The Late Effects of Ethanol Intake on the Glucose Response to Subcutaneous Glucagon in Type 1 Diabetes

Study Overview
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Brief Summary
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Objective: Because many people with type 1 diabetes drink ethanol and because glucagon is used to treat mild hypoglycaemia, it is essential to determine whether ethanol will impair the effectiveness of glucagon to increase glucose, which may impair the effectiveness of the dual hormone treatment in preventing hypoglycaemia. The purpose of this study is to determine, whether ethanol influences the glucose response to subcutaneous glucagon during mild hypoglycaemia. The investigators hypothesize that prior evening ethanol consumption does not reduce the effect of a glucagon bolus to raise plasma glucose compared with no prior ethanol consumption. The study aims: To determine the late effects of ethanol on the efficacy of subcutaneous glucagon to restore plasma glucose after an episode of mild hypoglycemia. To determine the late effects of ethanol on the counter-regulatory hormones and hypoglycaemia awareness during mild hypoglycaemia A double-blinded placebo-controlled study will be conducted. Participants will serve as their own controls. Eligible participants will after an informed consent complete two study visits, one with and one without ethanol consumption, in a random order. On each study visit, participants are induced a insulin induced hypoglycemia, seven-eight hours after a meal with or without ethanol. Once plasma glucose is below 3.9 mmol/l, a subcutaneous injection of 100 mcg glucagon is administered. Two hours later a second bolus is administered.

Official Title
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The Late Effects of Ethanol Intake on the Glucose Response to Subcutaneous Glucagon in Type 1 Diabetes

Conditions
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Hypoglycemia, Diabetes Mellitus, Type 1

