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NCT Number: NCT06143267

Neuronostatin - a Glucagonotropic Agent in Humans?

With the present study the investigators wish to delineate the effects of neuronostatin-13 (NST) on glucose-dependent glucagon secretion in humans. The main question it aims to answer is:

• What are the physiological effects of the naturally occuring hormone NST - especially with regards to glucagonotropic effects at different plasma glucose concentrations

In a randomized, double-blind crossover design, participants will undergo six experimental days with controlled plasma glucose levels, consisting of two euglycemic, two hyperglycemic (around 8mmol/l), and two hypoglycemic (around 2.5mmol/l) days, with each pair of similar days involving the administration of either saline (placebo) or NST.

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Key information

Conditions

Type 1 Diabetes Autoimmune Diseases Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucose Metabolism Disorders Hypoglycemia Immune System Diseases Metabolic Diseases Nutritional and Metabolic Diseases Type1diabetes

Age range

18 year–65 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Center for Clinical Metabolic Research, Gentofte Hospital

Hellerup, 2900, Denmark

About this study

With the present study the investigators wish to delineate the effects of neuronostatin on glucose-dependent glucagon secretion in humans. Thus, this study is designed to elucidate the physiological effects of the natural occurring hormone, neuronostatin, and not to examine a medical effect of a drug or treatment. However, if neuronostatin acts glucagonotropically during low plasma glucose concentrations it could potentially help to address the unmet medical need for a treatment that, ultimately, can counteract the high risk of hypoglycaemia in patients treated with insulin.

After being informed about the study and the potential risks, each participant giving written informed consent will participate in six double-blinded experimental days (Day A-F) in a randomized order. On each day, participants will receive an infusion of either saline (placebo)(day A, C and E) or NST (day B, D and F). On day A and B, blood glucose will be kept at fasting levels, on day C and D blood glucose will be increased to ~8mmol/l and on day E and F blood glucose will be lowered to ~2.5mmol/l.

Blood glucose will be adjusted with insulin and/or glucose to reach the desired levels on each day.

At the end of the study day, participants will receive an ad libitum meal.

The effects of each infusion will be evaluated with regards to glucagonotropic potency, as well as a series of exploratory outcomes.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Normal haemoglobin >8.3 mmol/l
  • Normal fasting plasma glucose below 7 mmol/l
  • Normal HbA1C <42 mmol/mol (6%)
  • Body mass index (BMI) 18.5-27 kg/m2
  • Oral and written informed consent

Exclusion criteria

  • Diabetes
  • Treatment with drugs that might interfere with glucose metabolism within a month prior to the research study
  • Treatment with any medication that cannot be paused for 12 hours
  • Known liver disease and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 × normal values
  • Nephropathy (eGFR <60 ml/min and/or albuminuria)
  • Any condition that the investigator feels would interfere with trial participation

Treatment and study plan

Infusion of either NST or placebo at different blood glucose levels

Other

In a randomized, double-blind crossover design, participants will undergo six experimental days with controlled plasma glucose levels, consisting of two euglycemic, two hyperglycemic (around 8mmol/l), and two hypoglycemic (around 2.5mmol/l) days, with each pair of similar days involving the administration of either saline (placebo) or NST.

Primary outcomes

  1. Total glucagon response

    Time frame: 0-150minutes

    Differences in glucagon responses, measured as baseline subtracted AUC (bsAUC), between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

Secondary outcomes

  1. Glucagon response during first 60 minutes

    Time frame: 0-60minutes

    Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 0 to 60minutes

  2. Glucagon response during "recovery"

    Time frame: 60-90minutes

    Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 60 to 90minutes

  3. Glucagon response during hypoglycemia

    Time frame: t[BG=3.0] and the following 30 minutes

    Difference in bsAUC for glucagon between the two hypoglycemic study days with NST and placebo, respectively in the 30 minutes following a blood glucose (BG) below 3.0mmol/L

  4. Total insulin response

    Time frame: 0-150minutes

    Difference in plasma levels of insulin between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  5. Total proinsulin-c-peptide response

    Time frame: 0-150minutes

    Difference in plasma levels of proinsulin-c-peptide between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  6. Amount of glucose infused

    Time frame: 0-150minutes

    Difference in infusion rates for glucose between study days between days with neuronostatin and placebo, respectively, at both hyperglycemic and hypoglycemic days

  7. Difference in epinephrine

    Time frame: 0-150minutes

    Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  8. Difference in norepinephrine

    Time frame: 0-150minutes

    Difference in plasma levels of norepinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  9. Difference in cortisol

    Time frame: 0-150minutes

    Difference in plasma levels of cortisol between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  10. Difference in growth hormone

    Time frame: 0-150minutes

    Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  11. Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP)

    Time frame: 0-150minutes

    Difference in plasma levels of P1NP between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  12. Difference in osteocalcin

    Time frame: 0-150minutes

    Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  13. Difference in carboxy-terminal collagen crosslinks (CTX)

    Time frame: 0-150minutes

    Difference in plasma levels of CTX between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  14. Difference in blood pressure

    Time frame: 0-150minutes

    Difference in blood pressure between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  15. Difference in heart rate

    Time frame: 0-150minutes

    Difference in heart rate between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  16. Energy expenditure

    Time frame: At -20 minutes, at 30 minutes, and at 75 minutes

    Difference in energy expenditure (measured by indirect calorimetry measuring respiratory gas exchange) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  17. Appetite

    Time frame: At -5 minutes, 25 minutes, 60 minutes, 90 minutes, and 120minutes

    Difference in appetite (assessed by visual analogue scale) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

  18. Food intake

    Time frame: At 125 minutes

    Difference in food intake (assessed by ad libitum meal) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

Sponsors and collaborators

Lead sponsor

University Hospital, Gentofte, Copenhagen

Other

Collaborators

  • The Novo Nordisk Foundation Center for Basic Metabolic Research

Registry information

Acronym: NSTCLAMP

Important dates

Study start
2022
Primary completion
2024
Study completion
2024
First posted
Nov 22, 2023
Registry last updated
Dec 10, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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