The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea (HNF1A-Clamp)

The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea

The Effect of GIP and GLP-1 on Insulin and Glucagon Secretion in Patients With HNF1A-diabetes Treated With or Without Sulphonylurea

The most prevalent monogenetic diabetic subtype is named maturity onset diabetes of the young type (MODY3) or hepatocyte nuclear factor 1α (HNF1A)-diabetes. The aim of this study is to evaluate the effects of supra-physiological levels of GIP and GLP-1, respectively, on insulin and glucagon secretion at fasting plasma glucose (FPG) and "post-prandial" PG levels (1.5 × FPG) in patients with HNF1A-diabetes and matched healthy controls treated with or without a low dose of glimepiride (sulphonylurea). In addition, we will evaluate the maximal insulin and glucagon secretory capacity in both groups.

A total of 6 experimental days will be performed. The following is an outline of an experimental day: Participants will meet after a 10-hour fast. A tablet of glimepiride 1.0 mg or placebo will be administered 90 minutes before the initiation of the experiment (-90 minutes) The mean FPG will be calculated from blood samples -105, -100 and -90 minutes. Two intravenous cannulas will be inserted in a cubital vein of each arm. One intravenous cannula will be used for infusions of glucose, arginine and GIP and the other will be used to collect venous blood. The forearm from which blood samples are drawn will be placed in a heating pad (50°C) throughout the experiment for arterialisation of venous blood. At time 0 minutes, a glucose clamp will be established at the FPG level for 60 minutes and hereafter a post-prandial clamp period of 1.5 × FPG for another 60 minutes. At time 120 minutes, a bolus of 5g of L-arginine (given as 50% arginine HCl) will be infused during 30 seconds. The post-prandial clamp will be maintained for another 10 minutes until time 130 minutes to prevent reactive hypoglycaemia. Throughout the experiment (0-130 minutes) a continuous infusion of either GIP (1.5 pmol/kg/min), GLP-1 (0.5 pmol/kg/min) or placebo (saline) will be administered. During the experiment PG will be kept stable by a continuous 20%-glucose infusion. The rate of infusion will be regulated according to PG determined by bed-site measurements every 5 minutes. After 60 minutes, a post-prandial clamp will be established by a bolus infusion over one minute using 50%-glucose to target 1.5 × FPG (the amount of glucose to be administered will calculated as follows: (1.5 × FPG - FPG) × 35 mg glucose × weight in kilogram).

Maturity-Onset Diabetes of the Young, Type 3, Glucose-dependent insulinotropic peptide, Glucagon-like-peptide 1, Dipeptidyl peptidase 4, Glimepiride, Sulphonylurea, Glucose clamp, Hepatocyte nuclear factor 1 alpha

Incremental area under the curve (iAUC) for insulin (measured as C-peptide) at time 0-60 minutes, time 60-120 minutes and time 0-120 minutes

Incremental area under the curve (iAUC) for plasma glucagon at time 0-60 minutes, time 60-120 minutes and time 0-120 minutes

Participants Ten patients with HNF1A-diabetes and ten matched healthy controls will be recruited. Different inclusion and exclusion criteria applies for the two groups: Inclusion criteria for HNF1A-patients Patients with HNF1A-diabetes verified by genetic testing Patients treated with diet or sulphonylurea monotherapy Normal haemoglobin (males 8.3-10.5 mmol/l, females 7.3-9.5 mmol/l) Informed consent Exclusion criteria for HNF1A-patients Nephropathy (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 and/or albuminuria) Liver disease (serum alanine aminotransferase (ALT) and/or serum aspartate aminotransferase (AST) above 2 × normal values) Pregnancy or breastfeeding Inclusion criteria for healthy controls FPG ≤6 mmol/l and glycated haemoglobin (HbA1c) ≤43 mmol/mol Normal haemoglobin as defined above Age ≥18 years Informed consent Exclusion criteria for healthy controls No family history of type 1 or type 2 diabetes Nephropathy (defined above) Liver disease (defined above) Pregnancy or breastfeeding

Christensen AS, Haedersdal S, Storgaard H, Rose K, Hansen NL, Holst JJ, Hansen T, Knop FK, Vilsboll T. GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1alpha Mutation Carriers. Diabetes. 2020 Sep;69(9):1989-2002. doi: 10.2337/db20-0074. Epub 2020 Jun 9.