Hepatic Glucose Metabolism
Conditions
Brief summary
the aim of this study is to examine the role of autonomic nervous system in the increase in hepatic glucose production in response to glucosuria caused by inhibition of renal glucose uptake
Detailed description
Purpose/Objectives: To investigate the effect of empagliflozin, an SGLT2 inhibitor on hepatic glucose production and the role of autonomic nervous system in mediating the increase in hepatic glucose production in response glucosuria Research Design/Plan: the role of autonomic nervous system in the increase in hepatic glucose production caused by empagliflozin will be examined with norepinephrine (NE) turnover in two protocols. The first protocol is cross sectional, in which 36 T2DM patients will receive hepatic glucose production (HGP) and NE turnover will be measured before and after empagliflozin or placebo administration. In protocol 2, diabetic and non-diabetic subjects will receive baseline HGP, NE turnover, hepatic glucose uptake (HGU) and liver fat measurement before at 2 days after the start and 12 weeks after empagliflozin or placebo treatment. Methods: the following techniques will be employed (1) Measurement of hepatic glucose production with 3H-glucose infusion, with and without glucose clamp, (2) substrate oxidation with indirect calorimetry and plasma ketone/lactate/insulin/glucagon concentrations; (3) Measurement of HGU with Oral-IV double tracer infusion; (4) Measurement of whole body norepinephrine turnover with 3H-norepinephrine infusion; (5) Measurement of heart rate variability; (6) Measurement of liver fat content with 1H-MRS Clinical Relevance: The results of the present studies will help identify the mechanism responsible for the increase in HGP caused by empagliflozin and the increase in ketone production. The first action of the drug ameliorates its clinical efficacy while the second increases the risk of adverse events (ketoacidosis). Identifying the mechanisms underlying these actions will help developing therapeutic strategies which increase the drug clinical efficacy and mitigates its adverse events.
Interventions
DRUGEmpagliflozin 25 MG
subjects will receive daily dose of 25mg of empagliflozin for 3 months
DRUGControl
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)
Masking description
the study is placebo controlled double blinded. randomization will be made by pharmacist and the randomization code will be kept in the pharmacy
Intervention model description
subjects will receive in parallel a treatment with empagliflozin or placebo for 3 months hepatic glucose metabolism and norepinephrine turnover will be studied before and after treatment
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* eGFR\>60 ml/min healthy volunteers type 2 diabetes patients who otherwise healthy
Exclusion criteria
* eGFR \<60 T2DM patients on insulin, GLP-1 RA or SGLT2 treatment Major organ disease type 1 diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Empagliflozin on Autonomic Nervous System | Baseline and 12 weeks | autonomic activity will be measured with as NE turnover rate. Total-body NE turnover rate was measured with 3H-NE infusion. A prime (3.8 µCi)-continuous (0.38 µCi/min) infusion of 3H-NE was started and continued for 60 minutes. Arterialized blood samples were collected before the start and between the 40-60 minute time period after the start of 3H-NE infusion. Total body NE turnover rate was calculated as the 3H-NE infusion rate (dpm/min) divided by the steady state plasma 3H-NE specific activity (dpm/pg) after 30 minutes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hepatic Glucose Production | Baseline and 12 weeks | HGP will be measured with tracer dilution technique |
Other
| Measure | Time frame | Description |
|---|---|---|
| Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content | Baseline and12 weeks | the effect of treatment on hepatic fat content will be measured with MRS. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment empagliflozin 25 mg per day
Empagliflozin 25 MG: subjects will receive daily dose of 25mg of empagliflozin for 3 months | 36 |
| Control matching placebo 1 pill per day
Control: Placebo | 36 |
| Total | 72 |
Baseline characteristics
| Characteristic | Control | Total | Treatment |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants | 72 Participants | 36 Participants |
| Age, Continuous | 46 years STANDARD_DEVIATION 2 | 51 years STANDARD_DEVIATION 2 | 55 years STANDARD_DEVIATION 2 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 36 participants | 72 participants | 36 participants |
| Sex: Female, Male Female | 17 Participants | 35 Participants | 18 Participants |
| Sex: Female, Male Male | 19 Participants | 37 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 2 / 36 | 1 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Effect of Empagliflozin on Autonomic Nervous System
autonomic activity will be measured with as NE turnover rate. Total-body NE turnover rate was measured with 3H-NE infusion. A prime (3.8 µCi)-continuous (0.38 µCi/min) infusion of 3H-NE was started and continued for 60 minutes. Arterialized blood samples were collected before the start and between the 40-60 minute time period after the start of 3H-NE infusion. Total body NE turnover rate was calculated as the 3H-NE infusion rate (dpm/min) divided by the steady state plasma 3H-NE specific activity (dpm/pg) after 30 minutes
Time frame: Baseline and 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Effect of Empagliflozin on Autonomic Nervous System | Baseline NE Turnover | 480 ng/min | Standard Error 42 |
| Treatment | Effect of Empagliflozin on Autonomic Nervous System | 12 weeks NE Turnover | 355 ng/min | Standard Error 52 |
| Control | Effect of Empagliflozin on Autonomic Nervous System | Baseline NE Turnover | 621 ng/min | Standard Error 87 |
| Control | Effect of Empagliflozin on Autonomic Nervous System | 12 weeks NE Turnover | 635 ng/min | Standard Error 99 |
Secondary
Hepatic Glucose Production
HGP will be measured with tracer dilution technique
Time frame: Baseline and 12 weeks
Population: one patient in treatment arm did not complete the study due to Covid-19.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Hepatic Glucose Production | Baseline | 2.57 mg/kg/min | Standard Error 0.15 |
| Treatment | Hepatic Glucose Production | Week 12 | 3.15 mg/kg/min | Standard Error 0.21 |
| Control | Hepatic Glucose Production | Baseline | 2.63 mg/kg/min | Standard Error 0.16 |
| Control | Hepatic Glucose Production | Week 12 | 2.50 mg/kg/min | Standard Error 0.15 |
Other Pre-specified
Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content
the effect of treatment on hepatic fat content will be measured with MRS.
Time frame: Baseline and12 weeks
Population: Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content | -2.39 percentage of liver fat content | Standard Error 0.79 |
| Control | Absolute Percentage Change From Baseline to 12 Weeks in Hepatic Fat Content | 0.91 percentage of liver fat content | Standard Error 0.64 |