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

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.

Study Overview

• Status: Recruiting
• Conditions: Hypoglycemia; Type1diabetes; Type 1 Diabetes
• Intervention / Treatment: Other: Infusion of GIP[1-42], GIP[1-30] or placebo

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 Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Asger B Lund, MD; Phone Number: +4561676558; Email: asger.lund.01@regionh.dk
• Study Contact Backup: Name: Nikolaj E Sørum, MD; Phone Number: +4528747623; Email: nikolaj.middelbo.soerum@regionh.dk

Study Locations

• Denmark
  • Copenhagen
    • Hellerup, Copenhagen, Denmark, 2900
      • Recruiting
      • Center for Clinical Metabolic Research, Gentofte Hospital
      • Contact: Asger B Lund, MD; Phone Number: +4561676558; Email: asger.lund.01@regionh.dk
      • Contact: Nikolaj E Sørum, MD; Phone Number: +4528747623; Email: nikolaj.middelbo.soerum@regionh.dk
      • Principal Investigator: Asger B Lund, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborators: The Novo Nordisk Foundation Center for Basic Metabolic Research

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 9, 2023
• First Submitted That Met QC Criteria: November 15, 2023
• First Posted (Actual): November 18, 2023

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Glucose-dependent insulinotropic polypeptide; Incretins; GIP; Alpha cell
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia
• Other Study ID Numbers: GIPHYPO2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All published data will be made available to other researchers upon reasonable request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No