Neuronostatin - a Glucagonotropic Agent in Humans?
- Conditions
- Type1diabetesHypoglycemiaType 1 Diabetes
- Interventions
- Other: Infusion of either NST or placebo at different blood glucose levels
- Registration Number
- NCT06143267
- Lead Sponsor
- University Hospital, Gentofte, Copenhagen
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 10
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Infusion of NST or placebo at different blood glucose levels 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.
- Primary Outcome Measures
Name Time Method 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
Name Time Method Difference in epinephrine 0-150minutes Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
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
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
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
Difference in growth hormone 0-150minutes Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
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
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
Difference in osteocalcin 0-150minutes Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
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
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
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
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
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 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 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 heart rate 0-150minutes Difference in heart rate 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
Trial Locations
- Locations (1)
Center for Clinical Metabolic Research, Gentofte Hospital
🇩🇰Hellerup, Denmark