# Effect of SGLT2 Inhibitors on Hepatic Glucose Metabolism: Role of Autonomic Nervous System

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $601,089

## Abstract

Sodium-Glucose cotransport inhibitors (SGLT2i) are a novel class of antidiabetic agents
which lower the plasma glucose concentration by inhibiting renal glucose reuptake and
producing glucosuria. In addition to lowering the plasma glucose concentration,
members of this class exert multiple metabolic actions in T2DM all of which have
significant clinical relevance and include: (1) stimulation of hepatic glucose production;
(2) reduce fasting plasma insulin concentration and stimulate glucagon secretion, these
hormonal changes were suggested to cause the increase in HGP; (3) inhibition of
glucose oxidation; and (4) increase in fat oxidation and ketone production. Our
preliminary data demonstrate that, in normal glucose tolerant individuals, SGLT2
inhibitors, stimulate glucose production, and cause significant increase in fat oxidation
without a change in plasma glucose, insulin, glucagon and ketone concentrations.
Further, SGLT2 inhibitors inhibited pyruvate oxidation in hepatocytes in culture. Based
upon these novel findings, we hypothesize that, signals (likely neuronal) other than
change in plasma insulin to glucagon ratio are activated by glucosuria and stimulate the
increase in HGP in non-diabetic and likely in diabetic individuals as well. Further, we
hypothesize that the increase in fat oxidation by SGLT2 inhibitors will depletes liver fat
content in IFG and T2DM patients, increase hepatic glucose uptake and decrease the
fasting plasma glucose concentration. To test these hypotheses, we will (1) Measure
autonomic balance (with heart rate variability) and sympathetic nervous system activity
(3H-norepinephrine turnover) in IFG, NGT and T2DM subjects (drug naïve with FPG
<160 mg/dl) at baseline and at day 1 and 12 weeks of treatment with SGLT2 inhibitors,
and (2) Measure FPG, bHGP (3H-glucose infusion), HGU (with Oral-IV double tracer
infusion), whole body fat oxidation (indirect calorimetry), plasma insulin, glucagon, FFA,
ketone and lactate concentrations, and hepatic fat content (1H-MRS) in IFG, NGT and
T2DM patients (drug naïve with FPG <160 mg/dl) at baseline and at day 1 and 12 weeks
after treatment with SGLT2 inhibitor

## Key facts

- **NIH application ID:** 9973065
- **Project number:** 5R01DK097554-09
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Muhammad Abdul-Ghani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $601,089
- **Award type:** 5
- **Project period:** 2012-09-21 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973065

## Citation

> US National Institutes of Health, RePORTER application 9973065, Effect of SGLT2 Inhibitors on Hepatic Glucose Metabolism: Role of Autonomic Nervous System (5R01DK097554-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973065. Licensed CC0.

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