GIPHYPO: The Effect of Glucose-dependent Insulinotropic Polypeptide on the Alpha Cell Response to Hypoglycaemia in Patients With Type 1 Diabetes
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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N/A |
Detailed Description
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Infusion of GIP[1-42], GIP[1-30] or placebo 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
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)
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Outcome Measures
Primary Outcome Measures
- Total glucagon response [0-135minutes]
Difference in baseline subtracted area under the curve (bsAUC) for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively
Secondary Outcome Measures
- Glucagon response during insulin infusion [30-90minutes]
Difference in bsAUC for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively during the insulin infusion
- Glucagon response after blood glucose (BG) falls below 3.0 mmol/L [t[BG<3.0] and the following 30 minutes]
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
- Glucagon response during recovery [90-135minutes]
Difference in bsAUC for glucagon between study days with GIP[1-42], GIP[1-30] and placebo, respectively during the recovery period
- Total insulin response [0-135minutes]
Difference in plasma levels of insulin between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Total c-peptide response [0-135minutes]
Difference in plasma levels of c-peptide between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Amount of glucose infused [0-135minutes]
Difference in infusion rates for glucose between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in epinephrine [0-135minutes]
Difference in plasma levels of epinephrine between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in norepinephrine [0-135minutes]
Difference in plasma levels of norepinephrine between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in cortisol [0-135minutes]
Difference in plasma levels of cortisol between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in growth hormone hormones [0-135minutes]
Difference in plasma levels of growth hormone between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP) [0-135minutes]
Difference in plasma levels of P1NP between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in carboxy-terminal collagen crosslinks (CTX) [0-135minutes]
Difference in plasma levels of CTX between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in blood pressure [0-135minutes]
Difference in blood pressure between study days with GIP[1-42], GIP[1-30] and placebo, respectively
- Difference in heart rate [0-135minutes]
Difference in heart rate between study days with GIP[1-42], GIP[1-30] and placebo, respectively
Eligibility Criteria
Criteria
Inclusion Criteria:
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Caucasian men
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Body mass index between 18-27kg/m2
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Type 1 diabetes (T1D) (diagnosed according to the criteria of the World Health Organization) with HbA1c<69 mmol/mol (<8.5%)
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T1D duration of 2-30 years
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C-peptide negative (stimulated C-peptide ≤ 100 pmol/l)
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Treatment with a stable basal-bolus or insulin pump regimen for ≥3 months
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Informed consent
Exclusion Criteria:
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Anaemia (haemoglobin below normal range)
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Liver disease (ALAT and/or ASAT >2 times normal values) or history of hepatobiliary disorder
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Late microvascular complications except mild nonproliferative retinopathy
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Allergy or intolerance to ingredients included in the standardized meals
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Prior myocardial infarction or other cardiac events
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Any physical or psychological condition that the investigator feels would interfere with trial participation
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Treatment with any glucose-lowering drugs beside insulin
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Center for Clinical Metabolic Research, Gentofte Hospital | Hellerup | Copenhagen | Denmark | 2900 |
Sponsors and Collaborators
- University Hospital, Gentofte, Copenhagen
- The Novo Nordisk Foundation Center for Basic Metabolic Research
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- GIPHYPO2022