Effect of Central Insulin Administration on Whole-body Insulin Sensitivity in Women

Study Overview
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Brief Summary
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The human brain is an insulin sensitive organ. Brain insulin action modulates peripheral insulin sensitivity in young lean men. As a underlying mechanism, the investigators previously detected suppression of endogenous glucose production and stimulation of glucose disappearance to peripheral tissue in response to brain insulin delivery by nasal spray. Whether this holds true in young woman is unknown, since differences in brain insulin response between sexes have been reported. The investigators will address this question by combining the delivery of insulin to the brain as nasal spray with hyperinsulinemic euglycemic clamp experiments in natural cycling women. In the planned randomized, placebo controlled cross-over study, female participants will undergo four hyperinsulinemic euglycemic experiments with tracer dilution, two in the first phase and two in the second phase of their menstrual cycle. On one of the study days per menstrual phase, subjects will receive intranasal insulin administration, on the other placebo spray. The protocol has been successfully applied previously in men. Based on the results of this trial, the investigators calculated a required sample size of N=10 for the planned study in women. These experiments will help to better understand the role of brain insulin action in a broader sense. The results can be the basis for larger clinical trials that address the sex-specific impact of brain insulin resistance for glucose metabolism and diabetes risk.

Detailed Description
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Effect of central insulin administration on whole-body insulin sensitivity in women The human brain is an insulin sensitive organ. Brain insulin action modulates peripheral insulin sensitivity in young lean men. As a underlying mechanism, the investigators previously detected suppression of endogenous glucose production and stimulation of glucose disappearance to peripheral tissue in response to brain insulin delivery by nasal spray. Whether this holds true in young woman is unknown, since differences in brain insulin response between sexes have been reported. The investigators will address this question by combining the delivery of insulin to the brain as nasal spray with hyperinsulinemic euglycemic clamp experiments in natural cycling women. In the planned randomized, placebo controlled cross-over study, female participants will undergo four hyperinsulinemic euglycemic experiments with tracer dilution, two in the first phase and two in the second phase of their menstrual cycle. On one of the study days per menstrual phase, subjects will receive intranasal insulin administration, on the other placebo spray. The protocol has been successfully applied previously in men. Based on the results of this trial, the investigators calculated a required sample size of N=10 for the planned study in women. These experiments will help to better understand the role of brain insulin action in a broader sense. The results can be the basis for larger clinical trials that address the sex-specific impact of brain insulin resistance for glucose metabolism and diabetes risk.

Official Title
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Effect of Central Insulin Administration on Whole-body Insulin Sensitivity in Women

Conditions
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Insulin Sensitivity

Intervention / Treatment
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* Drug: intranasal insulin
* Drug: Placebo spray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: female volunteer adults HbA1c <6.0% Age between 18 and 30 years Standard routine laboratory No underlying diseases No medication No hormonal contraception Understanding of the explanations of the study and the instructions Exclusion Criteria: Persons with limited temperature perception and / or increased temperature Sensitivity to warming of the body Cardiovascular disease, such as manifest coronary Heart disease, heart failure greater than NYHA 2, recent myocardial infarction People with a hearing disorder or increased sensitivity to loud Sounds persons with claustrophobia Minors or non-consenting subjects are also excluded Pregnancy or breastfeeding women Surgery less than 3 months ago Simultaneous participation in other interventional studies Acute illness or infection within the last 4 weeks Neurological and psychiatric disorders Subjects with hemoglobin Hb <12g / dl (at screening) Allergic diseases Individuals with a history of heparin-induced thrombocytopenia (HIT)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Insulin nasal spray<br>160 Units of human insulin as nasal spray | Drug: intranasal insulin<br>* application of 160 units human insulin<br>|
| Placebo Comparator: Placebo nasal spray<br>Nasal spray containing placebo solution | Drug: Placebo spray<br>* nasal spray containing placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the peripheral insulin sensitivity | Effect of nasal insulin versus placebo on peripheral insulin sensitivity assessed by euglycemic hyperinsulinemic clamp. | 60-90 minutes and 150-210 minutes during euglycemic clamp | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation with autonomous nervous system activity | Correlation of the change in peripheral insulin sensitivity by central insulin action with the simultaneous change of the autonomous nervous system (measured by heart rate variability). | 70-80 minutes and 190-200 minutes during euglycemic clamp | 
| Differential effects dependent on female sexual hormones | Correlation of the change in peripheral insulin sensitivity by central insulin action dependent on the time point in menstrual cycle | 60-90 minutes and 150-210 minutes during euglycemic clamp | 
| Effect of menstrual cycle on insulin sensitivity before spray application | Will be measured by hyperinsulinemic euglycemic clamp | 60-90minutes | 
| Effect of menstrual cycle on brain insulin sensitivity | Brain insulin sensitivity will be assessed by functional magnetic resonance imaging combined with intranasal insulin administration during the follicular and the luteal phase of the menstrual cycle | 60-90 minutes | 
| Effect of menstrual cycle on processing of food cues in the brain | Processing of food cues in the brain will be assessed by functional magnetic resonance imaging during the follicular and the luteal phase of the menstrual cycle | 20 minutes |