SGLT2i, Ketoacidosis, Volume Contraction, and Insulinopenia

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

Protocol III: SGLT2i, Ketoacidosis, Volume Contraction, and Insulinopenia

To examine the 2-HIT hypothesis that the SGLT2i-induced stimulation of EGP, lipolysis, and ketone production requires the combination of volume depletion plus insulinopenia in T2D individuals.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

After screening visit, subjects will participate in four additional visits and or at least one of the four visits that will be performed in random order starting at 6:00 AM to the Clinical Research Center at University Hospital-Texas Diabetes Institute.

Visit 2 (Study 1): At 6:00AM at (Study 1), a prime-continuous infusions of 6,6, D2-Glucose or U-3H-glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic glucose production (HGP) and fat break down (lipolysis).3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg). Plasma substrate, hormone concentrations, U-3H-glucose and U-14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minutes. If Principal Investigator (PI) use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 54, if PI will use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 54.

Visit 3 (Study 2, Optional): At 6:00AM prime-continuous infusions of 6,6, D2-Glucose or U-3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic glucose production (HGP) and lipolysis. 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At 7 AM an infusion of normal saline will be started at the rate of 150 ml/hour and continued to the end of study at 2 PM (total volume = 1050 ml; total Na and Cl = 154 meq) to provide volume replacement for blood loss. At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg). Plasma substrate, hormone concentrations, 3H-glucose and 14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 55. If PI use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 55.

Visit 4 (Study 3, Optional): At 6:00AM prime-continuous infusions 6,6, D2-Glucose or U-3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of Hepatic Glucose Production (HGP) and fat break down (lipolysis). 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At time zero (9:00 AM) subjects will ingest Empagliflozin (25 mg) and octreotide or somatostatin with insulin and glucagon will be given to reduce volume without insulinopenia. Plasma substrate and hormone concentrations and 3H-glucose/14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI use U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 55-56. If PI uses U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 56.

Visit 5 (Study 4, Optional): At 6:00AM prime-continuous infusions of 6,6, D2-Glucose or 3H-Glucose and U-2H-glycerol or U-14C-Glycerol are started and continued to study end (2:00 PM) to measure rates of hepatic (liver) glucose production (HGP) and fat break down (lipolysis). 3H-Glucose infusion to be given: (Prime=25µCi x (FPG/100), Continuous=0.25µCi/min x 480 min=120µCi). At 7 AM an infusion of normal saline will be started at the rate of 150 ml/hour and continued to the end of study at 2 PM (total volume = 1050 ml; total Na and Cl = 154 meq) to provide volume replacement for blood loss. At time zero (9:00 AM) subjects will ingest empagliflozin (25 mg) and octreotide or somatostatin with insulin and glucagon will be given. Plasma substrate and hormone concentrations and 3H-glucose/14C-glycerol specific activities will be measured every 5-30 minutes for 300 minutes (2:00 PM) and 295 minute. If PI uses U-2H-glycerol instead of U-14C Glycerol, PI will measure plasma U-2H-glycerol enrichment instead of U-14C-glycerol specific activities. Detailed explanation on page 56. If PI use U-6,6, D2-Glucose instead of U-3H Glucose, PI will measure plasma 2H-Glucose enrichment instead of 3H Glucose specific activities. Detailed explanation on page 56.

In Substudy II, PI will use stable isotopes (6,6-D2-glucose and U-2H-glycerol) or radioisotopes (U-3H-glucose and U-14C-glycerol) to measure endogenous glucose production (EGP) and fat breakdown (lipolysis), depending on isotope availability and cost. Both sets of isotopes will provide the necessary data to address research objectives.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
29

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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.
  • Statin therapy is permissible if the dose has been stable for at least 3 months

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Ketone Body Turnover (ketogenesis)
Time Frame: 0 and 300 minutes
Measurement of ketone body turnover rate during the baseline state and 240-300-minute time period, before and after Empagliflozin administration.
0 and 300 minutes

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The University of Texas Health Science Center at San Antonio

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 29, 2025

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2027

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 30, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 26, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 26, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 8, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 17, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 15, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 20230457HU - 504076
  • 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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