# SGLT2 Inhibition and Stimulation of Endogenous Glucose Production

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $513,780

## Abstract

PROJECT SUMMARY
Inhibition of the renal SGLT2 transporter has proven to be an effective therapeutic intervention
to reduce plasma glucose levels and HbA1c in type 2 diabetic patients. The glycemic-lowering
efficacy of the SGLT2 inhibitors results from two distinct mechanisms: (i) induction of
glucosuria, which amounts to ~70-90 grams per day and (ii) amelioration of glucotoxicity leading
to increased insulin sensitivity in muscle and improved beta cell function (JCI 124:509-514,
2014). However, the clinical efficacy of the SGLT2 inhibitors is countered by an increase in
endogenous glucose production (EGP) that offsets by ~50% the amount of glucose excreted in
the urine. The increase in EGP is associated with a rise in plasma glucagon concentration and
decline in plasma insulin concentration. In the present grant we will define: (1) the organ, liver
and/or kidney, responsible for the increase in EGP (Protocol One); (2) the role of increased
plasma glucagon, decline in plasma insulin, fall in plasma glucose concentration (Protocol Two);
and (3) the role of the renal nerves in the increase in EGP (Protocol Three) following inhibition
of the renal SGLT2 transporter with dapagliflozin. In Protocol Four, we will examine whether the
GLP-1 receptor agonist, exenatide, which stimulates insulin and inhibits glucagon secretion, can
block the increase in EGP following SGLT2 inhibition with dapagliflozin.

## Key facts

- **NIH application ID:** 9962381
- **Project number:** 5R01DK107680-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** RALPH A DEFRONZO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,780
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962381

## Citation

> US National Institutes of Health, RePORTER application 9962381, SGLT2 Inhibition and Stimulation of Endogenous Glucose Production (5R01DK107680-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9962381. Licensed CC0.

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