Mechanisms of Insulin Resistance in Critical Illness: Role of Systemic Inflammation and GLP-1

This study is currently recruiting participants.

Verified April 2011 by Rigshospitalet, Denmark

Sponsor:

Collaborators:

University of Copenhagen

Novo Nordisk

Information provided by (Responsible Party):

Kirsten Moller, Rigshospitalet, Denmark

ClinicalTrials.gov Identifier:

NCT01347801

First received: May 2, 2011

Last updated: November 30, 2012

Last verified: April 2011

History of Changes

Purpose

The purpose of this study is to determine the role of inflammation and the insulin regulating hormone GLP-1 during critical illness.

Condition	Intervention
Hypoglycaemia	Drug: GLP-1 Drug: Placebo (Saline) Drug: TNF-alfa Other: OGTT Other: IVGTT

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Basic Science
Official Title:	Mechanisms of Insulin Resistance in Critical Illness: Role of Systemic Inflammation and GLP-1

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines Hypoglycemia

U.S. FDA Resources

Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:

Substudy 2C (12 Healthy volunteers): GLP-1 [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
Increased plasma insulin and C-peptide (intact insulinotropic effect of GLP-1) during GLP-1 infusion in healthy volunteers.
Substudy 2A (12 Healthy volunteers): Insulin, C-peptide and incretin hormone response [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
Insulin, c-peptide and incretin hormone response to glucose stimulation during standardized systemic inflammation (TNF infusion) compared to placebo (saline infusion)
Substudy 1C(30 patients): Insulin, C-peptide and incretin hormone response [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
Insulin, c-peptide and incretin hormone response to glucose stimulation during IVGTT compared to OGTT in critically ill patients admitted to the ICU

Secondary Outcome Measures:

Substudy 2C (12 Healthy volunteers): Clamp [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
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.
Substudy 2A (12 Healthy volunteers): The incretin effect [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
The difference between the plasma insulin AUC obtained during OGTT and IVGTT (endogenous incretin effect).
Substudy 1C (30 patients): The incretin effect [ Time Frame: 6 weeks after intervention ] [ Designated as safety issue: No ]
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.

Estimated Enrollment:	54
Study Start Date:	March 2011
Estimated Study Completion Date:	July 2015
Estimated Primary Completion Date:	July 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: 2C - 1 TNF and OGTT and saline	Drug: Placebo (Saline) Normal saline (NaCl 0,9%) Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: OGTT Oral glucose tolerance test with 75 g glucose
Active Comparator: 2C - 2 TNF and OGTT and GLP-1	Drug: GLP-1 GLP-1 1,2pmol/kg/min i.v. infusion for 4 hours Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: OGTT Oral glucose tolerance test with 75 g glucose
Placebo Comparator: 2C - 3 TNF and IVGTT and saline	Drug: Placebo (Saline) Normal saline (NaCl 0,9%) Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: IVGTT Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
Active Comparator: 2C - 4 TNF and IVGTT and GLP-1	Drug: GLP-1 GLP-1 1,2pmol/kg/min i.v. infusion for 4 hours Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: IVGTT Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
Placebo Comparator: 2A-1 Saline infusion and OGTT	Drug: Placebo (Saline) Normal saline (NaCl 0,9%) Other: OGTT Oral glucose tolerance test with 75 g glucose
Placebo Comparator: 2A-2 Saline and IVGTT	Drug: Placebo (Saline) Normal saline (NaCl 0,9%) Other: IVGTT Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
Active Comparator: 2A-3 TNF and OGTT	Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: OGTT Oral glucose tolerance test with 75 g glucose
Active Comparator: 2A-4 TNF and IVGTT	Drug: TNF-alfa 1000ng/m2 BSA/hour i.v. infusion for 4-6 hours Other: IVGTT Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT
Experimental: 1C OGTT and corresponding IVGTT	Other: OGTT Oral glucose tolerance test with 75 g glucose Other: IVGTT Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT

Detailed Description:

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

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01347801

Contacts

Contact: Kirsten Møller, MD, PH.D., DMSc

+4540259674

Kirsten.Moller@dadlnet.dk

Locations

Denmark
Centre of Inflammation and Metabolism - Rigshospitalet 7641	Recruiting
Copenhagen, Denmark, 2100
Sub-Investigator: Lars M Pedersen, MD
Sub-Investigator: Thomas Solomon, Ph.D.
Sub-Investigator: Rikke Krogh-Madsen, MD, Ph.D
Principal Investigator: Kirsten Møller, MD, Ph.D., DMSc
Sub-Investigator: Signe Tellerup Nielsen, MD
University of Copenhagen	Active, not recruiting
Copenhagen, Denmark, 2400

Sponsors and Collaborators

Rigshospitalet, Denmark

University of Copenhagen

Novo Nordisk

Investigators

Principal Investigator:

Kirsten Møller, MD, Ph.D., DMSc

Centre of Inflammation and Metabolism

More Information

Publications:

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Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001 Dec;15(4):533-51. Review.

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. 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. Review.

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.

Wolfe RR, Martini WZ. Changes in intermediary metabolism in severe surgical illness. World J Surg. 2000 Jun;24(6):639-47.

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. Review.

Thijs LG, Hack CE. Time course of cytokine levels in sepsis. Intensive Care Med. 1995 Nov;21 Suppl 2:S258-63. Review.

Krogh-Madsen R, Plomgaard P, Møller 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. Epub 2006 Feb 7.

Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996 Jun 15;97(12):2859-65.

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.

Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003 Oct 15;290(15):2041-7.

van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67.

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.

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.

Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of the critically ill? Diabetologia. 2006 Aug;49(8):1722-5. No abstract available.

NICE-SUGAR Study Investigators; Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert 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. Epub 2009 Mar 24.

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. Review.

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.

Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. Review.

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.

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.

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.

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.

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.

Vilsbøll 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.

Vilsbøll 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.

Knop FK, Vilsbøll 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.

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 Mar;32(3):848-51.

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. Epub 2007 Jun 14.

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 Jan 21;15(1):R35 [Epub ahead of print]

Deane AM, Chapman MJ, Fraser RJ, Summers MJ, Zaknic AV, Storey JP, Jones KL, Rayner CK, Horowitz M. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med. 2010 May;38(5):1261-9.

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. Review.

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.

Responsible Party:	Kirsten Moller, MD, PH.D, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:	NCT01347801 History of Changes
Other Study ID Numbers:	HS:H-3-2009-108
Study First Received:	May 2, 2011
Last Updated:	November 30, 2012
Health Authority:	Denmark: Danish Dataprotection Agency Denmark: Ethics Committee

Keywords provided by Rigshospitalet, Denmark:

GLP-1
Inflammation
Glucose

Additional relevant MeSH terms:

Critical Illness
Hypoglycemia
Inflammation
Insulin Resistance
Disease Attributes
Pathologic Processes
Glucose Metabolism Disorders
Metabolic Diseases

Hyperinsulinism
Glucagon-Like Peptide 1
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 16, 2013

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