Mechanisms of Insulin Resistance in Critical Illness: Role of Systemic Inflammation and GLP-1
19. September 2014 aktualisiert von: Kirsten Moller, Rigshospitalet, Denmark
The purpose of this study is to determine the role of inflammation and the insulin regulating hormone GLP-1 during critical illness.
Studienübersicht
Status
Abgeschlossen
Bedingungen
Intervention / Behandlung
Detaillierte Beschreibung
Critically ill patients often exhibit hyperglycaemia. Although the cause of this hyperglycaemia is probably multifactorial, peripheral insulin resistance is a major contributor, similar to type 2 diabetes mellitus (T2D). There are several similarities between critical illness and T2D, including the presence of systemic inflammation and increased plasma free fatty acids (FFA), all of which may induce insulin resistance in healthy volunteers. In critical illness, elevated catecholamines, cortisol, growth hormone and glucagon may also contribute to insulin resistance.
The degree of hyperglycaemia correlates with mortality in ICU patients. van den Berghe et al. found that IV infusion of insulin to obtain strict normoglycaemia reduced mortality as well as morbidity in critically ill surgical patients and in some medical ICU patients.
However, insulin increases the risk of hypoglycaemia; this is a major obstacle to strict euglycaemia in ICU patients and may explain the inability of others to reproduce the benefits reported by van den Berghe et al. Thus, alternatives to insulin for controlling plasma glucose (PG) in ICU patients are warranted.
Aim:
To study the role of the incretin hormone, glucagon-like peptide (GLP)-1 for glycaemic, metabolic, hormonal and inflammatory profile in
- critically ill patients in the intensive care unit (ICU) and
- healthy volunteers exposed to a standardised systemic inflammation
Studientyp
Interventionell
Einschreibung (Tatsächlich)
40
Phase
- Unzutreffend
Kontakte und Standorte
Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.
Studienorte
-
-
-
Copenhagen, Dänemark, 2100
- Centre of Inflammation and Metabolism - Rigshospitalet 7641
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Copenhagen, Dänemark, 2400
- University of Copenhagen
-
-
Teilnahmekriterien
Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.
Zulassungskriterien
Studienberechtigtes Alter
18 Jahre bis 40 Jahre (Erwachsene)
Akzeptiert gesunde Freiwillige
Ja
Studienberechtigte Geschlechter
Männlich
Beschreibung
Inclusion Criteria healthy subjects:
- Healthy (assessed by medical history and clinical examination)
- Age 18-40years
- BMI < 30kg/m2
Exclusion Criteria healthy subjects:
- Previous resection of the small intestine (not including the appendix)
- presence of any inflammatory illness during the fortnight preceding the study
Inclusion Criteria critically ill patients:
- Age>18 years
- HbA1C<6,5%
- Admission to the ICU within the last 72 hours
Studienplan
Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.
Wie ist die Studie aufgebaut?
Designdetails
- Hauptzweck: Grundlegende Wissenschaft
- Zuteilung: Zufällig
- Interventionsmodell: Crossover-Aufgabe
- Maskierung: Keine (Offenes Etikett)
Waffen und Interventionen
Teilnehmergruppe / Arm |
Intervention / Behandlung |
|---|---|
|
Placebo-Komparator: 2C - 1
TNF and OGTT and saline
|
Normal saline (NaCl 0,9%)
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
Oral glucose tolerance test with 75 g glucose
|
|
Aktiver Komparator: 2C - 2
TNF and OGTT and GLP-1
|
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
Oral glucose tolerance test with 75 g glucose
GLP-1 1,2pmol/kg/min i.v.
infusion for 4 hours
|
|
Placebo-Komparator: 2C - 3
TNF and IVGTT and saline
|
Normal saline (NaCl 0,9%)
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
|
|
Aktiver Komparator: 2C - 4
TNF and IVGTT and GLP-1
|
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
GLP-1 1,2pmol/kg/min i.v.
infusion for 4 hours
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
|
|
Placebo-Komparator: 2A-1
Saline infusion and OGTT
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Normal saline (NaCl 0,9%)
Oral glucose tolerance test with 75 g glucose
|
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Placebo-Komparator: 2A-2
Saline and IVGTT
|
Normal saline (NaCl 0,9%)
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
|
|
Aktiver Komparator: 2A-3
TNF and OGTT
|
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
Oral glucose tolerance test with 75 g glucose
|
|
Aktiver Komparator: 2A-4
TNF and IVGTT
|
1000ng/m2 BSA/hour i.v.
infusion for 4-6 hours
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
|
|
Experimental: 1C
OGTT and corresponding IVGTT
|
Oral glucose tolerance test with 75 g glucose
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
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Was misst die Studie?
Primäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
Substudy 2C (12 Healthy volunteers): GLP-1
Zeitfenster: 6 weeks after intervention
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Increased plasma insulin and C-peptide (intact insulinotropic effect of GLP-1) during GLP-1 infusion in healthy volunteers.
|
6 weeks after intervention
|
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Substudy 2A (12 Healthy volunteers): Insulin, C-peptide and incretin hormone response
Zeitfenster: 6 weeks after intervention
|
Insulin, c-peptide and incretin hormone response to glucose stimulation during standardized systemic inflammation (TNF infusion) compared to placebo (saline infusion)
|
6 weeks after intervention
|
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Substudy 1C(8 patients, 8 healthy controls): Insulin, C-peptide and incretin hormone response
Zeitfenster: 6 weeks after intervention
|
Insulin, c-peptide and incretin hormone response to glucose stimulation during IVGTT compared to OGTT in critically ill patients admitted to the ICU
|
6 weeks after intervention
|
Sekundäre Ergebnismessungen
Ergebnis Maßnahme |
Maßnahmenbeschreibung |
Zeitfenster |
|---|---|---|
|
Substudy 2C (12 Healthy volunteers): Clamp
Zeitfenster: 6 weeks after intervention
|
Enhanced insulin response (AUC) and reduced difference between the AUC obtained during OGTT and IGGTT (reduced endogenous incretin effect) during an isoglycaemic intravenous glucose tolerance test (IVGTT) in healthy volunteers receiving TNF-infusion.
|
6 weeks after intervention
|
|
Substudy 2A (12 Healthy volunteers): The incretin effect
Zeitfenster: 6 weeks after intervention
|
The difference between the plasma insulin AUC obtained during OGTT and IVGTT (endogenous incretin effect).
|
6 weeks after intervention
|
|
Substudy 1C (8 patients, 8 healthy controls): The incretin effect
Zeitfenster: 6 weeks after intervention
|
The difference between the plasma insulin AUC obtained during OGTT and IVGTT (endogenous incretin effect)in non-diabetic critically ill patients admitted to the ICU.
|
6 weeks after intervention
|
Mitarbeiter und Ermittler
Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.
Sponsor
Ermittler
- Hauptermittler: Kirsten Møller, MD, Ph.D., DMSc, Centre of Inflammation and Metabolism
Publikationen und hilfreiche Links
Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.
Allgemeine Veröffentlichungen
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- Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003 Oct 15;290(15):2041-7. doi: 10.1001/jama.290.15.2041.
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- Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7. doi: 10.1172/JCI116186.
- Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996 Jun;19(6):580-6. doi: 10.2337/diacare.19.6.580.
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- Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. doi: 10.1056/NEJMoa052521.
- Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125-39. doi: 10.1056/NEJMoa070716.
- Kolligs F, Fehmann HC, Goke R, Goke B. Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide. Diabetes. 1995 Jan;44(1):16-9. doi: 10.2337/diab.44.1.16.
- Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986 Jan;29(1):46-52. doi: 10.1007/BF02427280.
- Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. doi: 10.1152/physrev.00034.2006.
- Sokos GG, Bolukoglu H, German J, Hentosz T, Magovern GJ Jr, Maher TD, Dean DA, Bailey SH, Marrone G, Benckart DH, Elahi D, Shannon RP. Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am J Cardiol. 2007 Sep 1;100(5):824-9. doi: 10.1016/j.amjcard.2007.05.022. Epub 2007 Jun 14.
- NICE-SUGAR Study Investigators; Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24.
- Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol. 2007 Mar-Apr;36(2):91-6. doi: 10.1080/03009740601179605.
- Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001 Dec;15(4):533-51. doi: 10.1053/beem.2001.0168.
