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Glucose Metabolism – The Key to Sepsis

Submitted:

01 December 2025

Posted:

01 December 2025

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Abstract
Sepsis initiates two primary metabolic responses: insulin resistance in insulin-responsive tissues and suppression of mitochondrial adenosine triphosphate (ATP) production. These mechanisms underpin the hypermetabolic and hypometabolic phases of sepsis. The hypermetabolic phase features a heightened metabolic rate, rapid immune activation, and increased glucose supply and consumption. In contrast, the hypometabolic phase involves a reduction in metabolic rate and physiological activity across multiple organs, mirroring hibernation-like states.During sepsis, the immune system receives priority access to available glucose, prompting insulin resistance that minimises glucose utilisation by less essential tissues. Concurrently, mitochondrial ATP production via oxidative phosphorylation (OXPHOS) is deprioritised, with the immune system relying on anaerobic glycolysis for ATP generation. This suppression of OXPHOS is only a temporary measure; mitochondrial ATP production must resume for complete recovery. Persistent suppression of mitochondrial ATP production can culminate in critical ATP deficits and cell death.This review examines glucose and insulin metabolism in sepsis, concluding that administering high-dose insulin alongside mild hyperglycaemia and intravenous thiamine—a pyruvate dehydrogenase kinase (PDK) inhibitor—may help restore physiological mitochondrial ATP production during a crucial window in the sepsis process, potentially improving survival outcomes.
Keywords: 
sepsis
;  
mitochondria
;  
adenosine triphosphate
;  
ATP
;  
pyruvate dehydrogenase complex
;  
PDHC
;  
thiamine
;  
glycolysis
;  
glucose
;  
insulin
;  
lipopolysaccharides
;  
LPS
;  
oxidative phosphorylation
;  
OXPHOS
;  
pyruvate dehydrogenase kinase
;  
PDK
;  
lactate
Subject: 
Medicine and Pharmacology  -   Clinical Medicine

Introduction

Sepsis is responsible for 20% of global deaths and ranks as the costliest condition in United States hospitals, averaging approximately $46,000 per patient. Despite this, treatment options remain largely supportive, with hospitalised patient mortality at around 27% and intensive care patient mortality reaching 42%. Notably, mortality rates in the United States remained static between 1999 and 2022 [1]. While early recognition is thought to enhance survival, the evidence underpinning Early Warning Scores (EWS) is limited [2].
Experimental studies, such as those with Holstein cows, have illuminated the sequence of metabolic events during sepsis. The administration of lipopolysaccharide (LPS)—a component of gram-negative bacterial membranes—caused serum glucose levels to spike from 60 mg/dL (4 mmol/l) to 155 mg/dL (10 mmol/l) within 30 minutes, indicating acute insulin resistance. Subsequently, glucose levels dropped to a deficiency at 30 mg/dL (2 mmol/l) due to increased immune demand, necessitating glucose infusion to maintain euglycemia. This diversion of glucose to the immune system, away from tissues like the mammary glands—which exhibited an 80% reduction in milk production—demonstrates the body’s prioritisation of immune function during perceived threats, even without live microbes [3].
Further imaging studies using radiolabelled glucose and positron emission tomography in Dutch dwarf rabbits have shown a marked reduction in glucose uptake by most organs after LPS administration, with increased renal glucose uptake to support the immune system. This diversion leads to hypothermia, as limited glucose availability curtails less critical functions like thermogenesis [4].
Another critical change during sepsis is the inhibition of the mitochondrial pyruvate dehydrogenase complex (PDHC), driven by increased activity of PDK enzymes. This suppression of mitochondrial ATP production is corroborated by proteome analyses, which demonstrate elevated PDK and reduced PDHC levels during sepsis [5,6].

