Testing Glial Pathways to HAAF in Human Subjects Using Carbon 13 Magnetic Resonance Spectroscopy

Study Overview
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Brief Summary
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Hypoglycemia-associated autonomic failure (HAAF), a condition commonly developed in diabetic patients, which causes them to have severely low blood sugar levels. This condition makes clinical management of blood sugar in diabetic patients very challenging. This research seeks to better understand how diabetic patients develop HAAF, and what can be done to prevent it.

Detailed Description
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Following the detection of severe hypoglycemia by the central nervous system (CNS), a series of physiological countermeasures are triggered which return serum glucose to euglycemic levels. This vital homeostatic response frequently becomes dysfunctional in both type 1 and type 2 diabetics, leaving them particularly vulnerable to life threatening bouts of hypoglycemia. This dysfunction, often termed hypoglycemia-associated autonomic failure (HAAF), is thought to be caused by maladaptive changes in the CNS. Currently, progress towards rectifying this HAAF is severely hindered by a lack of knowledge regarding the exact nature of these maladaptive changes and the antecedent events which cause them. Previous work by the PI, as well as others, has identified altered glial metabolism as a potential biological substrate driving HAAF. The alterations in glial metabolism associated with HAAF are strikingly similar to those induced by prolonged dietary restriction in rodents. This raises the intriguing possibility that HAAF may be driven by glial adaptations, normally induced only by prolonged starvation, which are triggered in diabetic individuals by treatment-induced exposure to severe hypoglycemia. The primary goal of our pilot project is to conduct a prospective observational study in humans to test the hypothesis that prolonged fasting will induce changes in glial metabolism similar to those previously measured in individuals with HAAF. The investigators will accomplish this goal via the following specific aims: Aim 1: Using a prospective observational study design in humans, test whether a 72 hour fast will induce acute alterations in glial metabolism, Aim 2: Determine if changes in plasma glucose and leptin levels following prolonged fasting are correlated with changes in glial adaptation. The investigators will utilize innovative 13C magnetic resonance spectroscopy to measure alterations in glial metabolism and substrate preference following acute dietary restriction in healthy young individuals. By demonstrating that metabolic adaptations of glial cells induced by prolonged fasting are similar to those previously associated with HAAF, the investigators can provide key insights into the precursors that may lead to the development of HAAF in diabetic individuals.

Conditions
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Diabetes Complications, Hypoglycemia

Intervention / Treatment
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* Behavioral: Fasting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male BMI 20.0-24.9 kg/m2 18-40 years old Willing to reside at Pennington Biomedical for 4 days Exclusion Criteria: Type 1 diabetes mellitus Type 2 diabetes mellitus Fasting glucose ≥ 110 mg/dL (determined at screening visit) Hyperketonuria >15 mg/dL, (determined at screening visit) Contraindication to MRI History of or current eating disorder History of obsessive compulsive disorder Current use of any medication (excluding over-the-counter pain medication) Contraindication to prolonged fasting Consume >10 alcoholic drinks/week

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy Men<br> | Behavioral: Fasting<br>* 72 hour fasting<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Enrichment of Bicarbonate as Measured by Magnetic Resonance Spectroscopy (MRS) |  | 80 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral Metabolic Rate of Acetate Ascertained Through Mathematical Modeling of MRS Data |  | 80 hours | 
| Astroglial TCA Cycle Rate Ascertained Through Mathematical Modeling of MRS Data |  | 80 hours | 
| Glucose Level |  | 72 hours | 
| Change in Leptin Levels |  | 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fasting, Carbon-13 Magnetic Resonance Spectroscopy, Neuroimaging