The Insulin Response to the Gut Hormone GIP After Near-normalisation of Plasma Glucose in Patients With Type 2 Diabetes (GA-16)

The Insulin Response to the Gut Hormone GIP After Near-normalisation of Plasma Glucose in Patients With Type 2 Diabetes

Beta Cell Responsiveness to Glucose-dependent Insulinotropic Polypeptide Following Near-normalisation of Plasma Glucose in Overweight Patients With Type 2 Diabetes

The investigators hypothesise that the insulinotropic effect of endogenous GIP is improvable in patients with type 2 diabetes after three weeks of near-normalisation of plasma glucose. To test this hypothesis, a randomised, placebo-controlled, double-blinded, crossover study employing a GIP receptor antagonist, will be carried out. Fifteen overweight (body mass index (BMI) > 25 kg/m2) dysregulated (HbA1c >/= 59 mmol/mol and treatment with metformin or >53 mmol/mol and treatment with metformin + add/on) patients with type 2 diabetes will attend two experimental days followed by a three-week-four-week period of plasma glucose near-normalisation (achieved by standard treatment of type 2-diabetes), followed by another two experimental days. On experimental days, patients will receive an infusion of GIP receptor antagonist or placebo during a 75 g oral glucose tolerance test. The primary endpoint is changes in levels of C-peptide divided by changes in levels of plasma glucose and secondary endpoints include changes in circulating levels of C-peptide, insulin, glucose, GIP, glucagon-like peptide 1 (GLP-1), glucagon and markers of bone turnover as well as indices of beta cell function. Furthermore, gastric emptying rate will be assessed.

Glucose-dependent insulinotropic polypeptide (GIP) exerts a strong insulinotropic effect in healthy individuals following meal ingestion. Studies in patients with type 2 diabetes have shown that the insulinotropic effect of exogenous GIP is severely reduced and recent data from the investigators' group suggest that the insulinotropic effect of endogenous GIP is compromised too. Interestingly, after near-normalisation of plasma glucose in patients with type 2 diabetes (continuing metformin and by using empagliflozin + intensive insulin treatment), the insulinotropic effect of exogenous GIP can be restored. The investigators have previously observed a similar restoration of the beta cell secretory response to exogenous GIP after therapy with DPP-4 inhibitors, the effects of which rely on preservation of incretins. The investigators hypothesise that the insulinotropic effect of endogenous GIP is improvable in patients with type 2 diabetes after three weeks-four weeks of near-normalisation of plasma glucose. To test this hypothesis, a randomised, placebo-controlled, double-blinded, crossover study employing a GIP receptor antagonist, will be carried out. Fifteen overweight (body mass index (BMI) > 25 kg/m2) dysregulated (HbA1c >/= 59 mmol/mol and treatment with metformin or >53 mmol/mol and treatment with metformin + add/on) patients with type 2 diabetes will attend two experimental days followed by a three-week/four-week period of plasma glucose near-normalisation (achieved by standard treatment of type 2-diabetes), followed by another two experimental days. On experimental days, patients will receive an infusion of GIP receptor antagonist or placebo during a 75 g oral glucose tolerance test. The primary endpoint is changes in levels of C-peptide divided by changes in levels of plasma glucose and secondary endpoints include changes in circulating levels of C-peptide, insulin, glucose, GIP, glucagon-like peptide 1 (GLP-1), glucagon and markers of bone turnover as well as indices of beta cell function. Furthermore, gastric emptying rate will be assessed. Glucose-lowering drugs based on the effects of another incretin hormone, GLP-1, are successfully being used in the treatment of type 2 diabetes. However, due to the reduced insulinotropic effect of GIP in patients with inadequately controlled type 2 diabetes, treatments based on GIP receptor activation are not on the market. Recently however, a dual GLP-1/GIP receptor agonist has shown promising phase II results. The importance of GIP receptor engagement for the efficacy of these compounds remains to be shown. The present project will answer to what extent the insulinotropic effect of endogenous GIP in patients with type 2 diabetes can be restored following near-normalisation of plasma glucose and thus, provide important perspectives on how to further advance the development of GIP-based therapeutics.

The primary endpoint is beta cell sensitivity to glucose as assessed by the C-peptide response to a 75 g-oral glucose tolerance test (OGTT) (as assessed by baseline-subtracted area under the curve (bsAUC)) divided by levels of plasma glucose (as assessed by bsAUC) during GIP(3-30)NH2 infusion compared to placebo before and after near-normalisation of plasma glucose.

Inclusion Criteria: Type 2 diabetes Metformin treatment Haemoglobin A1c (HbA1c) I. >/= 59 mmol/mol in case the diabetes treatment is only metformin II. 53-75 mmol/mol in case the diabetes treatment is metformin and add-on therapy Body Mass Index (BMI) > 25 kg/m2 Age > 18 years Caucasian Normal haemoglobin levels Exclusion Criteria: Treatment with GLP-1-receptor agonist Any treatment that cannot be paused for 12 hours Diabetes duration more than 20 years Weekly alcohol intake of more than 14 units for men or 7 units for women of alcohol (of 12 g) or narcotics abuse Liver disease Kidney disease (estimated glomerular filtration rate, eGFR < 60 ml/min/1,73 m2) Unusual dietary preferences or planned weight loss within the duration of the study Any other condition that in the opinion of the responsible investigators is disqualifying. For women I. Current or planned pregnancy for the duration of the study II. Positive pregnancy test at the screening or any of the experimental days III. Women who are currently breastfeeding

Gasbjerg LS, Helsted MM, Hartmann B, Jensen MH, Gabe MBN, Sparre-Ulrich AH, Veedfald S, Stensen S, Lanng AR, Bergmann NC, Christensen MB, Vilsboll T, Holst JJ, Rosenkilde MM, Knop FK. Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals. Diabetes. 2019 May;68(5):906-917. doi: 10.2337/db18-1123. Epub 2019 Jan 9.

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals