The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover

The Effect of Lifestyle-induced Hepatic Steatosis on Glucagon-stimulated Amino Acid Turnover

Many patients with type 2 diabetes exhibit elevated plasma concentrations of the glucose-mobilising pancreatic hormone glucagon; i.e. hyperglucagonaemia. This contributes to the hyperglycaemic state of the patients and is considered an important component in the pathophysiology of type 2 diabetes; but the mechanisms underlying this phenomenon remain unclear. The liver constitutes the main target organ of glucagon, and studies have shown that hyperglucagonaemia goes hand in hand with hyperaminoacidaemia and that both are associated with non-alcoholic fatty liver disease (NAFLD), independently of the presence of type 2 diabetes. In line with this, several recent studies support the existence of a feedback-cycle between the liver and the pancreatic alpha cells, governed by circulating glucagon and amino acids. The investigators hypothesise that the presence of hepatic steatosis results in hepatic glucagon resistance at the level of amino acid turnover, i.e. impaired glucagon-induced suppression of circulating amino acid concentrations. If this hypothesis proves correct, it would establish build-up of fat in the liver as a core mechanism underlying hyperglucagonaemia and, since the hyperglucagonemia is at least partly responsible for the fasting hyperglycaemia, as an important contributor to the hyperglycaemia of type 2 diabetes.

Inclusion Criteria:

• Normal fasting plasma glucose and glycated haemoglobin (HbA1c) <42 mmol/mol
• Body mass index (BMI) between 18.5 and 25 kg/m2
• Haemoglobin >8.3 mmol/l
• Habitual diet in accordance with the Nordic Nutrition Recommendations
• Age between 20 and 65 years
• Oral and written informed consent

Exclusion Criteria:

• Diabetes
• First-degree relatives with diabetes
• Fasting plasma triacylglycerol indicating dyslipidemia (≥2 mmol/l)
• Nephropathy (estimated glomerular filtration rate (eGFR) <60 ml/min and/or microalbuminuria with an albumin to creatinine ratio of 30-300 μg/mg)
• Known liver disease and/or alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >2 × normal values
• Signs of liver fibrosis and/or steatosis evaluated by FibroScan (CAP value >2380 dB/m and/or kPa >65.0) and/or FIB-4 score (>1.45)
• >5% steatosis evaluated by MRI carried out before experimental Day A (see Methods)
• Use of medication
• Use of dietary protein supplementation or any other dietary supplements that cannot be paused during participation
• Excessive training habits, defined as >2 weekly strength and/or aerobic training sessions
• Pregnancy and/or breastfeeding
• Implanted metal objects incompatible with magnetic resonance imaging (MRI)
• Any condition that the investigator feels would interfere with trial completion