# Gluconeogenesis and Glycogenolysis - Role and Regulation

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $706,500

## Abstract

Project Summary/Abstract
 The proposed studies are important because they will clarify the mechanisms by which insulin regulates
liver glucose uptake under feeding conditions, both when insulin is secreted by the pancreas as well as when it
is injected during the treatment of people with diabetes. Consuming a diet high in fat and fructose severely
impairs hepatic glucose uptake. We will determine the degree to which this is caused by the liver's defective
response to insulin and glucose, we will define its molecular correlates, and we will explore whether this
dysfunction can be effectively treated by interrupting sympathetic neural input or glucokinase activation. In
addition, glucagon is implicated in diabetic hyperglycemia and we will investigate whether glucagon acting in
the brain can affect hepatic glucose production. The specific aims of this proposal are 1) to determine the
impact of insulin's direct vs indirect effects on the regulation of hepatic glucose uptake and storage under
hyperglycemic hyperinsulinemic conditions, 2) to characterize the source of impairment in hepatic glucose
metabolism caused by a high fructose, high fat diet and to determine whether the withdrawal of sympathetic
neural tone or glucokinase activation can overcome those defects, and 3) to determine the effect of brain
glucagon action on the control of hepatic glucose production. Studies will be carried out in normal and diet
induced glucose intolerant conscious dogs. Several weeks before study catheters will be inserted into the
femoral artery, hepatic portal vein, and hepatic vein for measurement of hepatic glucose production and
uptake, as well as in other vessels and sites as needed (splenic, jejunal, and jugular veins, carotid and
vertebral arteries, the 3rd ventricle, etc.). The endocrine pancreas will be disabled with somatostatin, and
insulin, glucagon and glucose will be infused as required by the study design. Liver glucose metabolism will be
assessed using tracer and A-V difference techniques. Surgical and pharmacologic tools will also be used as
needed to create the conditions required for the experiments. We will also assess alterations at the cellular
level to better understand the physiologic phenotypes. The canine model is unique in that it allows for infusion
(insulin, glucagon, glucose) into the hepatic portal vein, thus recreating real-life feeding conditions under
steady state conditions which cannot be done in the human or rodent. In addition, the dog is unique in that it
permits the measurement hepatic glucose uptake as well as output, which can only be done in a large animal.
We believe that the knowledge gained from the proposed experiments will impact the development of new
therapeutic approaches to the treatment of glucose intolerance and diabetes.

## Key facts

- **NIH application ID:** 10167685
- **Project number:** 5R01DK018243-46
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Alan D Cherrington
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $706,500
- **Award type:** 5
- **Project period:** 1978-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167685

## Citation

> US National Institutes of Health, RePORTER application 10167685, Gluconeogenesis and Glycogenolysis - Role and Regulation (5R01DK018243-46). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10167685. Licensed CC0.

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