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Lipids

, Volume 51, Issue 6, pp 703–714 | Cite as

Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia

  • Prathima Nandivada
  • Gillian L. Fell
  • Amy H. Pan
  • Vania Nose
  • Pei-Ra Ling
  • Bruce R. Bistrian
  • Mark PuderEmail author
Original Article

Abstract

Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.

Keywords

Ketogenic diet Hypoglycemia Endotoxin Inflammation 

Abbreviations

CD

Control diet

EKD

Eucaloric ketogenic diet

FASN

Fatty acid synthase

HOMA-IR

Homeostatic assessment of insulin resistance

IL-6

Interleukin-6

IP

Intraperitoneal

LPS

Lipopolysaccharide

NASH

Nonalcoholic steatohepatitis

NFκB

Nuclear factor kappa-light-chain-enhancer of activated B cells

PEPCK

Phosphoenolpyruvate carboxykinase

PFK-1

Phosphofructokinase-1

SCD-1

Stearoyl-CoA desaturase-1

TNF-α

Tumor necrosis factor alpha

Notes

Compliance with Ethical Standards

Conflict of interest

The authors have no conflicts of interest pertaining to this work to report.

Funding sources

Research reported in this publication was supported by The Boston Children’s Hospital Surgical Foundation, Boston, MA; The Corkin and Maher Family Fund, Boston, MA; National Institutes of Health grant F32DK104525-01 (GLF); and the Joshua Ryan Rappaport Fellowship (PN). The funders did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Disclosures

We have no relevant financial disclosures.

References

  1. 1.
    Bagshaw SM, Bellomo R, Jacka MJ, Egi M, Hart GK, George C (2009) The impact of early hypoglycemia and blood glucose variability on outcome in critical illness. Crit Care 13:R91CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kreymann KG, Berger MM, Deutz NEP, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J, Ebner C, Hartl W, Heymann C, Spies C (2006) ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr 25(2):210–223CrossRefPubMedGoogle Scholar
  3. 3.
    Gosmanov AR, Umpierrez GE (2013) Management of hyperglycemia during enteral and parenteral nutrition therapy. Curr Diab 13(1):155–162CrossRefGoogle Scholar
  4. 4.
    Egi M, Bellomo R, Stachowski E, French CJ, Hart GK, Taori G, Hegarty C, Bailey M (2010) Hypoglycemia and outcome in critically ill patients. Mayo Clin Proc 85(3):217–224CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Phinney SD, Bistrian BR, Wolfe RR, Blackburn GL (1983) The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism 32(8):757–768CrossRefPubMedGoogle Scholar
  6. 6.
    Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E (2009) A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 297(5):E1197–E1204CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339(6116):211–214CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ruskin DN, Kawamura M, Masino SA (2009) Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet. PLoS One 4(12):e8349CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kim DY, Davis LM, Sullivan PG, Maalouf M, Simeone TA, van Brederode J, Rho JM (2007) Ketone bodies are protective against oxidative stress in neocortical neurons. J Neurochem 101(5):1316–1326CrossRefPubMedGoogle Scholar
  10. 10.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419CrossRefPubMedGoogle Scholar
  11. 11.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu Y-C, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41(6):1313–1321CrossRefPubMedGoogle Scholar
  12. 12.
    Ling P-R, Smith RJ, Bistrian BR (2005) Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats. Crit Care Med 33(5):1084–1089CrossRefPubMedGoogle Scholar
  13. 13.
    Filkins J, Cornell R (1974) Depression of hepatic gluconeogenesis and the hypoglycemia of endotoxin shock. Am J Physiol 227(4):778–781PubMedGoogle Scholar
  14. 14.
    Ling PR, Bistrian BR, Mendez B, Istfan NW (1994) Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake. Metabolism 43(3):279–284CrossRefPubMedGoogle Scholar
  15. 15.
    Westman EC, Mavropoulos J, Yancy WS, Volek JS (2003) A review of low-carbohydrate ketogenic diets. Curr Atheroscler Rep 5(6):476–483CrossRefPubMedGoogle Scholar
  16. 16.
    Westman EC, Feinman RD, Mavropoulos JC, Vernon MC, Volek JS, Wortman JA, Yancy WS, Phinney SD (2007) Low-carbohydrate nutrition and metabolism. Am J Clin Nutr 86(2):276–284PubMedGoogle Scholar
  17. 17.
    Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1(7285):785–789CrossRefPubMedGoogle Scholar
  18. 18.
    Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371(23):2236–2238CrossRefGoogle Scholar
  19. 19.
    Samuel VT, Liu Z-X, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279(31):32345–32353CrossRefPubMedGoogle Scholar
  20. 20.
    Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA (2011) Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 300(6):G956–G967CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Volek JS, Sharman MJ, Love DM, Avery NG, Gómez AL, Scheett TP, Kraemer WJ (2002) Body composition and hormonal responses to a carbohydrate-restricted diet. Metabolism 51(7):864–870CrossRefPubMedGoogle Scholar
  22. 22.
    Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu F-F, Kahn BB, Libermann TA, Maratos-Flier E (2007) A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 292(6):E1724–E1739CrossRefPubMedGoogle Scholar
  23. 23.
    Jornayvaz FR, Jurczak MJ, Lee H-Y, Birkenfeld AL, Frederick DW, Zhang D, Zhang X-M, Samuel VT, Shulman GI (2010) A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 299(5):E808–E815CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pissios P, Hong S, Kennedy AR, Prasad D, Liu F-F, Maratos-Flier E (2013) Methionine and choline regulate the metabolic phenotype of a ketogenic diet. Mol Metab 2(3):306–313CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D’Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269PubMedPubMedCentralGoogle Scholar
  26. 26.
    Ziegler DR, Ribeiro LC, Hagenn M, Siqueira IR, Araújo E, Torres ILS, Gottfried C, Netto CA, Gonçalves C-A (2003) Ketogenic diet increases glutathione peroxidase activity in rat hippocampus. Neurochem Res 28(12):1793–1797CrossRefPubMedGoogle Scholar
  27. 27.
    Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM (2004) The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol 55(4):576–580CrossRefPubMedGoogle Scholar
  28. 28.
    Veech RL (2004) The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 70(3):309–319CrossRefPubMedGoogle Scholar

Copyright information

© AOCS 2016

Authors and Affiliations

  • Prathima Nandivada
    • 1
  • Gillian L. Fell
    • 1
  • Amy H. Pan
    • 1
  • Vania Nose
    • 2
  • Pei-Ra Ling
    • 3
  • Bruce R. Bistrian
    • 3
  • Mark Puder
    • 1
    Email author
  1. 1.Vascular Biology Program and Department of SurgeryBoston Children’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Department of PathologyMassachusetts General HospitalBostonUSA
  3. 3.Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA

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