The Hypermetabolic Phase of Sepsis

Immune activation during sepsis raises metabolic rates by 37–55%. Leucocyte numbers surge and migrate to sites of infection and tissue injury. Insulin resistance reduces glucose uptake by less essential organs, while the liver boosts glucose output and the kidneys increase glucose reabsorption. Adipose tissue releases more free fatty acids and glycerol, which are used as alternative fuels or substrates for hepatic glucose production. Skeletal muscle is catabolised to supply amino acids for gluconeogenesis, and ATP production via OXPHOS is suppressed [5,6].
In severe infections like malaria, hepatic glucose output can double from 200 to 400 g/day. Children, who have lower glycogen reserves than adults, are especially vulnerable to severe hypoglycaemia, which can increase mortality four to sixfold compared to children without hypoglycaemia [7,8].
Anaerobic glycolysis becomes the preferred ATP-producing pathway, particularly for immune cells, as it is capable of generating ATP 100 times faster than OXPHOS and functions effectively under anaerobic or ischaemic conditions characteristic of infected or damaged tissues. Other organs, including the kidneys and heart, also partially switch to glycolysis for ATP production. Unlike exercise-induced rises in lactate, which do not suppress OXPHOS or increase morbidity [9], sepsis-related lactate elevations are linked to high mortality [10].
In healthy organisms, 95% of cellular ATP is produced via mitochondrial OXPHOS, amounting to 100–150 moles or 25–40 kg per day [6].

The Hypometabolic Phase of Sepsis

While glycolysis can rapidly supply ATP, it is insufficient for the ongoing energy needs of the entire organism. Its role is primarily to meet the urgent ATP demands of immune cells operating in low-oxygen or ischaemic environments [5,6]. This limitation is evident in sepsis-induced cardiac dysfunction, as the heart depends on continual ATP supply and mitochondrial dysfunction is central to septic cardiomyopathy, an organ with the highest mitochondrial density [11].
Non-surviving septic patients exhibit elevated respiratory capacity but reduced mitochondrial respiration associated with ATP synthesis, while survivors show increased mitochondrial activity during recovery [5]. There is a direct correlation between body temperature at emergency department admission and mortality: patients with temperatures below 35 °C have a 48% 30-day mortality rate, compared to 11% for those above 41 °C [12]. The generation of fever requires uncoupled mitochondrial respiration [13], and inhibition of mitochondrial function suppresses fever [14].
The hypometabolic phase is characterised by decreased oxygen consumption (VO2) and basal metabolic rate, despite high respiratory capacity and poor response to increased systemic oxygen. Multi-organ dysfunction syndrome (MODS) is a prominent feature, marked by minimal cell death, reduced substrate consumption, and normal or elevated tissue oxygen levels. MODS may represent an adaptive strategy to minimise energy requirements, similar to hibernation [6,15]. Even sepsis-induced cardiac dysfunction may reflect functional, adaptive changes to reduce oxygen and ATP consumption [16]. During recovery, hospital survivors show a 50–60% increase in systemic VO2 and resting metabolic rate, consistent with renewed mitochondrial ATP production [14].

Hyperglycaemia

Glucose availability is a key factor influencing both the risk of developing sepsis and subsequent mortality. Neonates, particularly those born preterm, are at increased risk due to limited glycogen and fat stores, low gluconeogenic enzyme expression, and high glucose requirements for their larger brain. Unable to adequately respond to hypoglycaemia, up to 60% require supplementary glucose to prevent morbidity and long-term complications [17], and they are more susceptible to sepsis and sepsis-related death [18,19].
Children aged 5–14 exhibit significantly lower sepsis-related mortality than adults, even when infection rates are similar. This phenomenon, observed in events like the 1918 flu pandemic and other infectious diseases, is likely linked to higher glucose availability [20]. Children have three times the normalised glucose production of adults [21,22] and lower insulin resistance, reflecting greater glucose surplus [23,24].
Data also indicate that patients with hyperthermia are more likely to survive sepsis than those with hypothermia [12]. Since glucose is the primary fuel for the activated immune system, those able to maintain elevated body temperatures during infection have surplus glucose beyond immune needs, whereas those with marginal glucose reserves may lack sufficient fuel for thermogenesis, resulting in hypothermia. Mechanically ventilated septic patients warmed with forced-air blankets for 48 hours experienced a 25% reduction in 28-day mortality [25].

