SGLT2i, Hepatic Glucose Production, and SNS

The University of Texas System (UT)

Status and phase

Enrolling

Early Phase 1

Conditions

Type 2 Diabetes

Treatments

Drug: Empagliflozin 25 MG

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT07053293

R01DK024092 (U.S. NIH Grant/Contract)

20230457HU - 504075

Details and patient eligibility

About

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.

Full 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.

Enrollment

22 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