Dapagliflozin and Hepatic Glucose Metabolism
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 5/25/2018 |
| Start Date: | May 20, 2018 |
| End Date: | January 31, 2023 |
| Contact: | Muhammad Abdul-Ghai, MD, PhD |
| Email: | ABDULGHANI@UTHSCSA.EDU |
| Phone: | 210 567 6691 |
Effect of Dapagliflozin on Hepatic Glucose Metabolism: Role of Autonomic Nervous System
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
hepatic glucose production in response to glucosuria caused by inhibition of renal glucose
uptake
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.
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.
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
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