Pathophysiological Implications of the Incretin Hormones in Patients With Liver Disease With and Without Diabetes

Study Overview
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Brief Summary
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The main objective of this study is to analyze the pathophysiological implications of glucagon and the incretin hormones in patients with liver disease (Non alcoholic fatty liver disease (NAFLD) or cirrhosis) with and without diabetes compared with healthy controls. The present study will contribute significantly to the understanding of the pathophysiology of liver disease and glucose metabolism. The final goal is that the results could pave the way for new treatment modalities for patients with liver disease.

Detailed Description
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Comparison of of insulin secretion (Area Under the Curve (AUC)) during the experimental days. Furthermore a comparison of GIP, GLP1 and glucagon responses as well as plasma glucose levels.

Official Title
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Pathophysiological Implications of the Incretin Hormones in Patients With Liver Disease With and Without Diabetes

Conditions
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Non Alcoholic Fatty Liver Disease, Type 2 Diabetes, Liver Cirrhosis

Intervention / Treatment
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* Other: OGTT
* Other: IIGI


Participation Criteria
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Eligibility Criteria
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I) Group 1: NAFLD patients with normal glucose tolerance Inclusion criteria NAFLD verified by a liver biopsy Caucasian >18 years of age Negative islet cell (ICA) and glutamic acid decarboxylase 65 (GAD65) autoantibodies Normal 75-g OGTT as specified in the WHO Criteria Normal haemoglobin and blood pressure (BP) Written informed consent II) Group 2: NAFLD patients with type 2 diabetes Inclusion criteria NAFLD verified by liver biopsy T2DM according to the WHO Criteria Caucasian >18 years of age Negative ICA and GAD65, normal haemoglobin, normal BP Written informed consent III) Group 3: NAFLD patients without type 2 diabetes Inclusion criteria NAFLD verified by liver biopsy Caucasian >18 years of age Normal 75-g OGTT Negative ICA and GAD65-autoantibodies Normal haemoglobin and BP Written informed consent IV) Group 4: Cirrhosis with or without type 2 diabetes Inclusion criteria Liver cirrhosis verified by liver biopsy Caucasian > 18 years of age Negative ICA and GAD65-autoantibodies Normal haemoglobin and BP Written informed consent V) Group 5: Healthy controls Inclusion criteria Caucasian >18 years of age Normal 75-g OGTT according to the WHO Criteria Negative ICA and GAD65-autoantibodies Normal haemoglobin and BP Written informed consent Exclusion criteria (all groups) Other known liver disease - viral hepatitis, hereditary haemochromatosis, autoimmune liver disease, alpha-1 trypsin deficiency, Wilson disease, drug induced liver Injury (DILI) Treatment with medications that cannot be discontinued for 12 hours Unwillingness to participate in protocols Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NAFLD<br>Non alcoholic fatty liver disease without type 2 diabetes | Other: OGTT<br>* 50g waterfree glucose dissolved in 300 ml water consumed over 5 min.<br>* Other names: Waterfree glucose, The Pharmacy of the capital region;Other: IIGI<br>* iso glycemic intravenous (iv) glucose infusion (IIGI) with 20% glucose<br>* Other names: Glucose infusion, 20%;|
| NAFLD+T2D<br>Non alcoholic fatty liver disease with type 2 diabetes | Other: OGTT<br>* 50g waterfree glucose dissolved in 300 ml water consumed over 5 min.<br>* Other names: Waterfree glucose, The Pharmacy of the capital region;Other: IIGI<br>* iso glycemic intravenous (iv) glucose infusion (IIGI) with 20% glucose<br>* Other names: Glucose infusion, 20%;|
| T2D<br>Type 2 diabetics without non alcoholic fatty liver disease | Other: OGTT<br>* 50g waterfree glucose dissolved in 300 ml water consumed over 5 min.<br>* Other names: Waterfree glucose, The Pharmacy of the capital region;Other: IIGI<br>* iso glycemic intravenous (iv) glucose infusion (IIGI) with 20% glucose<br>* Other names: Glucose infusion, 20%;|
| cirrhosis<br>Patients with liver cirrhosis | Other: OGTT<br>* 50g waterfree glucose dissolved in 300 ml water consumed over 5 min.<br>* Other names: Waterfree glucose, The Pharmacy of the capital region;Other: IIGI<br>* iso glycemic intravenous (iv) glucose infusion (IIGI) with 20% glucose<br>* Other names: Glucose infusion, 20%;|
| Kontrol groups<br>Healthy control subjects | Other: OGTT<br>* 50g waterfree glucose dissolved in 300 ml water consumed over 5 min.<br>* Other names: Waterfree glucose, The Pharmacy of the capital region;Other: IIGI<br>* iso glycemic intravenous (iv) glucose infusion (IIGI) with 20% glucose<br>* Other names: Glucose infusion, 20%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incretin effect | The difference in insulin responses, as assessed by the area under curve (AUC) for plasma insulin and C-peptide concentrations, during the two different glucose stimuli: Oral glucose tolerance test (OGTT) and isoglycemic iv glucose infusion in NAFLD patients with and without diabetes, and cirrhotic patients compared to healthy control subjects | pre dose 0,10, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180, 240 min post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Glucagon like peptide 1 (GLP-1) response | Comparing GLP-1 responses of the different experimental days, compared to healthy control subjects. | pre dose 0,10, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180, 240 min post dose | 
| Plasma Glucose-dependent insulinotropic peptide (GIP) response | Comparing GIP responses of the different experimental days, compared to healthy control subjects. | pre dose 0,10, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180, 240 min post dose | 
| Plasma glucagon response | Comparing glucagon responses of the different experimental days, compared to healthy control subjects. | pre dose 0,10, 20, 30, 40, 50, 60, 75, 90, 120, 150, 180, 240 min post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, Incretin hormones