Mechanisms of Insulin Resistance in Critical Illness: Role of Systemic Inflammation and GLP-1
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the role of inflammation and the insulin regulating hormone GLP-1 during critical illness.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
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
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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
|
Outcome Measures
Primary Outcome Measures
- Substudy 2C (12 Healthy volunteers): GLP-1 [6 weeks after intervention]
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 [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)
- Substudy 1C(8 patients, 8 healthy controls): Insulin, C-peptide and incretin hormone response [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
Secondary Outcome Measures
- Substudy 2C (12 Healthy volunteers): Clamp [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.
- Substudy 2A (12 Healthy volunteers): The incretin effect [6 weeks after intervention]
The difference between the plasma insulin AUC obtained during OGTT and IVGTT (endogenous incretin effect).
- Substudy 1C (8 patients, 8 healthy controls): The incretin effect [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.
Eligibility Criteria
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Centre of Inflammation and Metabolism - Rigshospitalet 7641 | Copenhagen | Denmark | 2100 | |
| 2 | University of Copenhagen | Copenhagen | Denmark | 2400 |
Sponsors and Collaborators
- Rigshospitalet, Denmark
- University of Copenhagen
- Novo Nordisk A/S
Investigators
- Principal Investigator: Kirsten Møller, MD, Ph.D., DMSc, Centre of Inflammation and Metabolism
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of the critically ill? Diabetologia. 2006 Aug;49(8):1722-5.
- 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. doi: 10.1097/CCM.0b013e3181d9d87a.
- 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.
- Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003 Oct 15;290(15):2041-7.
- 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.
- Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007 Oct;87(4):1409-39. Review.
- 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.
- Kolligs F, Fehmann HC, Göke R, Göke 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.
- 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.
- McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001 Jan;17(1):107-24. Review.
- 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.
- Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Pract Res Clin Endocrinol Metab. 2001 Dec;15(4):533-51. Review.
- Nauck M, Stöckmann 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.
- 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. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Thijs LG, Hack CE. Time course of cytokine levels in sepsis. Intensive Care Med. 1995 Nov;21 Suppl 2:S258-63. Review.
- 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.
- 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 critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67.
- 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.
- 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.
- 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.
- Wolfe RR, Martini WZ. Changes in intermediary metabolism in severe surgical illness. World J Surg. 2000 Jun;24(6):639-47.
- HS:H-3-2009-108