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

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

Detailed Description
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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

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

Conditions
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Hypoglycaemia

Intervention / Treatment
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* Drug: GLP-1
* Drug: Placebo (Saline)
* Drug: TNF-alfa
* Other: OGTT
* Other: IVGTT


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GLP-1, Inflammation, Glucose