Intervention / Treatment
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* Dietary Supplement: Alcohol
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 70 years T1D ≥ 3 year BMI 20-28 kg/m2 CSII ≥ 1 year Caucasian origin Hypoglycaemia awareness (assessed by Gold, Clarke and Pedersen-Bjergaard methods) Use of carbohydrate counting and the insulin pump bolus calculator for all meals Ethanol exposure once within 1 year consisting of at least 4 drinks (1 drink contains 12 gram ethanol) within four hours Exclusion Criteria: Allergy or intolerance to lactose or Glucagen®(Novo Nordisk, Bagsværd, DK) Allergy for ethanol or any food ingredients that will be used in the study. Impaired renal function (eGFR < 60 ml/min/1.73m2) Liver disease with ALAT > 2.5 times the upper limit of the reference interval Gastropareses (beat-beat variation < 10 beats per min and/or orthostatic systolic blood pressure > 20 mmHg) Insomnia, sleep apnoea or any troubles with sleeping that according to the investigator's assessment makes the individual unsuitable for study participation. Aldehyde dehydrogenase deficiency as determined by a screening questionnaire Unable to refrain from the consumption of ethanol at least 24 hours prior to study start History of drinking problems or alcoholism, regardless of whether active or in remission. Use of benzodiazepines or barbiturates or opiates or other central nervous system depressant drugs that could act synergistically with ethanol to lower the level of consciousness History of drug abuse Current participation in another diabetes-related clinical trial that, in the judgment of the principle investigator, will compromise the results of the study or the safety of the subject. Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start Use of medications that are known to cause QT interval prolongation Presence of pheochromocytoma Other concomitant medical or psychological condition that according to the investigator's assessment makes the individual unsuitable for study participation Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods. Females who have different basal insulin pattern depending on their menstrual cycle. Inability to understand the individual information and to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ethanol<br>Drinking a cocktail of ethanol (0.8 g ethanol per kg body weight), diet lemonade and water of 1:1:1 (volume distribution). | Dietary Supplement: Alcohol<br> <br> * Other names: Cocktail;|
| Placebo Comparator: Non-ethanol<br>Drinking a cocktail of diet lemonade and water of 1:2 (volume distribution). | Dietary Supplement: Placebo<br> <br> * Other names: Mocktail;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in plasma glucose | The primary endpoint is difference in increase in plasma glucose value after the first injection of 100 µg s.c. glucagon on study nights with ethanol vs. study nights without ethanol consumption. | 0-120 min after the first glucagon injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma glucose | Maximal plasma glucose after the first and second glucagon injection | 0-240 min after the first glucagon injection | 
| Increase in plasma glucose | Increase in plasma glucose caused by the second glucagon injection. | 0-120 min after the second glucagon injection | 
| Total AUC(0-120) | Total area under the glucose curve from 0-120 minutes after each glucagon injection | 0-240 min after the first glucagon injection | 
| PI-AUC(0-120) | positive incremental area under the glucose curve from 0-120 minutes after each glucagon injection | 0-240 min after the first glucagon injection | 
| Tmax | Time-to-peak glucose value after each glucagon injection glucagon injection | 0-240 min after the first glucagon injection | 
| Time above 4.0mM | Duration of glucose above 4.0 mmol/l after first and second glucagon injection | 0-240 min after the first glucagon injection | 
| Time above baseline | Duration of glucose above baseline after first and second glucagon injection | 0-240 min after the first glucagon injection | 
| Rescue rates | Numbers of first and second glucagon injections that raises PG > 4.9 mmol/l | 0-240 min after the first glucagon injection | 
| Hyperglycemia rates | Number of first and second glucagon injections that raises PG > 7.1 mmol/l | 0-240 min after the first glucagon injection | 
| Changes in plasma ketone bodies, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in plasma ketone bodies, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in plasma glucagon, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in plasma glucagon, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in insulin, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in insulin, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in growth hormones, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in growth hormones, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in serum corticole, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in serum corticole, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in plasma ethanol, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in plasma ethanol, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in free fatty acids, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in free fatty acids, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Changes in triglycerides, measured as area under the curve |  | 0-240 min after the first glucagon injection | 
| Changes in triglycerides, measured as incremental peak |  | 0-240 min after the first glucagon injection | 
| Average in blood pressure |  | 0-240 min after the first glucagon injection | 
| Average heart rate |  | 0-240 min after the first glucagon injection | 
| Intensity of hypoglycemia | Average changes in Edinburgh Hypoglycaemia Scale over time during insulin and glucagon phase | 0-240 min after the first glucagon injection | 
| Cognitive impairment | Average scores in cognitive test 30 min before each glucagon injection. | 0-240 min after the first glucagon injection | 
| Side effects | Average visual analogue scale score from 0-180 min for nausea and headache after glucagon injection | 0-240 min after the first glucagon injection | 
| Incidence of vomiting | Incidence of vomiting after 0-4 hours after each glucagon injection. | 0-240 min after the first glucagon injection | 
| Meal induced glucose excursion | Total and incremental area under the glucose curve from 0-120 and 0-240 min after eating the mixed meal | 0-3 hours after meal | 
| Meal induced hormonal changes | Total and incremental area under the glucose curve from 0-120 and 0-240 min after eating the mixed meal | 0-3 hours after meal | 
| Nocturnal changes in plasma glucose | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Nocturnal changes in corticol | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Nocturnal changes in growth hormone | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Nocturnal changes in ketones | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Nocturnal changes in ethanol | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Nocturnal changes in glucagon | Area under the curve during sleep | 0-6 hours after start of sleep | 
| Difference between the first second glucagon injection and between both study visits in peak change plasma glucose |  | 0-240 min after the first glucagon injection | 
| Difference between glucagon injections on both study visits in positive incremental area under the glucose curve from 0-120 minutes |  | 0-240 min after the first glucagon injection | 
| Difference between glucagon injections on both study visits in total area under the glucose curve from 0-120 minutes |  | 0-240 min after the first glucagon injection | 
| Difference between glucagon injections on both study visits in time-to-peak glucose value |  | 0-240 min after the first glucagon injection | 
| Difference between glucagon injections on both study visits in duration of glucose above 4.0 mmol/l after first and second glucagon injection |  | 0-240 min after the first glucagon injection | 
| Difference between glucagon injections on both study visits in duration of glucose above baseline after first and second glucagon injection |  | 0-240 min after the first glucagon injection | 
| Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - Mean absolute relative difference (MARD) values of glucose sensors compared with YSI from 7 PM- 8 AM. | Intentions to treat analysis | 0-10 hours after meal | 
| Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - Precision absolute relative difference (PARD) 120 min before and 120 after each glucagon injection. | Intentions to treat analysis | 0-10 hours after meal | 
| Difference in glucose sensor data on study night with alcohol vs. study night without alcohol - MARD values between glucose sensors 0-120 minutes after each glucagon injection. | Intentions to treat analysis | 0-10 hours after meal | 
| Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in range (glucose sensor value =4.0-10.0mmol/l) | Intentions to treat analysis | 0-2 days after the first glucagon injection | 
| Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in hypoglycaemia (glucose sensor value < 4.0 mmol/l) | Intentions to treat analysis | 0-2 days after the first glucagon injection | 
| Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Time in hyperglycaemia (glucose sensor value >10.0mmol/l) | Intentions to treat analysis | 0-2 days after the first glucagon injection | 
| Difference in glucose sensor data within 2 days after study night with alcohol vs. study night without alcohol - Number of hypoglycaemia episodes (glucose sensor value < 4.0 mmol/l) | Intentions to treat analysis | 0-2 days after the first glucagon injection | 
| Difference in glucose sensor data between the study period with and without alcohol - Clarke- Error Grid analysis for both sensors compared with YSI during study visit | Intentions to treat analysis | -2 to 4 days after study visits | 
| Difference in glucose sensor data between the study period with and without alcohol - PARD values from day 1-7 | Intentions to treat analysis | -2 to 4 days after study visits | 
| Difference in glucose sensor data between the study period with and without alcohol - PARD values <4.0 mmol/L from day 1-7 | Intentions to treat analysis | -2 to 4 days after study visits | 
| Difference in glucose sensor data between the study period with and without alcohol - PARD values 4.0-10.0 mmol/L from day 1-7 | Intentions to treat analysis | -2 to 4 days after study visits | 
| Difference in glucose sensor data between the study period with and without alcohol PARD values >10.0 mmol/L from day 1-7 | Intentions to treat analysis | -2 to 4 days after study visits | 
| Difference in glucose sensor data between the study period with and without alcohol - Number of hypoglycaemia episodes (glucose sensor value < 4.0 mmol/l) | Intentions to treat analysis | -2 to 4 days after study visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucagon, Ethanol