Neuronostatin - a Glucagonotropic Agent in Humans?

Type 1 Diabetes Clinical Trial

— NSTCLAMP  

Official title:

Neuronostatin - a Glucagonotropic Agent in Humans?

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06143267
• Other study ID #: NSTCLAMP
• Status: Recruiting
• Phase: N/A
• Start date: December 6, 2022
• Est. completion date: August 1, 2024

Study information

• Verified date: November 2023
• Source: University Hospital, Gentofte, Copenhagen
• Contact: Asger B Lund, MD
• Phone: +4561676558
• Email: Asger.Lund.01[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Hypoglycemia
• Type 1 Diabetes
• Type1diabetes

Intervention

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.

Locations

Country	Name	City	State
Denmark	Center for Clinical Metabolic Research, Gentofte Hospital	Hellerup

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Gentofte, Copenhagen	The Novo Nordisk Foundation Center for Basic Metabolic Research

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total glucagon response	Differences in glucagon responses, measured as baseline subtracted AUC (bsAUC), between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Glucagon response during first 60 minutes	Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 0 to 60minutes	0-60minutes
Secondary	Glucagon response during "recovery"	Differences in bsAUC for glucagon between days with neuronostatin and placebo at corresponding glucose concentrations, respectively, from 60 to 90minutes	60-90minutes
Secondary	Glucagon response during hypoglycemia	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	t[BG=3.0] and the following 30 minutes
Secondary	Total insulin response	Difference in plasma levels of insulin between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Total proinsulin-c-peptide response	Difference in plasma levels of proinsulin-c-peptide between study days between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Amount of glucose infused	Difference in infusion rates for glucose between study days between days with neuronostatin and placebo, respectively, at both hyperglycemic and hypoglycemic days	0-150minutes
Secondary	Difference in epinephrine	Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in norepinephrine	Difference in plasma levels of norepinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in cortisol	Difference in plasma levels of cortisol between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in growth hormone	Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP)	Difference in plasma levels of P1NP between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in osteocalcin	Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in carboxy-terminal collagen crosslinks (CTX)	Difference in plasma levels of CTX between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in blood pressure	Difference in blood pressure between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Difference in heart rate	Difference in heart rate between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	0-150minutes
Secondary	Energy expenditure	Difference in energy expenditure (measured by indirect calorimetry measuring respiratory gas exchange) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	At -20 minutes, at 30 minutes, and at 75 minutes
Secondary	Appetite	Difference in appetite (assessed by visual analogue scale) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	At -5 minutes, 25 minutes, 60 minutes, 90 minutes, and 120minutes
Secondary	Food intake	Difference in food intake (assessed by ad libitum meal) between days with neuronostatin and placebo at corresponding glucose concentrations, respectively	At 125 minutes