Clin Nutr 2011; 93: 525–534.

    Article  CAS  Google Scholar 

  51. Claessens M, Saris WHM, Van Baak MA . Glucagon and insulin responses after ingestion of different amounts of intact and hydrolysed proteins. Br J Nutr 2008; 100: 61–69.

    Article  CAS  Google Scholar 

  52. Power O, Hallihan A, Jakeman P . Human insulinotropic response to oral ingestion of native and hydrolysed whey protein. Amino Acids 2009; 37: 333–339.

    Article  CAS  Google Scholar 

  53. Krebs M, Krssak M, Bernroider E, Anderwald C, Brehm A, Meyerspeer M et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes 2002; 51: 599–605.

    Article  CAS  Google Scholar 

  54. Manders RJ, Little JP, Forbes SC, Candow DG . Insulinotropic and muscle protein synthetic effects of branched-chain amino acids: potential therapy for type 2 diabetes and sarcopenia. Nutr 2012; 4: 1664–1678.

    CAS  Google Scholar 

  55. Pal S, Ellis V . The acute effects of four protein meals on insulin, glucose, appetite and energy intake in lean men. Br J Nutr 2010; 104: 1241–1248.

    Article  CAS  Google Scholar 

  56. Ouellet V, Marois J, Weisnagel SJ, Jacques H . Dietary cod protein improves insulin sensitivity in insulin-resistant men and women: a randomized controlled trial. Diabetes Care 2007; 30: 2816–2821.

    Article  CAS  Google Scholar 

  57. Leenders M, Verdijk LB, van der Hoeven L, van Kranenburg J, Hartgens F, Wodzig WK et al. Prolonged leucine supplementation does not augment muscle mass or affect glycemic control in elderly type 2 diabetic men. J Nutr 2011; 141: 1070–1076.

    Article  CAS  Google Scholar 

  58. Skurk T, Rubio-Aliaga I, Stamfort A, Hauner H, Daniel H . New metabolic interdependencies revealed by plasma metabolite profiling after two dietary challenges. Metabolomics 2011; 7: 388–399.

    Article  CAS  Google Scholar 

  59. Adeva MM, Calviño J, Souto G, Donapetry C . Insulin resistance and the metabolism of branched-chain amino acids in humans. Amino Acids 2011; 1–11.

  60. Heslin MJ, Newman E, Wolf RF, Pisters PWT, Brennan MF . Effect of hyperinsulinemia on whole body and skeletal muscle leucine carbon kinetics in humans. Am J Physiol Endocrinol Metab 1992; 262: E911–E918.

    Article  CAS  Google Scholar 

  61. Newgard CB . Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 2012; 15: 606–614.

    Article  CAS  Google Scholar 

  62. Khamzina L, Veilleux A, Bergeron S, Marette A . Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 2005; 146: 1473–1481.

    Article  CAS  Google Scholar 

  63. Zoncu R, Efeyan A, Sabatini DM . MTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12: 21–35.

    Article  CAS  Google Scholar 

  64. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH . RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994; 78: 35–43.

    Article  CAS  Google Scholar 

  65. Li F, Yin Y, Tan B, Kong X, Wu G . Leucine nutrition in animals and humans: MTOR signaling and beyond. Amino Acids 2011; 41: 1185–1193.

    Article  CAS  Google Scholar 

  66. Ma XM, Blenis J . Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009; 10: 307–318.

    Article  Google Scholar 

  67. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L et al. The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008; 320: 1496–1501.

    Article  CAS  Google Scholar 

  68. Efeyan A, Zoncu R, Sabatini DM . Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 2012; 18: 524–533.

    Article  CAS  Google Scholar 

  69. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM . MTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010; 468: 1100–1106.

    Article  CAS  Google Scholar 

  70. Chotechuang N, Azzout-Marniche D, Bos C, Chaumontet C, Gausserès N, Steiler T et al. mTOR, AMPK, and GCN2 coordinate the adaptation of hepatic energy metabolic pathways in response to protein intake in the rat. Am J Physiol Endocrinol Metab 2009; 297: 6.

    Article  Google Scholar 

  71. Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F, Richard D, Cianflone K et al. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest 2007; 117: 387–396.

    Article  CAS  Google Scholar 

  72. Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S et al. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 2011; 60: 746–756.

    Article  CAS  Google Scholar 

  73. Koketsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima Y, Ono H et al. Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice. Am J Physiol Endocrinol Metabol 2008; 294: E719–E725.

    Article  CAS  Google Scholar 

  74. Howell JJ, Manning BD . MTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab 2011; 22: 94–102.

    Article  CAS  Google Scholar 

  75. Li S, Brown MS, Goldstein JL . Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 2010; 107: 3441–3446.

    Article  CAS  Google Scholar 

  76. Brown NF, Stefanovic-Racic M, Sipula IJ, Perdomo G . The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metab Clin Exp 2007; 56: 1500–1507.

    Article  CAS  Google Scholar 

  77. Stallone G, Infante B, Grandaliano G, Gesualdo L . Management of side effects of sirolimus therapy. Transplantation 2009; 87: S23–S26.

    Article  CAS  Google Scholar 

  78. Krebs M . Amino acid-dependent modulation of glucose metabolism in humans. Eur J Clin Invest 2005; 35: 351–354.

    Article  CAS  Google Scholar 

  79. Bentzinger CF, Romanino K, Cloëtta D, Lin S, Mascarenhas JB, Oliveri F et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 2008; 8: 411–424.

    Article  CAS  Google Scholar 

  80. Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005; 54: 2674–2684.

    Article  CAS  Google Scholar 

  81. Tremblay F, Marette A . Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 2001; 276: 38052–38060.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

JS was supported by a Marie Curie European Reintegration Grant within the 7th European Community Framework Programme.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Rietman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rietman, A., Schwarz, J., Tomé, D. et al. High dietary protein intake, reducing or eliciting insulin resistance?. Eur J Clin Nutr 68, 973–979 (2014). https://doi.org/10.1038/ejcn.2014.123

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2014.123

This article is cited by

Search

Quick links