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

Hypoglycaemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01347801
• Other study ID #: HS:H-3-2009-108
• Status: Completed
• Phase: N/A
• First received: May 2, 2011
• Last updated: September 19, 2014
• Start date: March 2011
• Est. completion date: September 2014

Study information

• Verified date: September 2014
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Critical Illness
• Hypoglycaemia
• Hypoglycemia
• Inflammation
• Insulin Resistance

Intervention

Drug:
• GLP-1
GLP-1 1,2pmol/kg/min i.v. infusion for 4 hours
• Placebo (Saline)
Normal saline (NaCl 0,9%)
• TNF-alfa
1000ng/m2 BSA/hour i.v. infusion for 4-6 hours

Other:
• OGTT
Oral glucose tolerance test with 75 g glucose
• IVGTT
Intravenous glucose tolerance test with infusion of 20% glucose matching the glucose profile of the corresponding OGTT

Locations

Country	Name	City	State
Denmark	Centre of Inflammation and Metabolism - Rigshospitalet 7641	Copenhagen
Denmark	University of Copenhagen	Copenhagen

Sponsors (3)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Novo Nordisk A/S, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (34)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of the critically ill? Diabetologia. 2006 Aug;49(8):1722-5. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001 Jan;17(1):107-24. Review. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Substudy 2C (12 Healthy volunteers): GLP-1	Increased plasma insulin and C-peptide (intact insulinotropic effect of GLP-1) during GLP-1 infusion in healthy volunteers.	6 weeks after intervention
Primary	Substudy 2A (12 Healthy volunteers): Insulin, C-peptide and incretin hormone response	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
Primary	Substudy 1C(8 patients, 8 healthy controls): Insulin, C-peptide and incretin hormone response	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
Secondary	Substudy 2C (12 Healthy volunteers): Clamp	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
Secondary	Substudy 2A (12 Healthy volunteers): The incretin effect	The difference between the plasma insulin AUC obtained during OGTT and IVGTT (endogenous incretin effect).	6 weeks after intervention
Secondary	Substudy 1C (8 patients, 8 healthy controls): The incretin effect	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