The Effect of Glucose-dependent Insulinotropic Polypeptide on the Alpha Cell Response to Hypoglycaemia in Patients With Type 1 Diabetes

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate the effects of the hormone glucose-dependent insulinotropic polypeptide (GIP) and its two isoforms, GIP[1-30] and GIP[1-42], in patients with type 1 diabetes. The main question it aims to answer is: • What dose and isoform of GIP can most potently stimulate glucagon secretion during low blood sugar in patients with type 1 diabetes? Participants will go through 5 experimental days that are identical except for an intravenous infusion of either placebo (saline), high or low dose GIP[1-42] or high or low dose GIP[1-30]. On all days, blood sugar will be lowered to around 2.5mmol/l for around 20-30min.

Detailed Description
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After being informed about the study and the potential risks, each participant giving written informed consent will participate in five double-blinded experimental days (Day A-E) in a randomized order. Each experimental day is identical except for an intravenous infusion of either placebo (saline), high (8pmol/kg/min) or low (4pmol/kg/min) dose GIP[1-42] or high (8pmol/kg/min) or low (4pmol/kg/min) dose GIP[1-30]. Each experimental day will consist of an induction period where the participant's blood sugar is adjusted to around 5-6mmol/l with either insulin or glucose. Then the infusion of either placebo or hormone will be initiated and continued for 135 minutes. After 30 minutes of hormone infusion, a separate infusion of insulin (1.5mU/kg/min) will be initiated and continued for 60 minutes. Based on frequent bed-side plasma glucose measurements and an adjustable 20% glucose infusion, plasma glucose will be clamped at 2.5 mmol/l until the insulin infusion is terminated. Following this is a 45 minute recovery period, during which a minimum of glucose is infused, to ensure a steady rise from 2.5mmol/l to 3.5mmol/l. After the study day, patients will receive a meal to prevent subsequent hypoglycemia. The effects of each infusion will be evaluated with regards to glucagonotropic potency, as well as a series of exploratory outcomes.

Official Title
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The Effect of Glucose-dependent Insulinotropic Polypeptide on the Alpha Cell Response to Hypoglycaemia in Patients With Type 1 Diabetes

Conditions
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Type1diabetes, Hypoglycemia, Type 1 Diabetes

Intervention / Treatment
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* Other: Infusion of GIP[1-42], GIP[1-30] or placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian men Body mass index between 18-27kg/m2 Type 1 diabetes (T1D) (diagnosed according to the criteria of the World Health Organization) with HbA1c<69 mmol/mol (<8.5%) T1D duration of 2-30 years C-peptide negative (stimulated C-peptide ≤ 100 pmol/l) Treatment with a stable basal-bolus or insulin pump regimen for ≥3 months Informed consent Exclusion Criteria: Anaemia (haemoglobin below normal range) Liver disease (ALAT and/or ASAT >2 times normal values) or history of hepatobiliary disorder Late microvascular complications except mild nonproliferative retinopathy 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 feels 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
Intervention Model: Single Group Assignment
Interventional Model Description: Randomized, double-blinded, single-arm study. Each participant goes through five experimental days in a randomized order - acting as their own controls
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion of GIP[1-42], GIP[1-30] or placebo<br>This is a single arm study. All participants will go through all five experimental days in a randomized order. The interventions are A) 4pmol/kg/min GIP[1-42] B) 8pmol/kg/min GIP[1-42] C) 4pmol/kg/min GIP[1-30] D) 8pmol/kg/min GIP[1-30] E) Saline (placebo) | Other: Infusion of GIP[1-42], GIP[1-30] or placebo<br>* This is a single arm study. All participants will go through all five experimental days in a randomized order. The interventions are A) 4pmol/kg/min GIP[1-42] B) 8pmol/kg/min GIP[1-42] C) 4pmol/kg/min GIP[1-30] D) 8pmol/kg/min GIP[1-30] E) Saline (placebo)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total glucagon response | Difference in baseline subtracted area under the curve (bsAUC) for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon response during insulin infusion | Difference in bsAUC for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively during the insulin infusion | 30-90minutes | 
| Glucagon response after blood glucose (BG) falls below 3.0 mmol/L | Difference in bsAUC for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively in the 30 minutes following a blood glucose of below 3.0 mmol/L | t[BG<3.0] and the following 30 minutes | 
| Glucagon response during recovery | Difference in bsAUC for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively during the recovery period | 90-135minutes | 
| Total insulin response | Difference in plasma levels of insulin between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Total c-peptide response | Difference in plasma levels of c-peptide between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Amount of glucose infused | Difference in infusion rates for glucose between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in epinephrine | Difference in plasma levels of epinephrine between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in norepinephrine | Difference in plasma levels of norepinephrine between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in cortisol | Difference in plasma levels of cortisol between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in growth hormone hormones | Difference in plasma levels of growth hormone between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP) | Difference in plasma levels of P1NP between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in carboxy-terminal collagen crosslinks (CTX) | Difference in plasma levels of CTX between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in blood pressure | Difference in blood pressure between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 
| Difference in heart rate | Difference in heart rate between study days with GIP[1-42], GIP[1-30] and placebo, respectively | 0-135minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incretins, GIP, Glucose-dependent insulinotropic polypeptide, Alpha cell