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Final Thesis Pinnell AMPK 2023.pdf (1.08 MB)

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5’-adenosine monophosphate-activated protein kinase (AMPK) agonists in novel combination therapy significantly alter insulin and glucose dynamics in experimentally-induced equine insulin dysregulation

Pinnell, Erin Frances
http://orcid.org/0009-0009-9194-7032
http://rave.ohiolink.edu/etdc/view?acc_num=osu1681398154188049

Abstract Details

2023, Master of Science, Ohio State University, Veterinary Clinical Sciences.
Equine metabolic syndrome is a collection of clinical and clinicopathologic findings including insulin dysregulation (ID), regional adiposity or obesity, and laminitis. Insulin dysregulation and hyperinsulinemia are associated with development of hyperinsulinemia-associated laminitis (HAL), resulting in significant welfare and financial implications. Previous research in our laboratory identified attenuation of activated 5’-adenosine monophosphate-activated protein kinase (AMPK) concentrations and increased downstream activation of mechanistic target of rapamycin (mTOR) signaling in digital lamellar tissue of horses with laminitis. Therapy with other AMPK agonists has been investigated alone and in combination (such as metformin and aspirin), yielding variable efficacy in altering ID. Since mTOR is upregulated in laminitis, resveratrol (RES) may also be an attractive therapeutic target for HAL. The purpose of this investigation was to evaluate the effects of combination treatment with RES (10 mg/kg PO q12hr), metformin (MET; 30 mg/kg PO q12hr), and aspirin (ASP; 20 mg/kg PO q24hr) on experimentally-induced ID. We hypothesized that co-administration of AMPK agonists would improve insulin and glucose dynamics in experimentally-induced equine ID. ID was induced in 33 healthy adult light-breed horses using dexamethasone (0.08 mg/kg by mouth every 24 hours). Horses were randomly assigned to one of 5 treatment groups: RES, MET/ASP, RES/ASP, RES/MET/ASP, and placebo (CON). Frequently-sampled insulin-modified IV glucose tolerance tests (FSIGTT) and oral sugar tests (OST) were performed at baseline, after 7 days of dexamethasone administration (ID), and after ID plus 7 additional days of AMPK agonist treatment. Minimal Model analysis was performed to calculate AIRg (acute insulin response to glucose), insulin sensitivity (SI), glucose effectiveness (Sg), and disposition index (DI) from the FSIGTT [insulin] and [glucose] data. Area under the curve of [insulin] (AUCins) and [glucose] (AUCg) (time 0-360 mins), along with peak insulin and glucose concentrations, were also calculated from the OST data. These parameters were compared between and within groups over time using a one-way ANOVA and paired t-tests to determine differences between treatment groups. The AIRg was significantly increased (p = 0.04) and the peak glucose concentration during the OST was significantly decreased (p = 0.002) in response to treatment with RES/MET/ASP. Additionally, insulin sensitivity (SI) and disposition index (DI) were increased, basal insulin and glucose values were decreased, and glucose and insulin area under the curve during the OST were decreased following treatment with RES/MET/ASP compared to other treatments. These results indicate that treatment with RES/MET/ASP improves some aspects of insulin and glucose dynamics in experimentally-induced equine ID and should be further evaluated in naturally-occurring ID and HAL.
Teresa Burns (Committee Chair)
Ramiro Toribio (Committee Member)
Laura Hostnik (Committee Member)
Endocrinology
Equine Metabolic Syndrome, Hyperinsulinemia-associated laminitis, OST, FSIGTT, AMPK, Resveratrol, Metformin, Aspirin, Horses

Recommended Citations

Citations

  • Pinnell, E. F. (2023). 5’-adenosine monophosphate-activated protein kinase (AMPK) agonists in novel combination therapy significantly alter insulin and glucose dynamics in experimentally-induced equine insulin dysregulation [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1681398154188049

    APA Style (7th edition)

  • Pinnell, Erin. 5’-adenosine monophosphate-activated protein kinase (AMPK) agonists in novel combination therapy significantly alter insulin and glucose dynamics in experimentally-induced equine insulin dysregulation . 2023. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1681398154188049.

    MLA Style (8th edition)

  • Pinnell, Erin. "5’-adenosine monophosphate-activated protein kinase (AMPK) agonists in novel combination therapy significantly alter insulin and glucose dynamics in experimentally-induced equine insulin dysregulation ." Master's thesis, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1681398154188049

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.