Neuronostatin - a Glucagonotropic Agent in Humans?

Study Overview
=================
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.

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.

Official Title
-----------------
Neuronostatin - a Glucagonotropic Agent in Humans?

Conditions
-----------------
Type 1 Diabetes, Hypoglycemia, Type1diabetes

Intervention / Treatment
-----------------
* Other: Infusion of either NST or placebo at different blood glucose levels


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Randomized, 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion of NST or placebo at different blood glucose levels<br>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<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Difference in epinephrine | Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| Difference in norepinephrine | Difference in plasma levels of norepinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| Difference in cortisol | Difference in plasma levels of cortisol between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| Difference in growth hormone | Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| 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 | 
| Difference in osteocalcin | Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| 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 | 
| Difference in blood pressure | Difference in blood pressure between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| Difference in heart rate | Difference in heart rate between days with neuronostatin and placebo at corresponding glucose concentrations, respectively | 0-150minutes | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Gut hormones, Alpha cell, Pancreas, Incretins