SGLT2i, Hepatic Glucose Production, and SNS

July 15, 2026 updated by: The University of Texas Health Science Center at San Antonio

Protocol II: SGLT2i, Hepatic Glucose Production, and Sympathetic Nervous System (SNS)

In this study, PI will test the hypothesis that distinct mechanisms account for the SGLT2i-induced stimulation of ketogenesis and lipolysis versus endogenous (hepatic) glucose production in patients with type 2 diabetes (T2D) that the increases in ketone production and lipolysis can be prevented by concomitant administration of the thiazolidinedione pioglitazone. Principal Investigator (PI) will conduct five distinct experiments to test this hypothesis in patients with T2D.

To examine the role of the SNS on the empagliflozin-induced stimulation of EGP, lipolysis, and ketone production in T2D by comparing the effect of empagliflozin versus empagliflozin plus propranolol.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Protocol: 22 T2D Subjects will be randomized to receive empagliflozin (n=20). Each subject will participate in two studies performed in random order. In Study 1, EGP will be measured with a prime-continuous 6,6, D2-glucose infusion and lipolysis will be measured with prime-continuous infusion of U-2H-glycerol. The rate of ketogenesis will be determined by infusion of 13C palmitate and quantitating the enrichment of 13C in 3-hydroxybutyrate (BHB). Total body NE turnover will be measured with 3H-norepinephrine (3H-NE) infusion before and after empagliflozin administration.

Visit 2 (Study 1): At approximately 6:00PM on the night prior to study subjects will ingest D2O (3 grams/kg ffm) to quantitate gluconeogenesis and de novo lipogenesis. At 6:00AM at Visit 1 prime-continuous infusions of 6,6, D2-glucose and U-2H-glycerol or U-14C-glycerol are started and continued to study end to measure rates of hepatic glucose production (HGP) and lipolysis. At 8:00AM a prime-continuous infusion of 3H-norepinephrine is started and continued to 9:00 AM at which time it will be stopped. Empagliflozin 25mg is administered at this time, 9:00 AM. At 1:00 PM (240 minutes after administration of Empagliflozin) a second prime-continuous 3H-Norepinephrine infusion is started for 60 minutes. Detailed explanation on page 52-53.

Visit 3 (Study 2, Optional): At approximately 6:00PM on the night prior to study subjects will ingest D2O (3 grams/kg ffm) to quantitate gluconeogenesis and de novo lipogenesis. This visit will be identical to Visit 2 for Aim 2 (Sub-study I) with one exception. At 8:30AM, 30 minutes prior to the ingestion of the Empagliflozin 25mg, a prime (200 ug/kg over 20 minutes)-continuous (80 ug/min) infusion of propranolol is started and continued to study end. Principal Investigator (PI) previously have shown that the steady state propranolol concentration achieved by this infusion rate is sufficient to significantly inhibit insulin-mediated glucose disposal.

Study Type

Interventional

Enrollment (Estimated)

22

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78229-3900
        • Recruiting
        • Texas Diabetes Institute/UH
        • Contact:
        • Principal Investigator:
          • Ralph DeFronzo, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Patients with T2D

Inclusion Criteria:

  • Ages 30-75
  • BMI (Body Mass Index) 21-45 kg/m2
  • HbA1c = 7.0-11%
  • eGFR (estimated glomerular filtration rate)> 60 ml/min/1.73m2
  • Blood Pressure (BP)≤160/90 mmHg
  • Participants must be in general good health based on medical history, physical exam, screening blood chemistries, CBC (Complete Blood Count), TSH/T4 (thyroid/thyroxine hormone), EKG (electrocardiogram), and urinalysis (UA)
  • Stable body weight (±1.5 kg) over the last 3 months and must not participate in an excessively heavy exercise program
  • Patients treated with diet, Sulfonylureas, Metformin, or Sulfonylureas/Metformin (Sulfo/MET)
  • Participants receiving a Glucagon like peptide -1 receptor agonist (GLP1-RA) must be on a stable dose for at least three months prior to study enrollment.
  • Participants receiving a Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitor) must be on a stable dose for at least two months prior to study enrollment.
  • SGLT2 inhibitors must be discontinued at least two months prior to study enrollment.

EXCLUSION CRITERIA

An individual who meets any of the following criteria will be excluded from participation in this study:

  • Patients treated with Thiazolidinediones (TZDs), or Insulin are excluded.
  • Patients taking medications other than Sulfonylureas/Metformin (SU/MET), stable dose of GLP1-RA and DPP4i known to affect glucose metabolism are excluded. Patients taking SGLT2i within 2 months of screening visit will be excluded from participating in this study, however they may be asked whether they would agree to discontinue the medication for two months to become eligible. (Please see clarification below.) *
  • Subjects with evidence of proliferative retinopathy or estimated glomerular filtration rate (eGFR) < 60 are excluded
  • Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices * Only participants who are taking SGLT2 inhibitors during the prescreening period will be asked to discontinue the medication at least two months prior to the screening visit. If they agree, they will return for an HbA1c measurement four weeks after stopping the SGLT2 inhibitor.

If their HbA1c rises to greater than 10%, treatment will be initiated with either metformin, a DPP-4 inhibitor, or a sulfonylurea. We do not anticipate any adverse effects during this initial period, provided the HbA1c remains below 10%.

HbA1c will be measured using a fingerstick test, which requires only a minimal amount of blood. No compensation will be provided during this phase.

After two months of medication discontinuation, participants will return for a screening visit. If they meet all eligibility criteria, they will be enrolled in the study and payment done by protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Empagliflozin
Empagliflozin 25 mg/day
Drug: Empagliflozin 25 MG
A medication used in the management and treatment of type 2 diabetes mellitus. It is in the sodium-glucose co-transporter (SGLT-2) class of medications.
Other Names:
  • Jardiance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Endogenous Glucose Production (EGP)
Time Frame: 0 and 300 minutes
Measurement of Endogenous Glucose Production (EGP) using stable isotope (6,6, D2- glucose infusion).
0 and 300 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Principal Investigator: Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 7, 2025

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

June 30, 2027

Study Registration Dates

First Submitted

June 26, 2025

First Submitted That Met QC Criteria

June 26, 2025

First Posted (Actual)

July 8, 2025

Study Record Updates

Last Update Posted (Actual)

July 17, 2026

Last Update Submitted That Met QC Criteria

July 15, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 20230457HU - 504075
  • R01DK024092 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Deidentified data will be shared with NIH and as a publication in a peer reviewed journal once data are published.

IPD Sharing Time Frame

At study end after analysis of data.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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