Understanding Individual Variability in Neuronal Signal Transmission to Target Organs in Health and Disease

Understanding Individual Variability in Neuronal Signal Transmission to Target Organs in Health and Disease

The goal of this clinical trial is to evaluate the influence of parasympathetic transmission from the brain to different metabolic organs. This transmission can be blocked with the muscarinic antagonist atropine.

Participants will undergo an oral glucose tolerance test combined with a double tracer dilution technique either with atropine infusion or placebo.

Healthy individuals and high-risk individuals will be compared to identify possible changes in signaling in high-risk groups. In addition, men and women will be included to take into account possible sex differences.

This research project aims to investigate to what extent the parasympathetic nervous system is responsible for the transmission of signals from the brain to peripheral organs. Furthermore, the study will investigate sex differences and differences between healthy and high-risk individuals on brain-derived coordination of postprandial signaling for metabolic control.

Therefore, parasympathetic blockade will be introduced by atropine infusion (on one day) versus saline infusion as placebo (on another day) in a randomized fashion. For safety reasons, only the participants will be blinded. Infusion will start 20 minutes before a 75 gram oral glucose tolerance test (oGTT) and last until the end of the 2h oGTT. The oGTT will introduce a postprandial state. Additionally, 1000 mg Paracetamol will be added to the solution to study gastric emptying.

This approach will be combined with a double-tracer dilution technique. Labeled glucose ([6,6-2H]glucose) will be infused 120 minutes before and during the oGTT (120 min) and will be used to address endogenous glucose production. The glucose drink from the oGTT will be enriched with [U-13C6]glucose to compute the glucose appearance rate (Ra). Basal endogenous glucose production will be calculated as well as post-load endogenous glucose production and rates of glucose disappearances (Rd).

Inclusion Criteria:

• Age: at least 18
• BMI: 20 - 24.9 kg/m2 (for the healthy groups) or more than 28 kg/m2 (for the overweight groups)
• For women: Hormonal contraception with a single-phase preparation (e.g. Nuvaring)
• Understanding and voluntarily signing an informed consent form prior to study-related examinations

Exclusion Criteria:

• Drug and/or alcohol abuse
• smoking
• Taking medication that affects blood sugar or addresses the central and/or autonomic nervous system (e.g. anti-epileptic drugs, beta blockers, dopamine agonists, antidepressants). Taking antihistamines.
• Pre-existing cardiac conditions
• Neurological pre-existing conditions
• Known cardiac arrhythmia
• Known allergies to ingredients, e.g. paracetamol and atropine
• Known narrow-angle glaucoma
• Known hyperthyroidism
• Known diseases of the urinary tract or prostate
• Pregnancy or breastfeeding
• At screening: Hb < 12 g/dl for women and Hb < 14 g/dl for men
• No consent to be informed about incidentally discovered pathological findings
• Any (clinical) condition which, in the opinion of the physician, could jeopardize the safety of the
• or would jeopardize the scientific success.
• Liver dysfunction
• Renal insufficiency