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

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ClinicalTrials.gov Identifier: NCT04228484
Recruitment Status : Recruiting
First Posted : January 14, 2020
Last Update Posted : January 14, 2020
Sponsor:
Information provided by (Responsible Party):
Filip Krag Knop, University Hospital, Gentofte, Copenhagen

Brief Summary:

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) patients with type 2 diabetes will attend two experimental days followed by a three-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.


Condition or disease Intervention/treatment Phase
Type2 Diabetes Drug: Insulin Drug: Empagliflozin Drug: Metformin Not Applicable

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 (using 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 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) patients with type 2 diabetes will attend two experimental days followed by a three-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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Beta Cell Responsiveness to Glucose-dependent Insulinotropic Polypeptide Following Near-normalisation of Plasma Glucose in Overweight Patients With Type 2 Diabetes
Actual Study Start Date : January 7, 2020
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Intervention
During the intervention period insulin, empagliflozin and metformin will be used as tools to near-normalise plasma glucose.
Drug: Insulin
Used as a tool to near-normalise plasma glucose

Drug: Empagliflozin
Used as a tool to near-normalise plasma glucose

Drug: Metformin
Used as a tool to near-normalise plasma glucose




Primary Outcome Measures :
  1. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. 59-75 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 insulin or 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04228484


Contacts
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Contact: Mads B Lynggaard, BSc.Med. 004538672463 mads.bank.lynggaard.02@regionh.dk

Locations
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Denmark
Center for Clinical Metabolic Research, Gentofte Hospital Recruiting
Hellerup, Capital Region, Denmark, 2900
Contact: Filip K Knop, MD, professor    004538674266    filip.krag.knop.01@regionh.dk   
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen
Investigators
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Principal Investigator: Filip K Knop, Professor, MD Director of Center for Clinical Metabolic Research, Gentofte Hospital

Additional Information:
Publications:
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Responsible Party: Filip Krag Knop, Professor, MD, PhD, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT04228484    
Other Study ID Numbers: H-19069850
First Posted: January 14, 2020    Key Record Dates
Last Update Posted: January 14, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Filip Krag Knop, University Hospital, Gentofte, Copenhagen:
Type 2 Diabetes,
Incretin Effect
GIP
Glucose-dependent Insulinotropic Polypeptide
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin
Insulin, Globin Zinc
Metformin
Empagliflozin
Gastric Inhibitory Polypeptide
Hypoglycemic Agents
Physiological Effects of Drugs
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists