Original Research
Long-term and Short-term Dopaminergic (Cabergoline) and Antidopaminergic (Sulpiride) Effects on Insulin Response to Glucose, Glucose Response to Insulin, or Both in Horses

https://doi.org/10.1016/j.jevs.2017.10.008Get rights and content

Highlights

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    Dopaminergic action on insulin sensitivity was studied.

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    Prolactin was used to monitor activities of the treatments.

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    Treatment with sulpiride did not affect insulin sensitivity.

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    Treatment with cabergoline did not affect insulin sensitivity.

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    Prolactin concentrations responded as expected to the treatment.

Abstract

Dopaminergic drugs, such as those used to treat pituitary pars intermedia dysfunction (PPID) in horses, have been shown to improve insulin sensitivity in other species. It has been suggested that pergolide, used to treat PPID, may enhance insulin sensitivity in resistant horses, although evidence for that remains unclear. Four experiments were conducted herein to determine possible effects of dopaminergic inhibition or stimulation on two indices of insulin sensitivity in horses: the glucose response to insulin (GR2I), administered intravenously (IV) using a fixed dose of recombinant human insulin, and the insulin response to an acute IV infusion of glucose (IR2G). The first experiment tested the short-term effects of sulpiride (in saline; IV) 5 minutes prior to IR2G in insulin-sensitive and insulin-insensitive mares. Experiment 2 tested the effects of a long-term sulpiride protocol (1.5 g intramuscularly [IM] every 5 days for 45 days) on GR2I and IR2G in insulin-sensitive and insulin-insensitive geldings. Experiment 3 tested the short-term effects of 5-mg cabergoline IM on GR2I and IR2G in insulin-sensitive and insulin-insensitive mares. The fourth experiment tested the long-term effects of cabergoline IM on GR2I in insulin-sensitive mares. Results from these experiments revealed that neither increased nor decreased dopaminergic activity, in the long or short term, had any impact on GR2I or IR2G in horses (P > .1), regardless of starting insulin sensitivity status. We conclude that dopaminergic agents have no benefit for treating insulin insensitivity in horses, in spite of a perception of such benefits permeating the industry.

Introduction

There is a perception in the horse industry that pergolide, a short-acting dopaminergic agonist, might be useful in treating insulin resistance in horses [1]. This presumption may have arisen from the fact that horses with pituitary pars intermedia dysfunction (PPID), concurrently afflicted with insulin dysregulation, showed improvement in outward symptoms (e.g., shedding of retained curly coat, improved muscle mass [2]) when treated with pergolide. However, there are currently no studies supporting the use of dopamine agonists for the treatment of insulin resistance. In a study conducted by Donaldson et al [3], neither insulin nor glucose concentrations changed when horses with PPID were treated with pergolide mesylate for an average of 2 months. Additionally, Arana Valencia et al [4] reported no change in insulin response to glucose infusion (IR2G) or glucose response to insulin administration (GR2I) when insulin-resistant mares were given 5 mg of cabergoline every 10 days for 60 days in the fall.

There are in fact reports in other species indicating a dopaminergic-pancreatic interaction [5]. For this reason, the experiments reported herein were designed to further explore the effects of dopaminergic antagonism with sulpiride and increased dopaminergic activity (by cabergoline treatment) on indices of insulin sensitivity in horses. Due to its strong antagonistic effects on the dopaminergic receptors of the pituitary, sulpiride was used to mimic the pathologic conditions of a horse in late-stage PPID. Cabergoline, on the other hand, was used to study the effects on insulin sensitivity under high dopaminergic activity.

We specifically evaluated the (1) short-term (basically 1 day) and long-term (45 days or more) administration of sulpiride on insulin-resistant and insulin-sensitive geldings, respectively; and (2) the short-term and long-term treatment of cabergoline on insulin-sensitive and insulin-resistant mares. Because both cabergoline and sulpiride have the expected biological effects in the horse on lactotropes of the adenohypophysis [4], [6], [7], [8], plasma prolactin concentrations were used in all experiments as a reflection of drug efficacy.

Section snippets

Materials and Methods

All procedures described in these experiments were approved by the Institutional Animal Care and Use Committee of the Louisiana State University Agricultural Center. Horses used in the described experiments were long-term residents of the LSU AgCenter Horse Farm in Baton Rouge, Louisiana, and were routinely maintained outdoors on native grass pastures during the warm seasons and on winter ryegrass when available. Alicia bermudagrass hay was supplemented as the availability of pasture grass

Experiment 1. Short-term Sulpiride Treatment

Mean plasma prolactin concentrations averaged over insulin-sensitive and insulin-insensitive mares treated with sulpiride or vehicle 5 minutes before an infusion of glucose are presented in Fig. 1. Sulpiride treatment increased (P < .0001) prolactin concentrations within 5 minutes, and they remained elevated for the entire sampling period. There was no effect of insulin sensitivity status on prolactin concentrations.

Glucose infusion increased (P < .001) plasma insulin concentrations in all

Discussion

The most common type of insulin dysregulation observed in horses is compensated insulin resistance [17], [18]. It is referred to as “compensated” because the resistance to the action of insulin at the tissue level (primarily muscle) is made up for by hypersecretion of insulin from the pancreas, thereby keeping blood glucose concentrations at or near normal. Thus, horses with compensated insulin resistance typically have blood glucose concentrations within normal limits, have higher than normal

Acknowledgments

The authors would like to acknowledge the contribution of Richard M. Gilley of BioRelease Technologies LLC, Birmingham, AL, who passed away in August, 2014. Rick generously supplied the sulpiride and the proprietary vehicle for experiment 2 presented herein.

The authors thank A. F. Parlow and the National Institute of Diabetes and Digestive and Kidney Diseases, National Hormone and Pituitary Program, Harbor-University of California Los Angeles Medical Center, Torrance, CA, for reagents.

Financial

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    Approved for publication by the Director of the Louisiana Agricultural Experiment Station as manuscript number 2017-230-31371.

    Animal welfare/ethical statement: Procedures used in these experiments were approved by the Institutional Animal Care and Use Committee of the Louisiana State University Agricultural Center.

    Conflict of interest statement: The authors declare that they have no conflict of interest.

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