Dapagliflozin and Hepatic Glucose Metabolism
Study Details
Study Description
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
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Detailed Description
Purpose/Objectives: To investigate the effect of dapagliflozin, 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 dapagliflozin 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 dapagliflozin 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 dapagliflozin 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 dapagliflozin 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Treatment dapagliflozin 10 mg per day |
Drug: Dapagliflozin 10mg
subjects will receive daily dose of 10 mg dapagliflozin for 3 months
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Placebo Comparator: control matching placebo 1 pill per day |
Drug: Control
Placebo
Other Names:
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Outcome Measures
Primary Outcome Measures
- effect of dapagliflozin on autonomic nervous system [12 weeks]
autonomic activity will be measured with as NE turnover rate
Secondary Outcome Measures
- hepatic glucose production and uptake [12 weeks]
HGP and HGU will be measured with tracer dilution technique
Other Outcome Measures
- hepatic fat content [12 weeks]
the effect of treatment on hepatic fat content will be measured with MRS
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Diabetes Division, UTHSCSA | San Antonio | Texas | United States | 78229 |
Sponsors and Collaborators
- The University of Texas Health Science Center at San Antonio
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Muhammad Abdul-Ghani, MD, PhD, Diabetes Division, UTHSCSA
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HSC20170214H
- 2R01DK097554-06