The Veterinary Journal 186 (2010) 275–276
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The Veterinary Journal
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Guest Editorial
Equine insulin resistance: The quest for sensitivity
Reduction in tissue sensitivity to circulating insulin (insulin
resistance; IR) is becoming an increasingly recognised health prob-
lem in horses (Geor, 2008). Insulin has a wide array of biological
responses, including stimulation of glucose uptake by cells, lipo-
genesis, diminishing lipolysis, DNA synthesis and cell replication.
Tissue sensitivity to insulin is essential to achieve metabolic and
haemodynamic homeostasis, and IR results in a reduced insulin-
mediated response in skeletal muscle, adipose tissue and the liver
to blood glucose levels (Kahn, 1978). In horses (as in humans) IR is
associated with obesity and altered fat metabolism with potential
physiological consequences, including glucose intolerance, endo-
thelial dysfunction, haemodynamic pathology, increased procoag-
ulant factors and increased expression of inflammatory markers
(Reaven, 2004).
IR has been described in horses with an ‘equine metabolic syn-
drome’ (EMS) phenotype, characterised by obesity, regional adipos-
ity, hypertriglyceridaemia, hyperleptinaemia and hypertension
(Frank et al., 2006; Treiber et al., 2006a; Bailey et al., 2008). A typ-
ical IR horse displays hyperinsulinaemia but, unlike in humans, it is
associated with normoglycaemia or only mild hyperglycaemia
(Treiber et al., 2005). Although the prevalence of IR is variable be-
tween breeds, hyperinsulinaemia has been identified in 10–28% of
horses in the populations studied (Geor et al., 2007; McGowan and
McGowan, 2008).
IR and hyperinsulinaemia are associated with an increased risk
of laminitis (Treiber et al., 2006b; Asplin et al., 2007; Bailey et al.,
2008). Indeed, pasture-associated laminitis resulting from IR is
now considered by some to be the most prevalent form of the dis-
ease (Geor and Frank, 2009; McGowan, 2009). The term ‘pre-lamin-
itic metabolic syndrome’ (PLMS) has been used to describe IR horses
at risk of developing laminitis when exposed to certain pasture
conditions (Treiber et al., 2006b). Chronic IR is also of importance
because of a suggested association with early-onset pituitary pars
intermedia dysfunction (PPID, or equine Cushing’s disease) (Frank,
2008).
The precise causal mechanisms linking IR to laminitis are un-
known. Whilst laminitis has been induced experimentally by intra-
venous infusion of high concentrations of insulin in a
hyperinsulinaemic–euglycaemic clamp model (Asplin et al.,
2007), it is unclear whether hyperinsulinaemia exerts a direct
‘lamimitogenic’ effect, or whether associated vascular dysfunction
and/or alteration in glucose metabolism are responsible. Because
of the clinical importance of IR, the condition represents a major
welfare issue, and effective treatment methods are therefore ur-
gently required.
In humans, managemental changes such as dietary modification
and increased exercise, are sometimes sufficient to alleviate IR
(Motala et al., 2006). Whilst regulation of correct feeding and exer-
1090-0233/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tvjl.2009.11.023
cise are both crucial to IR management, these are often difficult to
implement, and practitioners are looking for pharmacological
interventions (although currently there are no licensed products
for the treatment of IR in horses).
In this issue of The Veterinary Journal, an article by Kellie Tin-
worth from Charles Sturt University, and colleagues highlights a
number of potential mechanisms by which IR (or the effects of
IR) could be managed by herbal agents, based on studies in humans
and laboratory animals (Tinworth et al., 2010). The six possible
mechanisms of IR management reviewed are: (1) activation of
insulin receptors, (2) stimulation of glucose uptake, (3) rate reduc-
tion of carbohydrate absorption, (4) activation of peroxisome pro-
liferator-activated receptors, (5) reductions in obesity and (6)
reductions in oxidative stress. It is difficult to prioritise which
mechanisms may be of most benefit in tackling IR, and the authors
write that many of the herbal treatments may have more than one
action. Therapeutics that reduce obesity may be of particular value
in those horses in which control of weight and regional adiposity
through dietary management and exercise is problematic, for
example chronic laminitics with impaired locomotory function.
Tinworth et al. (2010) identified 19 herbal agents (many with
multiple modes of action), which they argue are prime targets
for further research for control of IR in the horse. It may be prudent
to focus any research priority in the first instance on those agents
where anecdotal evidence exists for successful treatment of equine
IR and/or pasture-associated laminitis resulting from IR. Examples
include Vitex agnus-castus (chasteberry), Amorphophallus konjac
(konjac) and Cinnamomum cassia (cinnamon). Appropriate clinical
trials are of course needed to substantiate putative efficacy of these
and other herbal agents in the horse. Data are required on safety,
bioavailability and clearance to allow species-specific dosing re-
gimes to be established.
Important lessons can be learnt from metformin, another natu-
rally-derived potential treatment for IR in horses. Metformin is a
dimethylbiguanide (originating from French Lilac, Galega offici-
nalis) and is the first-line pharmacological treatment of human
type-2 diabetes associated with IR (Hsueh and Law, 1998; Salpeter
et al., 2006). Theoretically, metformin provides a therapeutic strat-
egy for IR in horses, and is being used increasingly under the ‘cas-
cade scheme’ for veterinary application of human medicines to
treat the condition (Vick et al., 2006; Durham et al., 2008; Hustace,
2009). Whilst preliminary investigation into the efficacy of metfor-
min in the horse reported statistically significant effects on im-
proved insulin sensitivity (Durham et al., 2008), recent
pharmacokinetic studies have shown that the bioavailability in
horses was 36–52% lower than in humans and may not reach suf-
ficient levels at previously recommended dose rates to be effective
(Scheen, 1996; Hustace, 2009).