- Rusavy Z, Sramek V, Lacigova S, Novak I, Tesinsky P, Macdonald IA. Influence of insulin on glucose metabolism and energy expenditure in septic patients. Crit Care. 2004 Aug;8(4):R213-20. doi: 10.1186/cc2868. Epub 2004 May 26.
- Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA. 1994 Jan 19;271(3):226-33.
- Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 1999 May 15;353(9165):1649-52. doi: 10.1016/s0140-6736(99)01046-6.
- Wolfe RR, Martini WZ. Changes in intermediary metabolism in severe surgical illness. World J Surg. 2000 Jun;24(6):639-47. doi: 10.1007/s002689910105.
- Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002 Jun;32 Suppl 3:14-23. doi: 10.1046/j.1365-2362.32.s3.3.x.
- Thijs LG, Hack CE. Time course of cytokine levels in sepsis. Intensive Care Med. 1995 Nov;21 Suppl 2:S258-63. doi: 10.1007/BF01740764.
- Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen BK. Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E108-14. doi: 10.1152/ajpendo.00471.2005. Epub 2006 Feb 7.
- Voerman BJ, Strack van Schijndel RJ, Groeneveld AB, de Boer H, Nauta JP, Thijs LG. Effects of human growth hormone in critically ill nonseptic patients: results from a prospective, randomized, placebo-controlled trial. Crit Care Med. 1995 Apr;23(4):665-73. doi: 10.1097/00003246-199504000-00014.
- Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of the critically ill? Diabetologia. 2006 Aug;49(8):1722-5. doi: 10.1007/s00125-006-0306-4. No abstract available.
- Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004 Aug;287(2):E199-206. doi: 10.1152/ajpendo.00545.2003.
- Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988 Oct;123(4):2009-13. doi: 10.1210/endo-123-4-2009.
- Willms B, Idowu K, Holst JJ, Creutzfeldt W, Nauck MA. Overnight GLP-1 normalizes fasting but not daytime plasma glucose levels in NIDDM patients. Exp Clin Endocrinol Diabetes. 1998;106(2):103-7. doi: 10.1055/s-0029-1211959.
- Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001 Mar;50(3):609-13. doi: 10.2337/diabetes.50.3.609.
- Vilsboll T, Toft-Nielsen MB, Krarup T, Madsbad S, Dinesen B, Holst JJ. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1. Diabetes Care. 2000 Jun;23(6):807-12. doi: 10.2337/diacare.23.6.807.
- Knop FK, Vilsboll T, Larsen S, Madsbad S, Holst JJ, Krarup T. No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis. Diabetes Care. 2003 Sep;26(9):2581-7. doi: 10.2337/diacare.26.9.2581.
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- 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(1):R35. doi: 10.1186/cc9983. Epub 2011 Jan 21.
- Nielsen ST, Janum S, Krogh-Madsen R, Solomon TP, Moller K. The incretin effect in critically ill patients: a case-control study. Crit Care. 2015 Nov 16;19:402. doi: 10.1186/s13054-015-1118-z.
- Lehrskov-Schmidt L, Lehrskov-Schmidt L, Nielsen ST, Holst JJ, Moller K, Solomon TP. The effects of TNF-alpha on GLP-1-stimulated plasma glucose kinetics. J Clin Endocrinol Metab. 2015 Apr;100(4):E616-22. doi: 10.1210/jc.2014-4244. Epub 2015 Feb 12.
Studienaufzeichnungsdaten
Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.
Haupttermine studieren
Studienbeginn
1. März 2011
Primärer Abschluss (Tatsächlich)
1. September 2014
Studienabschluss (Tatsächlich)
1. September 2014
Studienanmeldedaten
Zuerst eingereicht
2. Mai 2011
Zuerst eingereicht, das die QC-Kriterien erfüllt hat
3. Mai 2011
Zuerst gepostet (Schätzen)
4. Mai 2011
Studienaufzeichnungsaktualisierungen
Letztes Update gepostet (Schätzen)
22. September 2014
Letztes eingereichtes Update, das die QC-Kriterien erfüllt
19. September 2014
Zuletzt verifiziert
1. September 2014
Mehr Informationen
Begriffe im Zusammenhang mit dieser Studie
Schlüsselwörter
Zusätzliche relevante MeSH-Bedingungen
Andere Studien-ID-Nummern
- HS:H-3-2009-108
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