Diabetes Complications, Hypoglycemia
Conditions
Keywords
Fasting, Carbon-13 Magnetic Resonance Spectroscopy, Neuroimaging
Brief summary
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
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.
Interventions
BEHAVIORALFasting
72 hour fasting
Sponsors
Pennington Biomedical Research Center
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Enrichment of Bicarbonate as Measured by Magnetic Resonance Spectroscopy (MRS) | 80 hours |
Secondary
| Measure | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Men Fasting: 72 hour fasting | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Healthy Men |
|---|---|
| Age, Continuous | 28.7 years STANDARD_DEVIATION 2.4 |
| Astroglial tricarboxylic acid cycle rate ascertained through mathematical modeling of MRS data | 0.5 micromol/g/min STANDARD_DEVIATION 0.2 |
| % body fat | 17.6 % body fat STANDARD_DEVIATION 7.3 |
| Body Mass Index | 23.5 kg/m^2 STANDARD_DEVIATION 2.7 |
| Cerebral Metabolic Rate of Acetate Ascertained Through Mathematical Modeling of MRS Data | 59 micromol/g/min STANDARD_DEVIATION 20.8 |
| Fasting glucose | 85.1 mg/dL STANDARD_DEVIATION 6.9 |
| Leptin | 7.2 ng/mL STANDARD_DEVIATION 5.9 |
| Percent enrichment of bicarbonate | 53.5 % enrichment STANDARD_DEVIATION 8.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 76.1 kg STANDARD_DEVIATION 13.7 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 4 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Percent Enrichment of Bicarbonate as Measured by Magnetic Resonance Spectroscopy (MRS)
Time frame: 80 hours
Population: Collected data from one participant were not considered valid due to an equipment malfunction
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Men | Percent Enrichment of Bicarbonate as Measured by Magnetic Resonance Spectroscopy (MRS) | 61.9 % enrichment | Standard Deviation 3.8 |
p-value: 0.0053t-test, 2 sided
Secondary
Astroglial TCA Cycle Rate Ascertained Through Mathematical Modeling of MRS Data
Time frame: 80 hours
Population: Collected data from one participant were not considered valid due to an equipment malfunction
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Men | Astroglial TCA Cycle Rate Ascertained Through Mathematical Modeling of MRS Data | 0.4 micromol/g/min | Standard Deviation 0.2 |
p-value: 0.917t-test, 2 sided
Secondary
Cerebral Metabolic Rate of Acetate Ascertained Through Mathematical Modeling of MRS Data
Time frame: 80 hours
Population: Collected data from one participant were not considered valid due to an equipment malfunction
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Men | Cerebral Metabolic Rate of Acetate Ascertained Through Mathematical Modeling of MRS Data | 71 micromol/g/min | Standard Deviation 15 |
p-value: 0.477t-test, 2 sided
Secondary
Change in Leptin Levels
Time frame: 72 hours
Population: Data from 3 participants was not available due to lack of blood volume during collections
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Men | Change in Leptin Levels | 5.2 ng/mL | Standard Deviation 1.2 |
p-value: 0.53t-test, 2 sided
Secondary
Glucose Level
Time frame: 72 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Men | Glucose Level | 71 mg/dL | Standard Deviation 4.9 |