# Insulin's acute regulation of hepatic glucose utilization

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $48,974

## Abstract

Project Summary
 Insulin controls hyperglycemia after feeding by stimulating glucose uptake and suppressing
endogenous glucose production. The liver contributes 90% of endogenous glucose production during fasting,
generated through glycogen breakdown and gluconeogenesis, thus insulin’s control of hepatic glucose
metabolism is crucial for restoring whole body glucose homeostasis. Insulin acutely suppresses hepatic
glucose production and promotes glucose uptake and storage within fifteen minutes of a glucose bolus. This is
accomplished through direct and indirect effects on the liver. The direct mechanism by which insulin acutely
controls hepatic glucose utilization is unclear, and previous studies suggest it becomes dysregulated with
insulin resistance. Our lab and others demonstrated that insulin directly controls liver glucose balance through
AKT, a serine/threonine kinase and an obligate insulin signaling intermediate in hepatocytes. The goal of this
study is to determine 1) the metabolic pathways AKT controls to acutely regulate glucose utilization and 2) the
mechanisms involved and how they becomes aberrant in metabolic disease. Preliminary stable isotope tracing
experiments suggest that AKT rapidly increases glucose contribution to glycolytic intermediates and lipogenic
precursors within 5 minutes, independent of changes to glycogen metabolism. I have also found that insulin
stimulates phosphorylation of an allosteric regulator of glycolysis, PFK2/FBPase2, in hepatocytes at Ser469
and Ser486 in an AKT-dependent manner. Phosphorylation at these residues correlates with increased PFK2
kinase activity. Thus, I hypothesize that insulin acutely shifts glucose balance in the liver from gluconeogenesis
to glycolysis postprandially through AKT-mediated PFK2 phosphorylation. I will test whether AKT suppression
of gluconeogenesis allows for the increased contribution of glucose to glycolytic intermediates and lipid
precursors, and the role of PFK2 phosphorylation downstream of insulin signaling in mediating AKT’s acute
effects on glucose flux. Finally, I will interrogate how the AKT-PFK2 pathway contributes to in vivo hepatic
glucose utilization in both healthy and insulin resistant states using diet interventions, hyperinsulinemic clamps
and adeno-associated virus delivery of phosphomutant PFK2. Overall, this study will determine the acute
mechanisms by which insulin directly controls hepatic glucose balance, which may reveal novel therapeutic
targets for treating insulin resistance and maintaining glucose homeostasis.

## Key facts

- **NIH application ID:** 10997139
- **Project number:** 1F31DK139617-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Megan Lynn Stefkovich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997139

## Citation

> US National Institutes of Health, RePORTER application 10997139, Insulin's acute regulation of hepatic glucose utilization (1F31DK139617-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10997139. Licensed CC0.

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