The Insulin Response to the Gut Hormone GIP After Near-normalisation of Plasma Glucose in Patients With Type 2 Diabetes (GA-16)

November 3, 2022 updated by: Filip Krag Knop, University Hospital, Gentofte, Copenhagen

Beta Cell Responsiveness to Glucose-dependent Insulinotropic Polypeptide Following Near-normalisation of Plasma Glucose in Overweight Patients With Type 2 Diabetes

The investigators hypothesise that the insulinotropic effect of endogenous GIP is improvable in patients with type 2 diabetes after three weeks of near-normalisation of plasma glucose. To test this hypothesis, a randomised, placebo-controlled, double-blinded, crossover study employing a GIP receptor antagonist, will be carried out.

Fifteen overweight (body mass index (BMI) > 25 kg/m2) dysregulated (HbA1c >/= 59 mmol/mol and treatment with metformin or >53 mmol/mol and treatment with metformin + add/on) patients with type 2 diabetes will attend two experimental days followed by a three-week-four-week period of plasma glucose near-normalisation (achieved by standard treatment of type 2-diabetes), followed by another two experimental days. On experimental days, patients will receive an infusion of GIP receptor antagonist or placebo during a 75 g oral glucose tolerance test. The primary endpoint is changes in levels of C-peptide divided by changes in levels of plasma glucose and secondary endpoints include changes in circulating levels of C-peptide, insulin, glucose, GIP, glucagon-like peptide 1 (GLP-1), glucagon and markers of bone turnover as well as indices of beta cell function. Furthermore, gastric emptying rate will be assessed.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Glucose-dependent insulinotropic polypeptide (GIP) exerts a strong insulinotropic effect in healthy individuals following meal ingestion. Studies in patients with type 2 diabetes have shown that the insulinotropic effect of exogenous GIP is severely reduced and recent data from the investigators' group suggest that the insulinotropic effect of endogenous GIP is compromised too. Interestingly, after near-normalisation of plasma glucose in patients with type 2 diabetes (continuing metformin and by using empagliflozin + intensive insulin treatment), the insulinotropic effect of exogenous GIP can be restored. The investigators have previously observed a similar restoration of the beta cell secretory response to exogenous GIP after therapy with DPP-4 inhibitors, the effects of which rely on preservation of incretins.

The investigators hypothesise that the insulinotropic effect of endogenous GIP is improvable in patients with type 2 diabetes after three weeks-four weeks of near-normalisation of plasma glucose. To test this hypothesis, a randomised, placebo-controlled, double-blinded, crossover study employing a GIP receptor antagonist, will be carried out.

Fifteen overweight (body mass index (BMI) > 25 kg/m2) dysregulated (HbA1c >/= 59 mmol/mol and treatment with metformin or >53 mmol/mol and treatment with metformin + add/on) patients with type 2 diabetes will attend two experimental days followed by a three-week/four-week period of plasma glucose near-normalisation (achieved by standard treatment of type 2-diabetes), followed by another two experimental days. On experimental days, patients will receive an infusion of GIP receptor antagonist or placebo during a 75 g oral glucose tolerance test. The primary endpoint is changes in levels of C-peptide divided by changes in levels of plasma glucose and secondary endpoints include changes in circulating levels of C-peptide, insulin, glucose, GIP, glucagon-like peptide 1 (GLP-1), glucagon and markers of bone turnover as well as indices of beta cell function. Furthermore, gastric emptying rate will be assessed.

Glucose-lowering drugs based on the effects of another incretin hormone, GLP-1, are successfully being used in the treatment of type 2 diabetes. However, due to the reduced insulinotropic effect of GIP in patients with inadequately controlled type 2 diabetes, treatments based on GIP receptor activation are not on the market. Recently however, a dual GLP-1/GIP receptor agonist has shown promising phase II results. The importance of GIP receptor engagement for the efficacy of these compounds remains to be shown. The present project will answer to what extent the insulinotropic effect of endogenous GIP in patients with type 2 diabetes can be restored following near-normalisation of plasma glucose and thus, provide important perspectives on how to further advance the development of GIP-based therapeutics.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
    • Capital Region
      • Hellerup, Capital Region, Denmark, 2900
        • Center for Clinical Metabolic Research, Gentofte Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Type 2 diabetes
  2. Metformin treatment
  3. Haemoglobin A1c (HbA1c) I. >/= 59 mmol/mol in case the diabetes treatment is only metformin II. 53-75 mmol/mol in case the diabetes treatment is metformin and add-on therapy
  4. Body Mass Index (BMI) > 25 kg/m2
  5. Age > 18 years
  6. Caucasian
  7. Normal haemoglobin levels

Exclusion Criteria:

  1. Treatment with GLP-1-receptor agonist
  2. Any treatment that cannot be paused for 12 hours
  3. Diabetes duration more than 20 years
  4. Weekly alcohol intake of more than 14 units for men or 7 units for women of alcohol (of 12 g) or narcotics abuse
  5. Liver disease
  6. Kidney disease (estimated glomerular filtration rate, eGFR < 60 ml/min/1,73 m2)
  7. Unusual dietary preferences or planned weight loss within the duration of the study
  8. Any other condition that in the opinion of the responsible investigators is disqualifying.
  9. For women I. Current or planned pregnancy for the duration of the study II. Positive pregnancy test at the screening or any of the experimental days III. Women who are currently breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Placebo infusion
Other: Placebo
Placebo infusion
Active Comparator: GIP receptor antagonization
GIP(3-30)NH2 infusion
Other: GIP receptor antagonization
GIP(3-30)NH2 infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in [plasma C-peptide] / [plasma glucose] after near-normalisation of plasma glucose
Time Frame: Assessed multiple times on each of the four study days
The primary endpoint is beta cell sensitivity to glucose as assessed by the C-peptide response to a 75 g-oral glucose tolerance test (OGTT) (as assessed by baseline-subtracted area under the curve (bsAUC)) divided by levels of plasma glucose (as assessed by bsAUC) during GIP(3-30)NH2 infusion compared to placebo before and after near-normalisation of plasma glucose.
Assessed multiple times on each of the four study days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Gentofte, Copenhagen

Investigators

  • Principal Investigator: Filip K Knop, Professor, MD, Director of Center for Clinical Metabolic Research, Gentofte Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 7, 2020

Primary Completion (Actual)

June 4, 2021

Study Completion (Actual)

October 1, 2022

Study Registration Dates

First Submitted

January 7, 2020

First Submitted That Met QC Criteria

January 13, 2020

First Posted (Actual)

January 14, 2020

Study Record Updates

Last Update Posted (Actual)

November 4, 2022

Last Update Submitted That Met QC Criteria

November 3, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-19069850

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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