The goal of this clinical trial is to evaluate the effects of the hormone glucose-dependent insulinotropic polypeptide (GIP) and its two isoforms, GIP\[1-30\] and GIP\[1-42\], in patients with type 1 diabetes. The main question it aims to answer is: • What dose and isoform of GIP can most potently stimulate glucagon secretion during low blood sugar in patients with type 1 diabetes? Participants will go through 5 experimental days that are identical except for an intravenous infusion of either placebo (saline), high or low dose GIP\[1-42\] or high or low dose GIP\[1-30\]. On all days, blood sugar will be lowered to around 2.5mmol/l for around 20-30min.
After being informed about the study and the potential risks, each participant giving written informed consent will participate in five double-blinded experimental days (Day A-E) in a randomized order. Each experimental day is identical except for an intravenous infusion of either placebo (saline), high (8pmol/kg/min) or low (4pmol/kg/min) dose GIP\[1-42\] or high (8pmol/kg/min) or low (4pmol/kg/min) dose GIP\[1-30\]. Each experimental day will consist of an induction period where the participant's blood sugar is adjusted to around 5-6mmol/l with either insulin or glucose. Then the infusion of either placebo or hormone will be initiated and continued for 135 minutes. After 30 minutes of hormone infusion, a separate infusion of insulin (1.5mU/kg/min) will be initiated and continued for 60 minutes. Based on frequent bed-side plasma glucose measurements and an adjustable 20% glucose infusion, plasma glucose will be clamped at 2.5 mmol/l until the insulin infusion is terminated. Following this is a 45 minute recovery period, during which a minimum of glucose is infused, to ensure a steady rise from 2.5mmol/l to 3.5mmol/l. After the study day, patients will receive a meal to prevent subsequent hypoglycemia. 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
This is a single arm study. All participants will go through all five experimental days in a randomized order. The interventions are A) 4pmol/kg/min GIP\[1-42\] B) 8pmol/kg/min GIP\[1-42\] C) 4pmol/kg/min GIP\[1-30\] D) 8pmol/kg/min GIP\[1-30\] E) Saline (placebo)
Center for Clinical Metabolic Research, Gentofte Hospital
Hellerup, Copenhagen, Denmark
Total glucagon response
Difference in baseline subtracted area under the curve (bsAUC) for glucagon between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Glucagon response during insulin infusion
Difference in bsAUC for glucagon between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively during the insulin infusion
Time frame: 30-90minutes
Glucagon response after blood glucose (BG) falls below 3.0 mmol/L
Difference in bsAUC for glucagon between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively in the 30 minutes following a blood glucose of below 3.0 mmol/L
Time frame: t[BG<3.0] and the following 30 minutes
Glucagon response during recovery
Difference in bsAUC for glucagon between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively during the recovery period
Time frame: 90-135minutes
Total insulin response
Difference in plasma levels of insulin between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Total c-peptide response
Difference in plasma levels of c-peptide between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Amount of glucose infused
Difference in infusion rates for glucose between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in epinephrine
Difference in plasma levels of epinephrine between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in norepinephrine
Difference in plasma levels of norepinephrine between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in cortisol
Difference in plasma levels of cortisol between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in growth hormone hormones
Difference in plasma levels of growth hormone between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in Procollagen 1 Intact N-Terminal Propeptide (P1NP)
Difference in plasma levels of P1NP between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in carboxy-terminal collagen crosslinks (CTX)
Difference in plasma levels of CTX between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in blood pressure
Difference in blood pressure between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
Difference in heart rate
Difference in heart rate between study days with GIP\[1-42\], GIP\[1-30\] and placebo, respectively
Time frame: 0-135minutes
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