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

September 19, 2014 updated by: 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2100
        • Centre of Inflammation and Metabolism - Rigshospitalet 7641
      • Copenhagen, Denmark, 2400
        • University of Copenhagen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: TNF-alfa
1000ng/m2 BSA/hour i.v. infusion for 4-6 hours
Other: OGTT
Oral glucose tolerance test with 75 g glucose
Drug: GLP-1
GLP-1 1,2pmol/kg/min i.v. infusion for 4 hours
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: TNF-alfa
1000ng/m2 BSA/hour i.v. infusion for 4-6 hours
Drug: GLP-1
GLP-1 1,2pmol/kg/min i.v. infusion for 4 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Substudy 2C (12 Healthy volunteers): GLP-1
Time Frame: 6 weeks after intervention
Increased plasma insulin and C-peptide (intact insulinotropic effect of GLP-1) during GLP-1 infusion in healthy volunteers.
6 weeks after intervention
Substudy 2A (12 Healthy volunteers): Insulin, C-peptide and incretin hormone response
Time Frame: 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
Substudy 1C(8 patients, 8 healthy controls): Insulin, C-peptide and incretin hormone response
Time Frame: 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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Substudy 2C (12 Healthy volunteers): Clamp
Time Frame: 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
Time Frame: 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
Time Frame: 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rigshospitalet, Denmark

Collaborators

Novo Nordisk A/S
University of Copenhagen

Investigators

  • Principal Investigator: Kirsten Møller, MD, Ph.D., DMSc, Centre of Inflammation and Metabolism

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2011

Primary Completion (Actual)

September 1, 2014

Study Completion (Actual)

September 1, 2014

Study Registration Dates

First Submitted

May 2, 2011

First Submitted That Met QC Criteria

May 3, 2011

First Posted (Estimate)

May 4, 2011

Study Record Updates

Last Update Posted (Estimate)

September 22, 2014

Last Update Submitted That Met QC Criteria

September 19, 2014

Last Verified

September 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HS:H-3-2009-108

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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