Insulin Sensitivity, Multiple Mitochondrial Dysfunctions Syndrome
Conditions
Keywords
Insulin sensitivity, Mitochondrial function, Glucose toxicity, Glucosuria
Brief summary
The purpose of this study is to examine the effect of the chronic treatment of type 2 diabetes (T2DM) with dapagliflozin on: (1) mitochondrial gene function/expression and insulin signaling/action and (2) oral glucose tolerance and beta cell function. Dapagliflozin is a potent, highly specific inhibitor of renal glucose transport \[SGLT2\].
Detailed description
Glucotoxicity has been implicated as a cause of insulin resistance and impaired beta cell function in T2DM. Abundant support for the glucotoxicity hypothesis has been provided by in vivo and in vitro studies in animals, but a rigorous test of this hypothesis in man is lacking. The investigators propose to test the glucotoxicity hypothesis by chronically reducing the plasma glucose in type 2 diabetic subjects (T2DM) with an inhibitor of renal glucose transport, dapaglifozin, and examining the effect of restoration of normoglycemia on mitochondrial function and insulin signaling/sensitivity. Lastly, the investigators will test the glucolipotoxicity hypothesis, which states that the toxic effects of elevated plasma FFA on insulin sensitive tissues (i.e., muscle) are magnified in the presence of concurrent hyperglycemia. Thus, high glucose levels increase malonyl CoA, which inhibits CPT I, leading to accumulation of FACoA/DAG, which impair mitochondrial function and inhibit insulin action.
Interventions
DRUGDapagliflozin
Treatment arm, 10 mg per day for 2 weeks
DRUGPlacebo
Patients are treated with placebo
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* T2DM * Drug Naive Or On Oral Therapy
Exclusion criteria
* Insulin Treatment * Major Organ Disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Sensitivity | baseline, two weeks | The change in insulin sensitivity and total glucose disposal measured at two weeks with the insulin clamp compared to baseline. This is measured using TGD (whole body tissue glucose disposal)/SSPI (steady state plasma insulin concentration) ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mitochondrial Function | baseline, two weeks | The change in mitochondrial function/gene expression at two weeks compared to baseline. This was measured by energy expenditure. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo this arm is control
Placebo: Patients are treated with placebo | 8 |
| Dapagliflozin Interventional arm
Dapagliflozin: Treatment arm, 10 mg per day for 2 weeks | 10 |
| Total | 18 |
Baseline characteristics
| Characteristic | Total | Dapagliflozin | Placebo |
|---|---|---|---|
| A1C (average blood glucose level over 3 months | 8.6 percentage STANDARD_DEVIATION 0.4 | 8.5 percentage STANDARD_DEVIATION 0.4 | 8.7 percentage STANDARD_DEVIATION 0.4 |
| Age, Continuous | 53.6 Years STANDARD_DEVIATION 2.2 | 51.9 Years STANDARD_DEVIATION 2.3 | 55.4 Years STANDARD_DEVIATION 2.1 |
| Body Mass Index (BMI) | 31.8 kg/m^2 STANDARD_DEVIATION 1.7 | 30.9 kg/m^2 STANDARD_DEVIATION 1.8 | 32.6 kg/m^2 STANDARD_DEVIATION 1.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 10 Participants | 8 Participants |
| Region of Enrollment United States | 18 participants | 10 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 18 Participants | 10 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 10 |
| other Total, other adverse events | 0 / 8 | 0 / 10 |
| serious Total, serious adverse events | 0 / 8 | 0 / 10 |
Outcome results
Primary
Change in Insulin Sensitivity
The change in insulin sensitivity and total glucose disposal measured at two weeks with the insulin clamp compared to baseline. This is measured using TGD (whole body tissue glucose disposal)/SSPI (steady state plasma insulin concentration) ratio
Time frame: baseline, two weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Insulin Sensitivity | Baseline Measurement | 3.18 mg/kg.min per µU/ml | Standard Deviation 0.51 |
| Placebo | Change in Insulin Sensitivity | 2 weeks | 3.57 mg/kg.min per µU/ml | Standard Deviation 0.51 |
| Dapagliflozin | Change in Insulin Sensitivity | Baseline Measurement | 3.85 mg/kg.min per µU/ml | Standard Deviation 0.71 |
| Dapagliflozin | Change in Insulin Sensitivity | 2 weeks | 5.22 mg/kg.min per µU/ml | Standard Deviation 0.56 |
Secondary
Change in Mitochondrial Function
The change in mitochondrial function/gene expression at two weeks compared to baseline. This was measured by energy expenditure.
Time frame: baseline, two weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Mitochondrial Function | Baseline Measurement | 1.06 cal/min.kg | Standard Deviation 0.1 |
| Placebo | Change in Mitochondrial Function | Measurement at 2 weeks | 1.0 cal/min.kg | Standard Deviation 0.1 |
| Dapagliflozin | Change in Mitochondrial Function | Baseline Measurement | 1.3 cal/min.kg | Standard Deviation 0.1 |
| Dapagliflozin | Change in Mitochondrial Function | Measurement at 2 weeks | 1.34 cal/min.kg | Standard Deviation 0.1 |