Glucose-dependent Insulinotropic Polypeptide as a Safeguard Against Hypoglycemia in Patients With Type 1 Diabetes

Study Overview
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Brief Summary
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In the present project the investigators will evaluate whether glucagonotropic properties of the gut-derived incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may be utilized as a safeguard against hypoglycemia in patients with T1D.

Official Title
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Glucose-dependent Insulinotropic Polypeptide as a Safeguard Against Hypoglycemia in Patients With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: glucose-dependent insulinotropic peptide
* Drug: Glucose-Dependent Insulin-Releasing Hormone[3-30]
* Drug: Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men Body mass index between 20-27 kg/m^2 T1D (diagnosed according to the criteria of the World Health Organization) with HbA1c<69 mmol/l (<8,5%) T1D duration between 2-20 years Stimulated C-peptide ≤ 100 pmol/mL) Treatment with a stable basal bolus or insulin pump regimen ≥ 3 months Informed consent Exclusion Criteria: Anemia (hemoglobin below normal range) Liver disease (ALAT and/or ASAT >2 times normal values) or history of hepatobiliary disorder Nephropathy (serum creatinine above normal range and/or albuminuria) Allergy or intolerance to ingredients included in the standardized meals Prior myocardial infarction or other cardiac events Any physical or psychological condition that the investigator fells would interfere with trial participation Treatment with any glucose-lowering drugs beside insulin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

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
Interventional Model Description: Double blinded, randomized, cross-over study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GIP<br>Infusion of Glucose-dependent insulinotropic peptide | Drug: glucose-dependent insulinotropic peptide<br>* Infusion of GIP<br>|
| Active Comparator: GIP[3-30]<br>Infusion of GIP[3-30] | Drug: Glucose-Dependent Insulin-Releasing Hormone[3-30]<br>* Infusion of GIP antagonist GIP[3-30]<br>|
| Placebo Comparator: Saline<br>Infusion of saline | Drug: Saline Solution<br>* Infusion of Saline<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma glucose concentration | plasma glucose excursions and plasma glucose nadir | At times (minute): - 30, - 15, 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 240 on study days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose regulatory hormones | Counter regulatory hormones: glucagon, noradrenalin, cortisol, somatotropin, and insulin/c-peptide. Incremental and total area under the Concentration-Time Curve | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| Incretin hormones | Incretin hormones GLP-1 and GIP. Incremental and total area under the Concentration-Time Curve | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| GIP[3-30] | GIP[3-30]. Incremental and total area under the Concentration-Time Curve | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| Free fatty acids (FFA) | Free fatty acids(FFA). Incremental and total area under the Concentration-Time Curve | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| Blood analysis of paracetamol as an assessment of gastric emptying | Assessment of gastric emptying | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| Fat mRNA | Fat biopsy to evaluate changes in fat mRNA | At time 240 minute on study days | 
| Fat Lipoprotein lipase (LPL) | Fat biopsy to evaluate LPL changes in fat | At time 240 minute on study days | 
| Fat Perilipin 4 | Fat biopsy to evaluate Perilipin 4 changes in fat | At time 240 minute on study days | 
| Fat Fatty acid binding protein 4 (FABP4) | Fat biopsy to evaluate Fatty acid binding protein 4 (FABP4) changes in fat | At time 240 minute on study days | 
| Fat Hormonse-sensitive lipase (HSL) | Fat biopsy to evaluate Hormonse-sensitive lipase (HSL) changes in fat | At time 240 minute on study days | 
| Fat Vascular endothelial growth factor 4 (VEGF-A) | Fat biopsy to evaluate Vascular endothelial growth factor 4 (VEGF-A) changes in fat | At time 240 minute on study days | 
| Fat GIP receptor (GIPR) | Fat biopsy to evaluate GIP receptor (GIPR) changes in fat | At time 240 minute on study days | 
| Blood pressure | Changes in blood pressure, mm Hg | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 
| Pulse | Changes in pulse, beats per minute | At times (minute): - 30, 0, 15, 30, 60, 90, 120, 150, 180, 210, 240 on study days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 1, Hypoglycemia, Gastric Inhibitory Polypeptide, Glucagon, Incretin