Clinical trial NCT06137586: The Effect of Glucose-dependent Insulinotropic Polypeptide on the Alpha Cell Response to Hypoglycaemia in Patients with Type 1 Diabetes
Official title: The Effect of Glucose-dependent Insulinotropic Polypeptide on the Alpha Cell Response to Hypoglycaemia in Patients with Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type1diabetes
Hypoglycemia
Type 1 Diabetes
Keywords: Incretins
GIP
Glucose-dependent insulinotropic polypeptide
Alpha cell
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
Collaborators: name: The Novo Nordisk Foundation Center for Basic Metabolic Research
First posted: 2023-11-18
Enrollment: 10
Sex: MALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Randomized, double-blinded, single-arm study. Each participant goes through five experimental days in a randomized order - acting as their own controls
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Total glucagon response
timeFrame: 0-135minutes
Secondary outcomes:
measure: Glucagon response during insulin infusion
timeFrame: 30-90minutes
measure: Glucagon response after blood glucose (BG) falls below 3.0 mmol/L
timeFrame: t[BG<3.0] and the following 30 minutes
measure: Glucagon response during recovery
timeFrame: 90-135minutes
measure: Total insulin response
timeFrame: 0-135minutes
measure: Total c-peptide response
timeFrame: 0-135minutes
measure: Amount of glucose infused
timeFrame: 0-135minutes
measure: Difference in epinephrine
timeFrame: 0-135minutes
measure: Difference in norepinephrine
timeFrame: 0-135minutes
measure: Difference in cortisol
timeFrame: 0-135minutes
measure: Difference in growth hormone hormones
timeFrame: 0-135minutes
measure: Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP)
timeFrame: 0-135minutes
measure: Difference in carboxy-terminal collagen crosslinks (CTX)
timeFrame: 0-135minutes
measure: Difference in blood pressure
timeFrame: 0-135minutes
measure: Difference in heart rate
timeFrame: 0-135minutes
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Center for Clinical Metabolic Research, Gentofte Hospital
state: Copenhagen
Study officials:
References: