Influence of Central Nervous Insulin Sensitivity on Insulin Secretion

Einfluss Der zentralnervösen Insulinsensitivität Auf Die Insulinsekretion

Insulin resistance is a central pathophysiological component of type 2 diabetes and is associated with a high risk of cardiovascular disease. The tissue in which it manifests are mainly muscle, liver, and adipose tissue. Since the transport of glucose to the brain is independent of insulin, this organ has traditionally not been studied in this regard. In animal experiments, however, knockout of the insulin receptor in the brain leads to obesity and peripheral insulin resistance. This finding of insulin action in the brain could also be confirmed in human studies.

The investigators intend to investigate whether central nervous insulin action affects insulin secretion in humans. For this purpose, nasal insulin and placebo are administered 15 minutes before a hyperglycemic hyperinsulinemic clamps, which stimulate insulin secretion. Insulin sensitivity of the brain is measured by a an established protocol with functional magnetic resonance imaging before and after nasal insulin administration.

Study Overview

• Status: Completed
• Conditions: Insulin Secretion
• Intervention / Treatment: Drug: Placebo; Drug: intranasal insulin

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • University of Tuebingen, Department of Internal Medicine IV

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• HbA1c ≤6.0%
• normal glucose tolerance during 75g oral glucose tolerance test (OGTT)

Exclusion Criteria:

• Not removable metal parts in or on the body
• manifest cardiovascular disease
• claustrophobia
• recent surgery (less than 3 months)
• Simultaneous participation in other studies
• Acute disease or infection within the last 4 weeks
• neurological and psychiatric disorders
• treatment with centrally acting drugs
• hemoglobin Hb <13g / dl
• Hypersensitivity to any of the substances used

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Insulin nasal spray; 160 Units of human insulin as nasal spray	Drug: intranasal insulin
Placebo Comparator: Placebo nasal spray; Nasal spray containing placebo solution	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Insulin secretion assessed as serum C-peptide levels during a hyperglycemic clamp	0-10 min during hyperglycemic clamp and 10-90 min during hyperglycemic clamp

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation with brain insulin sensitivity	Correlation of regional brain insulin sensitivity with the change of pancreatic insulin secretion due to central action of insulin. Changes in regional cerebral blood flow from before to after intranasal insulin administration will be assessed by functional magnetresonance imaging (fMRI)	15-30 minutes post insulin nasal spray
Differential effects in lean and overweight	Differences in the effect of nasal insulin versus placebo on C-peptide levels during a hyperglycemic clamp between lean and overweight men will be assessed.	0-10 min during hyperglycemic clamp and 10-90 min during hyperglycemic clamp
Correlation with autonomous nervous system activity	Correlation of the change in pancreatic insulin secretion by central insulin action with the simultaneous change of the autonomous nervous system (measured by heart rate variability).	10 - 150 minutes post nasal spray
Peripheral insulin sensitivity	Effect of nasal insulin versus placebo on peripheral insulin sensitivity assessed by hyperglycemic hyperinsulinemic clamp.	10-90 min and 70-90 min during hyperglycemic clamp

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Investigators: Principal Investigator: Martin Heni, MD, University Hospital Tuebingen

Publications and helpful links

General Publications

• Heni M, Wagner R, Willmann C, Jaghutriz BA, Vosseler A, Kubler C, Hund V, Scheffler K, Peter A, Haring HU, Preissl H, Kullmann S, Fritsche A. Insulin Action in the Hypothalamus Increases Second-Phase Insulin Secretion in Humans. Neuroendocrinology. 2020;110(11-12):929-937. doi: 10.1159/000504551. Epub 2019 Nov 5.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): April 1, 2018

Study Registration Dates

• First Submitted: August 9, 2016
• First Submitted That Met QC Criteria: August 16, 2016
• First Posted (Estimate): August 17, 2016

Study Record Updates

• Last Update Posted (Actual): May 8, 2018
• Last Update Submitted That Met QC Criteria: May 2, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: 086/2016BO1

Plan for Individual participant data (IPD)

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