NSTCLAMP: Neuronostatin - a Glucagonotropic Agent in Humans?

Sponsor

University Hospital, Gentofte, Copenhagen (Other)

Overall Status

Recruiting

CT.gov ID

NCT06143267

Collaborator

The Novo Nordisk Foundation Center for Basic Metabolic Research (Other)

Enrollment

Location

Arm

19.8

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Hypoglycemia Type1diabetes	Other: Infusion of either NST or placebo at different blood glucose levels	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

10 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Randomized, double-blinded, single-arm study. Each participant goes through six experimental days in a randomized order - acting as their own controlsRandomized, double-blinded, single-arm study. Each participant goes through six experimental days in a randomized order - acting as their own controls

Masking:

None (Open Label)

Masking Description:

The randomized order of infusions is blinded to both participant and investigator

Primary Purpose:

Basic Science

Official Title:

Neuronostatin - a Glucagonotropic Agent in Humans?

Actual Study Start Date :

Dec 6, 2022

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Infusion of NST or placebo at different blood glucose levels 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.	Other: Infusion of either NST or placebo at different blood glucose levels 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.

Arm

Intervention/Treatment

Experimental: Infusion of NST or placebo at different blood glucose levels

Other: Infusion of either NST or placebo at different blood glucose levels

Outcome Measures

Primary Outcome Measures

Total glucagon response [0-150minutes]
Differences in glucagon responses, measured as baseline subtracted AUC (bsAUC), between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

Secondary Outcome Measures

Glucagon response during first 60 minutes [0-60minutes]
Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 0 to 60minutes
Glucagon response during "recovery" [60-90minutes]
Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 60 to 90minutes
Glucagon response during hypoglycemia [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
Total insulin response [0-150minutes]
Difference in plasma levels of insulin between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Total proinsulin-c-peptide response [0-150minutes]
Difference in plasma levels of proinsulin-c-peptide between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Amount of glucose infused [0-150minutes]
Difference in infusion rates for glucose between study days between days with neuronostatin and placebo, respectively, at both hyperglycemic and hypoglycemic days
Difference in epinephrine [0-150minutes]
Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in norepinephrine [0-150minutes]
Difference in plasma levels of norepinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in cortisol [0-150minutes]
Difference in plasma levels of cortisol between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in growth hormone [0-150minutes]
Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP) [0-150minutes]
Difference in plasma levels of P1NP between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in osteocalcin [0-150minutes]
Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in carboxy-terminal collagen crosslinks (CTX) [0-150minutes]
Difference in plasma levels of CTX between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in blood pressure [0-150minutes]
Difference in blood pressure between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Difference in heart rate [0-150minutes]
Difference in heart rate between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Energy expenditure [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
Appetite [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
Food intake [At 125 minutes]
Difference in food intake (assessed by ad libitum meal) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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