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Highly Accessed Commentary

The gut-brain axis in the critically ill: Is glucagon-like peptide-1 protective in neurocritical care?

Mark P Plummer12*, Juris J Meier3 and Adam M Deane12

Author Affiliations

1 Discipline of Acute Care Medicine, Level 5, Eleanor Harold Building, University of Adelaide, North Terrace, Adelaide, South Australia, Australia 5000

2 Intensive Care Unit, Level 4, Emergency Services Building, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000

3 Diabetes Division, Department of Medicine I, St Josef Hospital, Klinikum der Ruhr Universität Bochum, Gudrunstrasse 56, 44791 Bochum, Germany

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Critical Care 2013, 17:163  doi:10.1186/cc12758


See related research by Bakiner et al., http://ccforum.com/content/17/3/R123


The electronic version of this article is the complete one and can be found online at: http://ccforum.com/content/17/4/163


Published:9 July 2013

© 2013 BioMed Central Ltd

Abstract

Enteral nutrient is a potent glucagon-like peptide-1 (GLP-1) secretagogue. In vitro and animal studies indicate that GLP-1 has immune-modulatory and neuroprotective effects. To determine whether these immune-modulatory and neuroprotective effects of GLP-1 are beneficial in the critically ill, studies achieving pharmacological GLP-1 concentrations are warranted.

Commentary

In the previous issue of Critical Care, Bakiner and colleagues [1] reported the effects of so-called 'early' enteral nutrition (EN) on biomarkers of inflammation and early clinical recovery in patients admitted to a neurointensive care unit after thromboembolic stroke. The rationale underlying this study is that enteral nutrient is a potent stimulant of glucagon-like peptide-1 (GLP-1) secretion [2], and, in animal models, pharmacological GLP-1 administration has been reported to have immune-modulating and neuroprotective properties [3,4]. For these reasons, Bakiner and colleagues hypothesized that 'early' EN, when compared with 'delayed' EN, would stimulate endogenous GLP-1 secretion, thereby effecting cell-mediated immunity and improving neurological recovery.

GLP-1 is secreted from L cells that are located throughout the small and large intestine [2]. Physiologically, GLP-1 is a hormone that stimulates insulin and suppresses glucagon secretion and slows gastric emptying [5], and pharmacological administration of GLP-1 potently lowers blood glucose concentrations in healthy persons, patients with diabetes, and those who are critically ill [6-8]. Though originally identified in islet β-cells, the GLP-1 receptor is known to be widely expressed in extrapancreatic tissue; in particular, the receptor is found on neurons, and expression is increased in the ischemic penumbra [9]. Hence, in the central nervous system, GLP-1 functions as a neuropeptide [4]. In animals, pharmacological administration of a GLP-1 agonist or dipeptidylpeptidase-4 (DPP-4) inhibitor (which inhibits GLP-1 degradation) is reported to affect immune modulation [3]. Furthermore, preliminary animal data indicate that GLP-1 has neuroprotective effects, and pretreatment with a GLP-1 agonist administered intraventricularly reduced infarct size by 50% in a rodent model of stroke [10]. Although the question of whether plasma GLP-1 can cross an intact blood-brain barrier is controversial [4], pre-treatment with supratherapeutic doses of linagliptin, a DPP-4 inhibitor, reduced neuronal loss in a mouse model of stroke [11], suggesting that GLP-1 may indeed have a central effect after injury. Accordingly, there is a strong rationale for evaluating the effects of GLP-1 on patients after an acute thromboembolic stroke.

Using a prospective, sequential-allocation, parallel open-label study design, Bakiner and colleagues compared the interventions of 'early' and 'late' EN to evaluate the effects of endogenous GLP-1 on this group of patients. Unfortunately, a potential confounder was that patients receiving 'late' EN also received parenteral nutrition (PN) while awaiting EN. The authors reported no difference in the primary outcome measure, plasma GLP-1 concentrations, between the two groups but did report significant increases in T-helper and regulatory T cell numbers and a reduction in cytotoxic T cells in the patients receiving 'early' EN.

Although the rationale for the study was robust, there were substantial limitations with the study design chosen to answer the question. GLP-1 concentrations were measured during EN, but because EN was delayed in the 'late' group, there may have been a period of 48 hours that went unmeasured when GLP-1 concentrations were greater in the 'early' group. Moreover, because intestinal nutrient is a potent GLP-1 secretagogue and gastric emptying is frequently delayed in critical illness, nutrient must be infused directly into the small intestine at a sufficient load (>2 kcal per minute) to guarantee GLP-1 excursions [12,13]. Accordingly, measuring 'postprandial' GLP-1 concentrations after intragastric nutrient delivery represents an inadequate stimulus to achieve even physiological concentrations. As the beneficial effects in the animal models used pharmacological concentrations of GLP-1 agonists (administered either intraventricularly or with systemic doses many fold greater than administered in humans), studies evaluating the effects of GLP-1 at pharmacological concentrations are needed to adequately address this question posed by Bakiner and colleagues.

Perhaps of even more importance to the immune-modulatory effect was the period of PN. Administration of early PN when there is no contraindication for EN is associated with greater rates of infection [14]. The study by Casaer and colleagues [14] strongly supports the concept that early PN may actually be harmful if administered when not required. Hence, the inflammatory response observed by Bakiner and colleagues may be due to the 'toxicity' of PN rather than a beneficial effect secondary to 'early' EN. Although 'early' EN is intuitively appealing [15], we suggest that these data from Bakiner and colleagues be interpreted cautiously and that 'early' EN be compared with fasting to more effectively isolate the effects of 'early' EN on cell-mediated immunity.

This study, though preliminary, represents a novel foray into the potential therapeutic benefit of GLP-1 as an immune-modulator and neuroprotective agent in critical illness. Although the rationale for this approach is sound, we suggest that further studies targeting pharmacological GLP-1 concentrations are desirable to accurately evaluate the effect in neurocritical care.

Abbreviations

DPP-4: dipeptidylpeptidase-4; EN: enteral nutrition; GLP-1: glucagon-like peptide-1; PN: parenteral nutrition.

Competing interests

AMD has received a travel grant from Baxter Healthcare (Deerfield, IL, USA). JJM has received consulting or lecture fees from the following companies: AstraZeneca (London, UK), Berlin-Chemie (Florence, Italy), Bristol-Myers Squibb Company (Princeton, NJ, USA), Boehringer-Ingelheim (Ingelheim, Germany), Eli Lilly and Company (Indianapolis, IN, USA), Merck Sharp & Dohme Corp. (Whitehouse Station, NJ, USA), NovoNordisk (Bagsvaerd, Denmark), Novartis (Basel, Switzerland), Roche (Basel, Switzerland), and Sanofi (Paris, France). MPP declares that he has no competing interests.

References

  1. Bakiner O, Bozkirli E, Giray S, Arlier Z, Kozanoglu I, Sezgin N, Sariturk C, Ertorer E: Impact of early versus late enteral nutrition on cell mediated immunity and its relationship with glucagon like peptide-1 in intensive care unit patients: a prospective study.

    Crit Care 2013, 17:R123. PubMed Abstract | BioMed Central Full Text OpenURL

  2. Deane A, Chapman MJ, Fraser RJ, Horowitz M: Bench-to-bedside review: the gut as an endocrine organ in the critically ill.

    Crit Care 2010, 14:228. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  3. Hadjiyanni I, Baggio LL, Poussier P, Drucker DJ: Exendin-4 modulates diabetes onset in nonobese diabetic mice.

    Endocrinology 2008, 149:1338-1349. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  4. Holst JJ, Burcelin R, Nathanson E: Neuroprotective properties of GLP-1: theoretical and practical applications.

    Curr Med Res Opin 2011, 27:547-558. PubMed Abstract | Publisher Full Text OpenURL

  5. Deane AM, Nguyen NQ, Stevens JE, Fraser RJ, Holloway RH, Besanko LK, Burgstad C, Jones KL, Chapman MJ, Rayner CK, Horowitz M: Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia.

    J Clin Endocrinol Metab 2010, 95:215-221. PubMed Abstract | Publisher Full Text OpenURL

  6. Meier JJ, Weyhe D, Michaely M, Senkal M, Zumtobel V, Nauck MA, Holst JJ, Schmidt WE, Gallwitz B: Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes.

    Crit Care Med 2004, 32:848-851. PubMed Abstract | Publisher Full Text OpenURL

  7. Deane AM, Chapman MJ, Fraser RJ, Burgstad CM, Besanko LK, Horowitz M: The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study.

    Crit Care 2009, 13:R67. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  8. Deane AM, Summers MJ, Zaknic AV, Chapman MJ, Fraser RJ, Di Bartolomeo AE, Wishart JM, Horowitz M: Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes.

    Crit Care 2011, 15:R35. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  9. Lee CH, Yan B, Yoo KY, Choi JH, Kwon SH, Her S, Sohn Y, Hwang IK, Cho JH, Kim YM, Won MH: Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia.

    J Neurosci Res 2011, 89:1103-1113. PubMed Abstract | Publisher Full Text OpenURL

  10. Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH: GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism.

    Proc Natl Acad Sci USA 2009, 106:1285-1290. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  11. Darsalia V, Ortsater H, Olverling A, Darlof E, Wolbert P, Nystrom T, Klein T, Sjoholm A, Patrone C: The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride.

    Diabetes 2013, 62:1289-1296. PubMed Abstract | Publisher Full Text OpenURL

  12. Ma J, Pilichiewicz AN, Feinle-Bisset C, Wishart JM, Jones KL, Horowitz M, Rayner CK: Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes.

    Diabetic Med 2012, 29:604-608. PubMed Abstract | Publisher Full Text OpenURL

  13. Deane AM, Rayner CK, Keeshan A, Cvijanovic N, Marino Z, Nguyen NQ, Chia B, Sim JA, van Beek T, Chapman MJ, et al.: The effects of critical illness on intestinal glucose sensing, transporters and absorption.

    Crit Care Med, in press. OpenURL

  14. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G: Early versus late parenteral nutrition in critically ill adults.

    N Engl J Med 2011, 365:506-517. PubMed Abstract | Publisher Full Text OpenURL

  15. Heyland DK, Cahill NE, Dhaliwal R, Wang M, Day AG, Alenzi A, Aris F, Muscedere J, Drover JW, McClave SA: Enhanced protein-energy provision via the enteral route in critically ill patients: a single center feasibility trial of the PEP uP protocol.

    Crit Care 2010, 14:R78. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL