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

Overview

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.

Detailed description

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).

Interventions

• Other Oral glucose tolerance test with double-tracer dilution and atropine infusion
  Subjects will undergo a 75 g oGTT (180 min) combined with a double tracer dilution. The double-tracer dilution technique will be used to quantify endogenous glucose production, glucose appearance and disappearance rate. \[6,6-2H\]glucose will be infused for a total of 300 minutes, while the infusion will start 120 minutes prior the oGTT and will last until the end of the oGTT. Atropine infusion will be administered 20 minutes before the start of the oGTT. The drink consumed at time point 0 min c
• Other Oral glucose tolerance test with double-tracer dilution and saline infusion (placebo)
  Subjects will undergo a 75 g oGTT (180 min) combined with a double tracer dilution. The double-tracer dilution technique will be used to quantify endogenous glucose production, glucose appearance and disappearance rate. \[6,6-2H\]glucose will be infused for a total of 300 minutes, while the infusion will start 120 minutes prior the oGTT and will last until the end of the oGTT. Saline infusion will be administered 20 minutes before the start of the oGTT. The drink consumed at time point 0 min con

Primary outcome measures

• Glucose tolerance [Time frame: 120 minutes]
• Insulin Sensitivity [Time frame: 120 minutes]
• Insulin Secretion [Time frame: 180 minutes]

Secondary outcome measures (9)

• Lipolysis [Time frame: 120 minutes]
• Gastric emptying [Time frame: 120 minutes]
• Amino Acid Metabolism [Time frame: 120 minutes]
• Bile acid metabolism [Time frame: 120 minutes]
• Substrate oxidation [Time frame: 230 Minutes]
• Incretin secretion [Time frame: 120 minutes]
• Sex differences [Time frame: 180 minutes]
• Autonomic nervous system [Time frame: 180 minutes]
• Blood coagulation parameters [Time frame: 120 Minutes]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

Germany · 1 center

• Ulm University Hospital — Ulm

Identifiers

NCT: NCT06912048 · 467/2024 · 101125605

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