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

This study has been completed.
Sponsor:
Collaborators:
University of Copenhagen
Novo Nordisk A/S
Information provided by (Responsible Party):
Kirsten Moller, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01347801
First received: May 2, 2011
Last updated: September 19, 2014
Last verified: September 2014
  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:


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(8 patients, 8 healthy controls): 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 (8 patients, 8 healthy controls): 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.


Enrollment: 40
Study Start Date: March 2011
Study Completion Date: September 2014
Primary Completion Date: September 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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01347801

Locations
Denmark
Centre of Inflammation and Metabolism - Rigshospitalet 7641
Copenhagen, Denmark, 2100
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
  More Information

Publications:

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: September 19, 2014
Health Authority: Denmark: Danish Dataprotection Agency
Denmark: Ethics Committee

Keywords provided by Rigshospitalet, Denmark:
GLP-1
Inflammation
Glucose

Additional relevant MeSH terms:
Inflammation
Insulin Resistance
Hypoglycemia
Critical Illness
Pathologic Processes
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Disease Attributes
Glucagon-Like Peptide 1
Glucagon
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Gastrointestinal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 30, 2014