SGLT2i, Ketoacidosis, Volume Contraction, and Insulinopenia

The University of Texas System (UT)

Status and phase

Enrolling

Phase 1

Conditions

Type 2 Diabetes

Treatments

Drug: Empagliflozin 25 MG

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT07053306

R01DK024092 (U.S. NIH Grant/Contract)

20230457HU - 504076

Details and patient eligibility

About

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.

Full 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.

Enrollment

29 estimated patients

Sex

All

Ages

30 to 75 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Patients with T2D

Inclusion Criteria:

Ages 30-75 years
Body Mass Index (BMI) 21-45 kg/m2
Hemoglobin A1C (HbA1c) = 7.0-11%
Estimated glomerular filtration rate (eGFR) > 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, complete blood chemistry (CBC), thyroid stimulating hormone/thyroxine (TSH/T4), electrocardiogram (EKG), and urinalysis
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, sulfonylurea (SU), metformin (MET), or SU/MET
Statin therapy is permissible if the dose has been stable for at least 3 months

Exclusion Criteria:

Patients treated with Glucagon-like peptide 1 receptor agonists (GLP-1 RA), Dipeptidyl Peptidase IV inhibitors (DPP-4i), Thiazolidinediones (TZD), or insulin are excluded
Patients taking medications (other than SU/MET) known to affect glucose metabolism are excluded
Subjects with evidence of proliferative retinopathy or eGFR < 60 are excluded
Women of childbearing potential are excluded unless they are taking/using appropriate contractive medications/devices