the effect of glucose-dependent insulinotropic polypeptide on the alpha cell response to hypoglycaemia in patients with type 1 diabetes

Conditions: Type1diabetes; Hypoglycemia; Type 1 Diabetes

Summary: 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.

Eligibility criteria:
inclusion criteria: * caucasian men * body mass index between 18-27kg/m2 * type 1 diabetes (t1d) (diagnosed according to the criteria of the world health organization) with hba1c\<69 mmol/mol (\<8.5%) * t1d duration of 2-30 years * c-peptide negative (stimulated c-peptide ≤ 100 pmol/l) * treatment with a stable basal-bolus or insulin pump regimen for ≥3 months * informed consent exclusion criteria: * anaemia (haemoglobin below normal range) * liver disease (alat and/or asat \>2 times normal values) or history of hepatobiliary disorder * late microvascular complications except mild nonproliferative retinopathy * allergy or intolerance to ingredients included in the standardized meals * prior myocardial infarction or other cardiac events * any physical or psychological condition that the investigator feels would interfere with trial participation * treatment with any glucose-lowering drugs beside insulin

Keywords: incretins gip glucose-dependent insulinotropic polypeptide alpha cell