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Wednesday, March 30, 2011

Laminitis Research: Equine Insulin Resistance Does Not Respond to Metformin Medication; Diet and Exercise Remain Key to Laminitis Prevention

Morning all
Researchers in Australia tested the effects of a human medication, metformin, on ponies with insulin resistance, a condition that puts horses at risk for developing the endocrine or metabolic form of laminitis. The medication had no effect. (J.A. Holland image)
New research on the pharmacological management of the condition of insulin-resistance in horses and ponies has suggested that diet and exercise are still key in any management plan.

Insulin resistance (IR) is defined as the diminished ability of a given concentration of insulin to exert its normal effect on glucose dynamics in particular. This causes the body to keep releasing more and more insulin in order to elicit an effect. This may be one of the most predictable factors that determines whether a horse or pony could be more susceptible to what is commonly known as the "endocrine" or "metabolic" form of laminitis.
The University of Minnesota College of Veterinary Medicine's Equine Genetics and Genomics Laboratory explains insulin resistance this way:
Insulin  is a hormone involved in the regulation of glucose (sugar) levels in  the blood and tissues of the body.  In response to feeding, insulin is  secreted by the pancreas into the blood stream. Insulin in the blood  stream directs the glucose (sugar) absorbed from the food into the  body’s tissues including liver, fat and muscle.  Insulin resistance  occurs when insulin no longer has a normal effect on the tissues. In the  insulin resistant horse, the pancreas releases insulin into the blood  stream, and the insulin arrives at the tissues and binds the cells,  however the glucose enters the tissue cells at a much lower rate than  normal. This lower rate of glucose uptake into tissues results in higher  levels of blood glucose.

Horses and ponies compensate for  insulin resistance by secreting even more insulin into the bloodstream  in order to keep the blood glucose concentration within the normal  range.  Therefore, horses and ponies with EMS (Equine Metabolic Syndrome) have a higher  concentration of insulin within the blood, which can be measured to  determine if insulin resistance is present.
An important goal for owners and vets should be to prevent IR from developing, or to manage it before it contributes to the development/progression of other potentially life-threatening conditions. While the correct management of energy intake and exercise levels is thought to be essential, in some cases medication is also considered, especially when increased exercise is not possible. With no licensed drugs currently available for the treatment of IR in horses and ponies, off-label medications used for IR in humans are sometimes prescribed.

A trial was conducted by the School of Animal and Veterinary Sciences at Charles Sturt University in New South Wales, Australia and the Department of Clinical Studies at the University of Pennsylvania's New Bolton Center, in collaboration with the Waltham Equine Studies Group in Great Britain.

The study's intention was to confirm the positive effect of the human medication metformin on insulin and glucose dynamics in insulin-resistant ponies so that this treatment could be used as a positive control in other studies.

Glenys Noble BAppSc(Equine Studies) PhD, along with PhD candidate Kellie Tinworth BSc(hons) MSc, carried out the clinical trial in Australia. Six insulin resistant, non-obese ponies were repeatedly monitored by means of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin ia a drug reported to enhance insulin sensitivity of peripheral tissues in humans without stimulating insulin secretion. It was administered twice-daily (15mg/kg BW BID) to three of the ponies for 21 days.

Meanwhile, the three remaining ponies formed a control group, and each received a placebo. After a wash-out period, the treatments were crossed over.  A Frequently Sampled Intravenous Glucose Tolerance Test (FSIGT) was conducted to evaluate the level of insulin resistance before and after each treatment.  The ponies' body weight, body condition score and cresty neck score were also assessed. They did not change during this study.

Ray Boston MSc PhD
is Professor of Applied Biomathematics in Clinical Studies at the University of Pennsylvania's New Bolton Center. He analyzed the data using MinMod, a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test, and Stata 10.1 statistics analysis software. No change in insulin sensitivity or glucose dynamics was seen under the control conditions or in response to the dose of metformin given in this study to these ponies.  

What does this study mean to horse owners? Clare Barfoot RNutr is the research and development manager at the British feed company Spillers®; she reviewed the research and said: “Although clinical trials with metformin are ongoing, this trial was consistent with our previous work showing that the bioavailability of metformin in horses is poor, and chronic dosing at these levels may not achieve therapeutic blood concentrations.”

She continued: “On this basis it would seem that a fiber-based diet that is low in starch (found in cereals) as well as  (being low in) sugar and fructans (found in grass), in conjunction with regular exercise if possible, is still the safest and most effective way to manage insulin-resistant ponies. It is important to recognize that, even if other doses of metformin are shown to be beneficial in the future for certain sub-groups of animals, full consideration to diet and management should remain a key tactic.”

The Waltham® Equine Studies Group, headed up by Dr Pat Harris MA PhD, VetMB DipECVCN MRCVS, provides the scientific support for the Spillers® and Winergy® brands sold in Great Britain.

To learn more: K. D. Tinworth, R. C. Boston, P. A. Harris, M. N. Sillence, S. L. Raidal, G. K. Noble (In press). The effect of oral metformin on insulin sensitivity in insulin-resistant ponies The Veterinary Journal; Available online 23 February 2011, doi:10.1016/j.tvjl.2011.01.015.

Thanks to Spillers for sharing this information with Hoofcare and Lameness.

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2 comments:

Heidi Meyer said...

Of course, frequent and correct trimming that balances the coffin bone and keeps the torque of high heel/long toes from causing stress on the laminae should be THE most important thing. A healthy hoof capsule can handle more stress to the laminae than one that is already compromised.

El-Goog said...

Inadequate dose.
Inadequate sample size.
Inadequate study length (maximum of 3 weeks dosing).
Inappropriate outcome measures vs clinically meaningful weight loss or laminitis episodes.
Contradicted in rhe same journal - see http://onlinelibrary.wiley.com/doi/10.1111/evj.12068/full