Hyperinsulinemia

Insulin availability similarly impacts sepsis risk and outcomes. The heart, with the highest ATP consumption of any organ, is particularly sensitive to ATP availability. Patients with chronic heart failure often exhibit elevated insulin resistance, and low insulin levels are associated with increased mortality [26]. Studies in animal models have shown that insulin administration improves cardiac output, oxygen delivery, and vascular resistance following LPS challenge [27].
Mitochondrial protein synthesis is vital for cellular function and increases only when essential amino acids are infused alongside high insulin concentrations [28]. Glucose is a major myocardial fuel, especially under low-oxygen or ischaemic conditions, and insulin orchestrates glucose uptake, glycolysis, and mitochondrial oxidation, directly enhancing ATP production [29].
Acute kidney injury (AKI) affects over 40% of septic patients, with mitochondrial dysfunction contributing through excessive reactive oxygen species (ROS), ATP depletion, and membrane potential disruption. Insulin therapy mitigates mitochondrial damage, reverses ATP depletion, reduces oxidant production, improves antioxidant levels, and suppresses renal mitophagy [30].
Elevated insulin concentrations in septic patients increase glucose uptake and oxidation [31]. In animal studies, high-dose insulin (HDI) improved survival rates during septic shock [32]. In mice, LPS administration raised insulin levels without altering blood glucose, but blocking insulin secretion resulted in severe hyperglycaemia and increased mortality. Non-survivors had significantly lower insulin levels compared to survivors [33]. In paediatric burn patients, intensive insulin therapy decreased infection and sepsis incidence, alleviated insulin resistance, reduced catabolism, and lowered mortality [34]. Insulin also enhanced survival and reduced positive blood cultures in rodent models of burn wound infection [35].

Glucose Plus Insulin

Both increased glucose and insulin availability individually improve sepsis survival, and their combination has a compounded effect. In vitro, cardiomyocytes exposed to simulated ischemia showed up to 75% greater ATP production and 40% less lactate when treated with glucose and insulin, reducing cellular injury [36]. Septic rats treated to maintain blood glucose between 8–10 mmol/L displayed superior glucose utilisation and increased expression of glucose transporter GLUT4 [37].
Much morbidity and mortality from septic shock stem from refractory hypotension and cardiovascular collapse; thus, counteracting these effects may improve outcomes. Administration of glucose-insulin-potassium (GIK) to patients with severe sepsis and septic shock improved mean arterial pressure and reduced heart rate in those with hypodynamic myocardial depression. The total insulin dose correlated with haemodynamic improvement [38].

The Pyruvate Dehydrogenase Complex

Restoring mitochondrial ATP production during sepsis requires overcoming two barriers: severe insulin resistance and suppression of PDHC. High-dose insulin can address insulin resistance, increasing intracellular glucose. Suppression of PDHC, which inhibits pyruvate transfer into mitochondria, is mediated by PDK enzymes. Glycolysis produces ATP by converting glucose to pyruvate and lactate in the cytoplasm (yielding two ATP units). Under aerobic conditions, pyruvate enters mitochondria and is oxidised to acetyl-CoA via PDHC, producing 36 ATP units. PDHC is suppressed in sepsis, but PDK activity can be inhibited by agents such as dichloroacetate (DCA), thiamine, amrinone, TNF-binding protein, and ciprofloxacin, each enhancing mitochondrial pyruvate uptake and ATP generation [39].
PDHC activity changes are not limited to immune cells; sepsis-induced cardiomyopathy—a major cause of death—correlates with increased PDK4 levels and PDHC inhibition [40]. PDK inhibitors also rebalance metabolic and transcriptional responses in liver cells during the low-energy, anti-inflammatory phase of sepsis [41].

