SGLT2 Inhibition and Stimulation of Endogenous Glucose Production: Protocol 2

Protocol 2: Elucidation of Mechanisms Responsible for the Increase in EGP Following SGLT2 Inhibition: Decrease in Plasma Glucose Conc or Change in Islet Hormone (Glucagon/Insulin) Secretion

In Protocol 2, the investigators will determine the role of pancreatic hormones (increase in plasma glucagon and decrease in plasma insulin concentration) in the stimulation of EGP following SGLT2 inhibition.

Study Overview

• Status: Completed
• Conditions: Type II Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin

Detailed Description

The inhibition of the renal (kidney) SGLT2 transporter has proven to be an effective therapeutic intervention to reduce plasma glucose levels (amount of glucose found in the liquid part of blood) and HbA1c.

In this study, the investigators hope to define the role of increased plasma glucagon, decline in plasma insulin, and fall in plasma glucose concentration. The investigators will examine whether the signal for the increase in EGP (endogenous glucose production) caused by glucosuria (an excess of sugar in the urine, typically associated with diabetes) is mediated via the decrease in plasma glucose and insulin concentrations, or by the increase in plasma glucagon concentration.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• T2DM subjects
• 18 - 70 yrs old
• BMI = 25-45 kg/m2
• Must be on a stable dose (more than 3 months) of monotherapy or combination therapy with metformin and/or a sulfonylurea
• HbA1c <10.0%
• Stable body weight (± 3 lbs) over preceding 3 months
• Do not participate in excessively heavy exercise

Exclusion Criteria:

• Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea)
• Individuals with evidence of proliferative diabetic retinopathy, plasma creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin; 20 subjects will receive dapagliflozin 10mg	Drug: Dapagliflozin; SGLT2 inhibitor (dapagliflozin); Other Names: Farxiga
Placebo Comparator: Placebo; 10 subjects will receive placebo	Drug: Placebo; Placebo Comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Glucose Concentration	Change from baseline to the last hour of the study (240-300 minutes) in plasma glucose concentration	Baseline to 240-300 minutes
Change in Endogenous Glucose Production (EGP)	The change in endogenous glucose production is measured from baseline until the last hour of the study	Baseline to 240-300 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Insulin During Measurement of EGP	Measurement of change in plasma insulin concentration during measurement of of EGP from baseline to last hour of the study	Baseline to 240-300 minutes
Change in Glucagon During EGP Measurement	Measurement of change in glucagon during EGP measurement from baseline to the last hour of the study	Baseline to 240-300 minutes

Collaborators and Investigators

• 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 A. DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Publications and helpful links

General Publications

• Alatrach M, Laichuthai N, Martinez R, Agyin C, Ali AM, Al-Jobori H, Lavynenko O, Adams J, Triplitt C, DeFronzo R, Cersosimo E, Abdul-Ghani M. Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors. Diabetes. 2020 Apr;69(4):681-688. doi: 10.2337/db19-0770. Epub 2020 Jan 8.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2015
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): October 31, 2019

Study Registration Dates

• First Submitted: October 14, 2015
• First Submitted That Met QC Criteria: October 28, 2015
• First Posted (Estimate): October 30, 2015

Study Record Updates

• Last Update Posted (Actual): September 17, 2020
• Last Update Submitted That Met QC Criteria: September 15, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: HSC20150668H; 5R01DK107680-02 (U.S. NIH Grant/Contract)