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

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.

Study Overview

• Status: Recruiting
• Conditions: Autonomic Function
• Intervention / Treatment: Other: Oral glucose tolerance test with double-tracer dilution and atropine infusion; Other: Oral glucose tolerance test with double-tracer dilution and saline infusion (placebo)

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).

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Martin Heni, MD; Phone Number: +4973150044505; Email: martin.heni@uniklinik-ulm.de
• Study Contact Backup: Name: Andrea Geissler; Email: andrea.geissler@uniklinik-ulm.de

Study Locations

• Germany
  • Ulm, Germany, 89081
    • Recruiting
    • Ulm University Hospital
    • Contact: Sabrina Wangler; Phone Number: +4973150044782; Email: sabrina.wangler@uniklinik-ulm.de
    • Contact: Andrea Geissler; Email: andrea.geissler@uniklinik-ulm.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline infusion	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 contains 75 gram glucose, enriched with [U-13C6]-glucose.
Experimental: Atropine Infusion; 5 µg x kg fat free mass-1 x h-1	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 contains 75 gram glucose, enriched with [U-13C6]-glucose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose tolerance	Effect of parasympathetic blockade with atropine versus placebo on glucose tolerance assessed as area under the glucose curve (0-120 minutes) and glucose levels at timepoint 120 minutes during the 75 g oral glucose tolerance test.	120 minutes
Insulin Sensitivity	Effect of parasympathetic blockade with atropine versus placebo on insulin sensitivity assessed from glucose and insulin measurements during the 75 g oral glucose tolerance test.	120 minutes
Insulin Secretion	Effect of parasympathetic blockade with atropine versus placebo on insulin secretion assessed from glucose and insulin/C-peptide measurements during the 75 g oral glucose tolerance test.	180 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipolysis	Effect of parasympathetic blockade with atropine versus placebo on the suppression of lipolysis during a 75 g oral glucose tolerance test.	120 minutes
Amino Acid Metabolism	Effect of parasympathetic blockade with atropine versus placebo on amino acid metabolism assessed by amino acid measurements during the 75 g oral glucose tolerance test.	120 minutes
Bile acid metabolism	Effect of parasympathetic blockade with atropine versus placebo on bile acid metabolism assessed by bile acid measurements during the 75 g oral glucose tolerance test.	120 minutes
Substrate oxidation	Effect of parasympathetic blockade with atropine versus placebo on substrate oxidation assessed by indirect calorimetry at timepoints -110 Minutes, 30 Minutes, 60 Minutes and 120 Minutes during the 75 g oral glucose tolerance test.	230 Minutes
Incretin secretion	Effect of parasympathetic blockade with atropine versus placebo on incretin secretion during the 75 g oral glucose tolerance test.	120 minutes
Sex differences	Explore sex differences in the effect of parasympathetic blockade with atropine versus placebo in the mentioned outcome measures.	180 minutes
Autonomic nervous system	Effect of parasympathetic blockade with atropine versus placebo on the autonomic nervous system assessed by heart rate variability during the 75 g oral glucose tolerance test.	180 minutes
Gastric emptying	Effect of parasympathetic blockade with atropine versus placebo on gastric emptying during the 75 g oral glucose tolerance test.	120 minutes
Blood coagulation parameters	Influence of of parasympathetic blockade with atropine versus placebo on blood coagulation parameters. This is assessed through global coagulation tests and single coagulation factors.	120 Minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating peptides	Effect of parasympathetic blockade with atropine versus placebo on circulating proteins/peptides during the 75 g oral glucose tolerance test.	120 minutes
Lipids and lipoproteins	Effect of parasympathetic blockade with atropine versus placebo on lipids and lipoproteins assessed by lipid measurements during the 75 g oral glucose tolerance test.	120 minutes
Metabolites	Effect of parasympathetic blockade with atropine versus placebo on circulating metabolites during the 75 g oral glucose tolerance test.	120 minutes
Immune cell composition	Effect of parasympathetic blockade with atropine versus placebo on immune cell composition assessed by flow cytometry during the 75 g oral glucose tolerance test.	120 minutes
Insulin clearance	Effect of parasympathetic blockade with atropine versus placebo on insulin clearance assessed from insulin and C-peptide measurements during the 75 g oral glucose tolerance test.	120 minutes
Metabolic flexibility	Effect of parasympathetic blockade with atropine versus placebo on metabolic flexibility assessed by the change in respiratory quotient during the 75 g oral glucose tolerance test.	180 minutes

Collaborators and Investigators

• Sponsor: University of Ulm
• Investigators: Principal Investigator: Martin Heni, MD, Ulm University Hopital

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: March 28, 2025
• First Submitted That Met QC Criteria: March 28, 2025
• First Posted (Actual): April 4, 2025

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: July 4, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: insulin sensitivity; sex differences; autonomic nervous system; metabolism; insulin secretion; endogenous glucose production; high risk population; parasympathetic transmission; brain periphery crosstalk
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Anti-Arrhythmia Agents; Adjuvants, Anesthesia; Respiratory System Agents; Anti-Asthmatic Agents; Bronchodilator Agents; Muscarinic Antagonists; Cholinergic Antagonists; Cholinergic Agents; Parasympatholytics; Mydriatics; Atropine
• Other Study ID Numbers: 467/2024; 101125605 (Other Grant/Funding Number: European Research Council)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No