Thiamine

Thiamine, a vitamin and PDK inhibitor, is linked to improved clinical outcomes in sepsis. A review of over 11,500 Sepsis-3 patients found that intravenous thiamine reduced 28-day mortality and the risk of myocardial infarction [42]. However, clinical trials of thiamine supplementation have yielded mixed results, potentially due to differences in dosage, administration route, timing, presence or absence of deficiency, duration, sample size, septic phenotype, and medication combinations. Some trials have shown positive effects, particularly in patients with severe pneumonia [43], while others have found no benefit in septic shock [44].

Summary

While the therapeutic value of thiamine plus glucose plus insulin on sepsis has not been experimentally evaluated a recent study evaluated the impact of thiamine plus glucose.
A cecal ligation and puncture (CLP) model of mouse sepsis evaluated antibiotics, thiamine and glucose [10]. All four groups of animals were administered antibiotics. One group was also administered intravenous glucose. Another group was also administered intravenous thiamine. A third group was also administered intravenous glucose and intravenous thiamine. The fourth group was administered the antibiotics only.
Survival of the thiamine plus glucose plus antibiotic group at 100 hours was 90% whereas survival of the antibiotic only group at 100 hours was 10%.
Theoretically insulin should further enhance this outcome because it counteracts insulin resistance and thereby enhances glucose transfer into the intracellular cytoplasm.

Conclusion

High-dose insulin combined with mild hyperglycaemia and PDK inhibitors such as intravenous thiamine act on distinct enzymatic pathways, overcoming barriers to mitochondrial ATP production. This combination, if administered during a critical window in the sepsis process, may enhance survival.

