Relative Contribution of Brain Insulin Action for Postprandial Metabolism (BrainInsPPM)

The goal of this clinical trial is to clarify (i) the contribution of brain insulin action on regulation of systemic metabolism, (ii) sex-specific differences in the central regulation and (iii) the influence of the menstrual cycle in women.

Therefore, participants will undergo oral glucose tolerance tests combined with a double tracer dilution technique. This approach will be compared between days with insulin delivery to the brain as nasal spray and days with placebo spray.

Study Overview

• Status: Recruiting
• Conditions: Glucose Metabolism Disorders
• Intervention / Treatment: Other: Oral glucose tolerance test with double-tracer dilution and intranasal insulin spray; Other: Oral glucose tolerance test with double-tracer dilution and intranasal placebo spray

Detailed Description

This research project aims to investigate to what extent brain insulin action is responsible for the control of postprandial metabolism compared to direct effects of insulin in peripheral target tissues. Furthermore, the study will investigate sex differences and the influence of the menstrual cycle on brain-derived coordination of postprandial signaling for metabolic control.

Therefore, insulin action in the brain will be introduced by application of insulin as nasal spray (on one day) versus carrier solution as placebo nasal spray (on another day) in a randomized, blinded fashion. Spray administration will be performed 15 minutes before a 75 gram oral glucose tolerance test that will introduce a postprandial state. On placebo day, the known spillover of tiny amounts of nasal insulin into the systemic circulation will be mimicked by an appropriate i.v. insulin bolus. 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 (180 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). Using this approach, brain-derived regulation of postprandial metabolism including endogenous glucose production, glucose disappearance, insulin secretion, and secretion of proglucagon-cleavage products (incretins) will be examined.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Julia Hummel, Phd; Phone Number: +4973150044744; Email: julia.hummel@uniklinik-ulm.de
• Study Contact Backup: Name: Martin Heni, MD; Phone Number: +4973150044505; Email: martin.heni@uniklinik-ulm.de

Study Locations

• Germany
  • Ulm, Germany, 89081
    • Recruiting
    • Universityhospital Ulm
    • Contact: Julia Hummel, Phd; Phone Number: +4973150044744; Email: julia.hummel@uniklinik-ulm.de
    • Contact: Rebecca Spies, MD; Email: rebecca.spies@uniklinik-ulm.de

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• BMI < 24 kg/m2
• no known primary diseases
• no hormonal contraception

Exclusion Criteria:

• Alcohol or drug abuse
• Smoking
• At screening: Hb < 12 g/dl for women and Hb < 14 g/dl for men
• Any (clinical) condition that would endanger participant's safety or question scientific success according to a physician's opinion.

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
Experimental: Intranasal insulin spray; 160 Units of human insulin as nasal spray	Other: Oral glucose tolerance test with double-tracer dilution and intranasal insulin spray; 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. Intranasal insulin will be administered 15 minutes prior to the start of the OGTT. The drink consumed at time point 0 min contains 75 gram glucose, enriched with [U-13C6]-glucose.
Placebo Comparator: Placebo spray; Nasal spray containing placebo solution	Other: Oral glucose tolerance test with double-tracer dilution and intranasal placebo spray; 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. Placebo spray will be administered 15 minutes prior to the start of the OGTT. The drink consumed at time point 0 min contains 75 gram glucose, enriched with [U-13C6]-glucose. To mimic insulin spill-over from nasal spray into systemic circulation, an i.v. insulin bolus of 3 mU × kg-1. will be administered over ten minutes starting at time point -15 minutes on the placebo spray day. On the insulin spray day a comparable amount of saline will be infused.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endogenous glucose production	Effect of intranasal insulin versus placebo on endogenous glucose production assessed with Steele's non-steady state model during an oral glucose tolerance test combined with double-tracer dilution technique.	-120 minutes - 180 minutes during oral glucose tolerance test
Rate of glucose disappearance	Effect of intranasal insulin versus placebo on rate of glucose disappearance (Rd) assessed with Steele's non-steady state model during an oral glucose tolerance test combined with double-tracer dilution technique.	-120 minutes - 180 minutes during oral glucose tolerance test

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proglucagon cleavage products	Effect of intranasal insulin versus placebo on secretion of proglucagon cleavage products assessed by oral glucose tolerance test.	0-120 minutes during oral glucose tolerance test
Glucose tolerance	Effect of intranasal insulin 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.	0-120 minutes during oral glucose tolerance test
Whole-body insulin sensitivity	Effect of intranasal insulin versus placebo on whole-body insulin sensitivity, assessed from glucose and insulin measurements during the 75 g OGTT.	0-120 minutes during oral glucose tolerance test
Insulin secretion	Effect of intranasal insulin versus placebo on insulin secretion assessed from glucose and insulin/C-peptide measurements during the 75 g oral glucose tolerance test.	0-180 minutes during oral glucose tolerance test
Post-absorptive energy expenditure	Effect of intranasal insulin versus placebo on post-absorptive energy expenditure assessed by indirect calorimetry at timepoint 30 min and 180 min during an oral glucose tolerance test combined with double-tracer dilution technique.	30 minutes and 180 minutes during oral glucose tolerance test
Sex differences	Explore sex differences in the brain-derived regulation of postprandial metabolism during the 75 g oral glucose tolerance tests. Outcomes 1-7 will be compared between sexes.	-120 minutes - 180 minutes during oral glucose tolerance test
Menstrual cycle effects	Differences between the follicular and the luteal phase of the menstrual cycle in the brain-derived regulation of postprandial metabolism during the 75 g oral glucose tolerance tests: Outcomes 1-7 will be compared between the phases of the menstrual cycle.	-120 minutes - 180 minutes during oral glucose tolerance test
Autonomic nervous system activity	Effect of intranasal insulin versus placebo on autonomic nervous system activity assessed by heart rate variability using an 3-channel ECG at timepoint -15 min until 180 min during an oral glucose tolerance test combined with double-tracer dilution technique.	-15 minutes - 180 minutes during oral glucose tolerance test

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): January 1, 2026

Study Registration Dates

• First Submitted: February 8, 2024
• First Submitted That Met QC Criteria: March 5, 2024
• First Posted (Actual): March 6, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: menstrual cycle; insulin sensitivity; sex differences; insulin secretion; endogenous glucose production; postprandial glucose metabolism; brain insulin action; proglucagon cleavage products
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 300/2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No