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.
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 Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
10
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.
Center for Clinical Metabolic Research, Gentofte Hospital
Hellerup, Denmark
Total glucagon response
Differences in glucagon responses, measured as baseline subtracted AUC (bsAUC), between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 0-150minutes
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 0-150minutes
Difference in epinephrine
Difference in plasma levels of epinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 0-150minutes
Difference in norepinephrine
Difference in plasma levels of norepinephrine between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 0-150minutes
Difference in cortisol
Difference in plasma levels of cortisol between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 0-150minutes
Difference in growth hormone
Difference in plasma levels of growth hormone between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 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
Time frame: 0-150minutes
Difference in osteocalcin
Difference in plasma levels of osteocalcin between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 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
Time frame: 0-150minutes
Difference in blood pressure
Difference in blood pressure between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 0-150minutes
Difference in heart rate
Difference in heart rate between days with neuronostatin and placebo at corresponding glucose concentrations, respectively
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: At 125 minutes
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