References

  1. Morrissey R, Lee J, Baral J, Tauseef A, Sood A, Mirza M, Jabbar A, Demographic and regional trends of sepsis mortality in the United States, 1999-2022. BMC Infect Dis 2025: 25;504. [CrossRef]
  2. Verma, A. Toward the Rigorous Evaluation of Early Warning Scores. JAMA Network Open. 2024;7(10): e2428966. [CrossRef]
  3. Kvidera S, Horst E, Abuajamieh M, Mayorga E, Sanz-Fernandez M, Baumgard L. Glucose requirements of an activated immune system in Holstein cows. J Dairy Sci 2017; 100:2360-74.
  4. Luna-Reyes I, Perez-Hernandez E, Delgado-Coello B, Avila-Rodriguez M, Mas-Oliva J. Peptide VSAK maintains tissue glucose uptake and attenuates pro-inflammatory responses caused by LPS in an experimental model of the systemic inflammatory response syndrome: a PET study. Sci Rep 2021; 11:14752.
  5. Preau S, Vodovar D, Jung B, Lancel S, Zafrani l, Flatres A, et al. Energetic dysfunction in sepsis: a narrative review. Ann Intensive Care 2021;11(1):104.
  6. Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci 2022; 79:456.
  7. Zijlmans W, van van Kempen A, Serlie M, Sauerwein H. Glucose metabolism in children: influence of age, fasting, and infectious diseases. Metabolism 2009;58(9):1356-65.
  8. Zijlmans W, van van Kempen A, Serlie M, Kager P, Sauerwein H. Adaptation of glucose metabolism to fasting in young children with infectious diseases: a perspective. J Pediatr Endocrinol Metab 2013; 27:5-13.
  9. Mandadzhiev, N. The contemporary role of lactate in exercise physiology and exercise prescription – a review of the literature. Folia Medica (Plovdiv) 2025 Feb 24; 67(1). [CrossRef]
  10. Nuyttens L, Heyerick M, Heremans G, Moens E, Roes M, Van Dender C, et al. Unravelling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis. Cell Rep. 2025 Aug 26; 44(8):116032. [CrossRef]
  11. Jarczak D, Kluge S, Nierhaus A. Sepsis-Pathophysiology and Therapeutic Concepts. Front Med (Lausanne). 2021 May 14; 8:628302. [CrossRef]
  12. Inghammar M, Sunden-Cullberg J. Prognostic significance of body temperature in the emergency department vs ICU in Patients with severe sepsis or septic shock: A nationwide cohort study. PLoS ONE 2020;15(12): e0243990.
  13. Greco E, Arulkumaran N, Dyson A, Singer M. 0035. Mitochondrial uncoupling contributes to fever in sepsis. Intensive Care Medicine Experimental. 2014 Sep;2(Suppl 1). PMCID: PMC 479280.
  14. Guimaraes N, Alves D, Vilela W, de-Souza-Ferreira E, Gomes B, Ott D, et al. Mitochondrial pyruvate carrier as a key regulator of fever and neuroinflammation. Brain Behav Immun 2021; 92:90-101.
  15. Wasyluk W, Zwolak A. Metabolic Alterations in Sepsis. J Clin Med 2021; 10:2412.
  16. Mokhtari B, Yavari R, Badalzadeh R, Mahmoodpoor A. An Overview on Mitochondrial-Based Therapies in Sepsis-Related Myocardial Dysfunction: Mitochondrial Transplantation as a Promising Approach. Can J Infect Dis Med Microbiol 2022; 2022:3277274.
  17. Sharma A, Davis A, Shekhawat P. Hypoglycemia in the preterm neonate: etiopathogenesis, diagnosis, management and long-term outcomes. Tranl Pediatr 2017;6(4):335-48.
  18. Watson R, Carcillo J, Linde-Zwirble W, Clermont G, Lidicker J, Angus D. The Epidemiology of Severe Sepsis in Children in the United States. Am J Respir Crit Care Med 2003; 167:695-701.
  19. Li L, Sunderland N, Rathnayake K, Westbrook J (2021). Sepsis epidemiology in Australian Public Hospitals, a nationwide longitudinal study (2013-2018). Infection, Disease & Health, ISSN:2468-0451,Vol:26,Page:59.
  20. Joachim R, Altschuler G, Hutchinson J, Wong H, Hide W, Kobzik L. The relative resistance of children to sepsis mortality: from pathways to drug candidates. Mol Syst Biol 2018;14:e7998.
  21. Bier D, Leake R, Haymond M, Arnold K, Gruenke L, Sperling M, Kipnis D. Measurement of “true” glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;26(11):1016-23.
  22. Kuzawa C, Chugani H, Grossman L, Lipovich L, Muzik O, Hof P, et al. Metabolic costs and evolutionary implications of human brain development. PNAS 2014;111(36):13011.
  23. Jeffery A, Metcalf B, Hosking J, Streeter A, Voss L, Wilkin T. Age Before Stage: Insulin Resistance Rises Before the Onset of Puberty. Diabetes Care 2012; 35:536-41.
