The Effect of Insulin-induced Hypoglycaemia on Gut-derived Glucagon Secretion (Px-Hypo)

Study Overview
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Brief Summary
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The overall objective of this study is to investigate whether hypoglycaemia (the most potent stimulus of pancreatic glucagon secretion) affects the secretion of gut-derived glucagon in totally pancreatectomized patients.

Detailed Description
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The investigators want to assess the plasma glucagon response to insulin-induced hypoglycaemia in totally pancreatectomised patients and at the same time evaluate whether hypoglycaemia affects a range of other products from endocrine cells in the gastrointestinal tract including ghrelin, gastrin, cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP), GLP-1, glucagon-like peptide-2 (GLP-2), oxyntomodulin and peptide YY (PYY). Furthermore the investigators will evaluate how hypoglycaemia in these patients affects other counter-regulatory mechanisms including plasma responses of the hormones adrenaline, noradrenaline, growth hormone and cortisol as well as the rate of gastric emptying rate (which under normal circumstances accelerates during hypoglycaemia) during an oral glucose tolerance test (OGTT).

Official Title
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The Effect of Insulin-induced Hypoglycaemia on Gut-derived Glucagon Secretion

Conditions
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Diabetes After Total Pancreatectomy

Intervention / Treatment
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* Other: Oral glucose tolerance test
* Other: Clamp experiment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pancreatectomised patients Caucasian above 30 years of age who have undergone total pancreatectomy Blood haemoglobin >7.0 mmol/l for males and >6.5 mmol/l for females Non-diabetic control subjects Normal fasting plasma glucose and normal HbA1c (according to the World Health Organization (WHO) criteria) Normal blood haemoglobin Caucasian above 30 years of age BMI (body mass index) 17-30 Informed consent Exclusion Criteria: Pancreatectomised patients Pancreatectomy within the last 3 months Ongoing chemotherapy or chemotherapy within the last 3 months Previous or ongoing treatment with GLP-1 receptor agonists or dipeptidyl peptidase 4 (DPP-4) inhibitors Inflammatory bowel disease Gastrointestinal resection (other than the gastro-duodenectomy performed in connection with total pancreatectomy) and/or ostomy Nephropathy (eGFR<60 and/or albuminuria) Known liver disease (excluding non-alcoholic fatty liver disease) and/or serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >3 × normal values) Severe lung disease Pregnancy and/or breastfeeding Age above 85 years Uncontrolled hypertension and/or significant cardiovascular disease Any condition that the investigator feels would interfere with trial participation Non-diabetic control subjects Diabetes or prediabetes (according to WHO criteria) First-degree relatives with diabetes Inflammatory bowel disease Gastrointestinal resection and/or ostomy Nephropathy (serum creatinine >150 µmol/l and/or albuminuria) Known liver disease (excluding non-alcoholic fatty liver disease) and/or serum ALAT and/or serum ASAT >3 × normal values) Severe lung disease Pregnancy and/or breastfeeding Age above 85 years Uncontrolled hypertension and/or significant cardiovascular disease Any condition that the investigator feels would interfere with trial participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 12 totally pancreatectomized patients and 12 healthy control subjects
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Totally pancreatectomized patients<br>Oral glucose tolerance test + insulin-induced hypoglycaemic clamp followed by an oral glucose tolerance test | Other: Oral glucose tolerance test<br>* 50 grams OGTT<br>Other: Clamp experiment<br>* insulin-induced hypoglycaemic clamp followed by an 50 grams OGTT<br>|
| Experimental: Healthy controls<br>Oral glucose tolerance test + insulin-induced hypoglycaemic clamp followed by an oral glucose tolerance test | Other: Oral glucose tolerance test<br>* 50 grams OGTT<br>Other: Clamp experiment<br>* insulin-induced hypoglycaemic clamp followed by an 50 grams OGTT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| p-glucagon | Plasma glucagon excursions measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90, 105, 120, 135, 150, 165, 180, 210, 240 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| p-glucose | plasma glucose excursions measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90, 105, 120, 135, 150, 165, 180, 210, 240 minutes | 
| GIP, GLP-1, GLP-2, GIP, oxyntomodulin, ghrelin, peptide YY, gastrin | excursions in Gut hormones measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90, 105, 120, 135, 150, 165, 180, 210, 240 minutes | 
| catecholamines | p-adrenaline and p-noradrenaline, excursions measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90 minutes | 
| cortisol | p-cortisol excursions measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90 minutes | 
| growth hormone | p-growth hormone excursions measured as incremental area under the curve (iAUC) | -30, -15, 0, 15, 40, 50, 60, 70, 80, 90 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucagon