The Effect of Central Insulin on Insulin Sensitivity and Energy Metabolism

Study Overview
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Brief Summary
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Insulin has a direct effect on the energy metabolism of the brain under basal conditions and has an effect on the hepatic glucose production, lipid metabolism and the secretion of various hormone. The effect of intranasal insulin on peripheral metabolism in humans supposedly is mediated by the vagus nerve. The purpose of this study is to determine whether central insulin influences the human peripheral insulin sensitivity of liver and muscle and whether vagus nerve stimulation can mimick this effect.

Detailed Description
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Insulin has a direct effect on the energy metabolism of the brain under basal conditions and has an effect on the hepatic glucose production, lipid metabolism in the mouse model. The purpose of this study is to determine whether central insulin influences the human peripheral insulin sensitivity of liver and muscle and energy metabolism. Intranasal insulin can be used in humans to deliver insulin to the brain and studies have shown that intranasal insulin might reduce food intake, lower body weight and modulate muscle glucose and adipose tissue lipid metabolism in himans. These effects are likely mediated by the vagus nerve as skeletal muscle insulin sensitization after intranasal insulin relates to parasympathetic tone activity (Heni et al. Diabetes 2014). Transcutaneous auricular vagus nerve stimulation (taVNS) activates non-invasively the sensory branches of the vagus nerve and is applied in humans as adjuvant treatment in drug-resistant epilepsy (Frangos et al. 2015). Thereby it can be used to examine whether the vagus nerve indeed mediates brain insulin signals to the periphery. Here we aim to investigate the effects of intranasal insulin on hepatic glucose, lipid and energy metabolism. We further aim to test whether taVNS can mimick intranasal insulin effects on peripheral metabolism in humans.

Official Title
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The Effect of Central Insulin on Insulin Sensitivity and Energy Metabolism

Conditions
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Diabetes

Intervention / Treatment
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* Drug: intransal insulin
* Drug: Placebo
* Device: taVNS
* Device: sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 30 and ≤ 70 years balanced gender ratio (50: 50) BMI 20-25 kg/m² (normal weight subjects) BMI 25-35 kg/m² (obese subjects) Exclusion Criteria: acute illness within the last 2 weeks before the examination autoimmune diseases and disorders immune- compromised (leukocytes <5000/μl) renal insufficiency (creatinine> 1.5 mg / dl) heart disease, condition after heart attack anemia (Hb <12 g / l, controls at each examination), blood donation within 4 weeks before the examination participation in another study within 2 months before the examination wear a metal or magnetic objects on or in the body claustrophobia use of immunomodulatory drugs (cortisol, antihistamines, aspirin) thyroid disease taking glitazones and insulin therapy pregnancy, lactation, menstruation cigarette smoking, use of alcohol or drugs, psychiatric disorders risk for / or manifest AIDS (HIV) or hepatitis B or C liver disease is not attributed to the existence of a non-alcoholic steatosis night shift work or circumstances, which do not allow the normal day-night rhythm bleeding disorders or disorders in wound healing hypersensitivity to local anesthetics malignant cancer heart rhythm disorders polyneuropathy

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intranasal insulin in patients<br>intranasal insulin is applied to diabetic patients under fasting conditions | Drug: intransal insulin<br>* 4x 40mU intranasal insulin<br>* Other names: intranasal insulin;|
| Experimental: intransal insulin in study participants<br>intranasal insulin is applied to healthy patients under fasting conditions | Drug: intransal insulin<br>* 4x 40mU intranasal insulin<br>* Other names: intranasal insulin;|
| Placebo Comparator: placebo in patients<br>placebo spray is applied intranasally in type 2 diabetes patients under fasting conditions | Drug: Placebo<br> <br> * Other names: intranasal placebo spray;|
| Experimental: placebo in study participants<br>placebo spray is applied intranasally in healthy participants under fasting conditions | Drug: Placebo<br> <br> * Other names: intranasal placebo spray;|
| Experimental: taNVS<br>Transcutanoues auricular vagus nerve stimulation is applied for 14 min in the external ear in healthy participants | Device: taVNS<br> <br> * Other names: transcutaneous auricular vagus nerve stimulation;|
| Placebo Comparator: Sham stimulation<br>Sham stimulation in the ear lobe is applied for 14 min in healthy participants | Device: sham stimulation<br> <br> * Other names: sham stimulation in the ear lobe;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin sensitivity | Assessment of insulin sensitivity with gold standard methods | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Energy metabolism | Energy metabolism is assessed from gold standard methods | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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central insulin, insulin resistance, energy metabolism