  24. Amiel S, Sherwin R, Simonson D, Lauritano A, Tamborlane W. Impaired Insulin Action in Puberty. N Eng J Med 1986; 315:215-9.
  25. Drewry A, Mohr N, Ablordeppey E, Dalton C, Doctor R, Fuller B, Kollef M, Hotchkiss R. Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial. Crit Care Med 2022;50(6):924-34.
  26. Nogi M, Kawakami R, Ishihara S, Kirai K, Nakada Y, Nakagawa H, et al. Low insulin Is an Independent Predictor of All-Cause and Cardiovascular Death in acute Decompensated Heart Failure Patients Without Diabetes Mellitus. J Am Heart Assoc 2020;9: e015393.
  27. Levenbrown Y, Penfil S, Rodriguez E, Zhu Y, Hossain J, Bhat M, et al. Use of Insulin to Decrease Septic Shock-Induced Myocardial Depression in a Porcine Model. Inflammation 2013; 36:1494-1502.
  28. Robinson M, Soop M, Sohn T, Morse D, Schimke J, Klaus K, Nair K. High Insulin Combined With Essential Amino Acids Stimulates Skeletal Muscle Mitochondrial Protein Synthesis While Decreasing Insulin Sensitivity in Healthy Humans. J Clin Endocrinol Metab 2014;99(12): E2574-E2583.
  29. Karwi Q, Wagg C, Altamimi T, Uddin G, Ho K, Darwesh A, et al. Insulin directly stimulates mitochondrial glucose oxidation in the heart. Cardiovasc Diabetol 2020; 19:207.
  30. Chen GD, Zhang JL, Chen YT, Zhang JX, Wang T, Zeng QY. Insulin alleviates mitochondrial oxidative stress involving upregulation of superoxide dismutase 2 and uncoupling protein 2 in septic acute kidney injury. Exp Ther Med 2018; 15:3967-75.
  31. Rusavy Z, Sramek V, Lacigova S, Novak I, Tesinsky P, Macdonald I. Influence of insulin on glucose metabolism and energy expenditure in septic patients. Crit Care 2004;8: R213-R220.
  32. Holger J, Dries D, Barringer K, Peake B, Flottemesch T, Marini J. Cardiovascular and Metabolic Effects of High-dose Insulin in a Porcine Septic Shock Model. Acad Emerg Med 2010;17(4):429-35.
  33. Woodske M, Yokoe T, Zou B, Romano L, Rosa T, Garcia-Ocana A, et al. Hyperinsulinemia predicts survival in a hyperglycemic mouse model of critical illness. Crit Care Med 2009;37(9):2596-603.
  34. Jeschke M, Kulp G, Kraft R, Finnerty C, Micak R, Lee J, Herndon D. Intensive Insulin Therapy in Severely burned Pediatric Patients. Am J Respir Crit Care Med 2010; 182:351-9.
  35. Gauglitz G, Toliver-Kinsky T, Williams F, Song J, Cui W, Herndon D, Jeschke M. Insulin increases resistance to burn wound infection-associated sepsis. Crit Care Med 2010; 38(1):. [CrossRef]
  36. Rao V, Merante F, Weisel R, Shirai T, Ikonomidis J, Cohen G, et al. Insulin stimulates pyruvate dehydrogenase and protect human ventricular cardiomyocytes from simulated ischemia. J Thorac Cardiovasc Surg 1998; 116:485-94.
  37. Lu G, Cui P, Cheng Y, Lu Z, Zhang L, Kissoon N. Insulin Control of Blood Glucose and GLUT4 Expression in the Skeletal Muscle of Septic Rats. West Ind Med J 2015;64(2):62-70.
  38. Kim W, Baek M, Kim Y, Seo J, Huh J, Lim C, et al. Glucose-insulin-potassium correlates with hemodynamic improvement in patients with septic myocardial dysfunction. J Thorac Dis 2016;8(12):3648-57.
  39. Zeng Z, Huang Q, Mao L, Wu J, An S, Chen Z, Zhang W. The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy. Front Nutr 2021; 8:783164.
  40. Shimada B, Boyman L, Huang W, Zhu J, Yang Y, Chen F, et al. Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome. Shock 2022;57(4):553-64.
  41. Mainali R, Zabalawi M, Long D, Buechler N, Quillen E, Key C, et al. Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction. Elife 2021;10: e64611.
  42. Zhang L, Zhang F, Li S, Xu F, Zheng X, Huang T, et al. Thiamine supplementation may be associated with improved prognosis in patients from sepsis, Br J Nutr 2022 Oct 19;1-10. [CrossRef]
  43. Kim W-Y, Jo E-J, Eom J-S, Mok J, Kim M-H, Kim K, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study. J Crit Care 2018; 47:211-8.
  44. Hwang S, Ryoo S, Park J, Jo Y, Jang D-H, Suh G, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blind randomized, controlled study. Intensive Care Med 2020; 46:2015-25.
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