276 Guest Editorial / The Veterinary Journal 186 (2010) 275–276
There is a need for funding bodies to support large scale clinical
trials in this important field of equine research, with studies ideally
following similar robust, detailed and standard protocols thereby
maximising benefits of subsequent meta-analysis of therapeutic
interventions of IR in preventing laminitis. In this regard, World
Horse Welfare is currently funding a double-blinded, randomised
controlled trial to assess the clinical benefit of metformin in lamin-
itic horses in Great Britain. The results from this and other studies
investigating the herbal agents suggested by Tinworth et al. (2010)
will give further understanding of effective management of IR and
our quest to restore tissue sensitivity to insulin to the benefit of the
horse.
Claire E. Wylie
Simon N. Collins
Animal Health Trust,
Lanwades Park Kentford Newmarket,
Suffolk CB8 7UU,
UK
E-mail address: claire.wylie@aht.org.uk (C.E. Wylie)
References
Asplin, K.E., Sillence, M.N., Pollitt, C.C., McGowan, C.M., 2007. Induction of laminitis
by prolonged hyperinsulinaemia in clinically normal ponies. The Veterinary
Journal 174, 530–535.
Bailey, S.R., Habershon-Butcher, J.L., Ransom, K.J., Elliott, J., Menzies-Gow, N.J., 2008.
Hypertension and insulin resistance in a mixed-breed population of ponies
predisposed to laminitis. American Journal of Veterinary Research 69, 122–129.
Durham, A.E., Rendle, D.I., Newton, J.E., 2008. The effect of metformin on
measurements of insulin sensitivity and beta cell response in 18 horses and
ponies with insulin resistance. Equine Veterinary Journal 40, 493–500.
Frank, N., 2008. Endocrinopathies: which test and when? In: Proceedings of the
47th British Equine Veterinary Association Congress, Liverpool, England, pp.
285–287.
Frank, N., Elliott, S.B., Brandt, L.E., Keisler, D.H., 2006. Physical characteristics, blood
hormone concentrations, and plasma lipid concentrations in obese horses with
insulin resistance. Journal of the American Veterinary Medical Association 228,
1383–1390.
Geor, R., Frank, N., 2009. Metabolic syndrome – from human organ disease to
laminar failure in equids. Veterinary Immunology and Immunopathology 129,
151–154.
Geor, R.J., 2008. Metabolic predispositions to laminitis in horses and ponies: obesity,
insulin resistance and metabolic syndromes. Journal of Equine Veterinary
Science 28, 753–759.
Geor, R.J., Thatcher, C.D., Pleasant, R.S., Elvinger, F., Gay, L., Werre, S.R., 2007.
Prevalence of hyperinsulinaemia in mature horses: relationship to adiposity.
Journal of Veterinary Internal Medicine 21, 601.
Hsueh, W.A., Law, R.E., 1998. Cardiovascular risk continuum: implications of insulin
resistance and diabetes. American Journal of Medicine 105, 4S–14S.
Hustace, J.L., 2009. Pharmacokinetics and bioavailability of metformin in horses.
American Journal of Veterinary Research 70, 665–668.
Kahn, C.R., 1978. Insulin resistance, insulin insensitivity, and insulin
unresponsiveness: a necessary distinction. Metabolism 27, 1893–1902.
McGowan, C.M., 2009. Epidemiology and clinical perspective of endocrinopathic
laminitis. In: Proceedings of the 48th British Equine Veterinary Association
Congress 48th, Birmingham, England, p. 31.
McGowan, C.M., McGowan, T.W., 2008. Prevalence and risk factors for
hyperinsulinaemia in ponies. Journal of Veterinary Internal Medicine 22,
734.
Motala, A.A., Pirie, F.J., Rauff, S., Bacus, H.B., 2006. Cost-effective management of
diabetes mellitus. Ethnicity and Disease 16 (S2), 79–84.
Reaven, G.M., 2004. Insulin resistance, cardiovascular disease, and the metabolic
syndrome: how well do the emperor’s clothes fit? Diabetes Care 27, 1011–1012.
Salpeter, S., Greyber, E., Pasternak, G., Salpeter, E., 2006. Risk of fatal and nonfatal
lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane
Database Systematic Review (CD002967).
Scheen, A.J., 1996. Clinical pharmacokinetics of metformin. Clinical
Pharmacokinetics 30, 359–371.
Tinworth, K.D., Harris, P.A., Sillence, M.N., Noble, G.K., 2010. Potential treatments for
insulin resistance in the horse: a comparative multi-species review. The
Veterinary Journal 186, 282–291.
Treiber, K.H., Kronfeld, D.S., Geor, R.J., 2006a. Insulin resistance in equids: possible
role in laminitis. Journal of Nutrition 136, 2094S–2098S.
Treiber, K.H., Kronfeld, D.S., Hess, T.M., Byrd, B.M., Splan, R.K., 2005. Pre-laminitic
metabolic syndrome in genetically predisposed ponies involves compensated
insulin resistance. Journal of Animal Physiology and Animal Nutrition 89, 427–
433.
Treiber, K.H., Kronfeld, D.S., Hess, T.M., Byrd, B.M., Splan, R.K., Staniar, W.B., 2006b.
Evaluation of genetic and metabolic predispositions and nutritional risk factors
for pasture-associated laminitis in ponies. Journal of the American Veterinary
Medical Association 228, 1538–1545.
Vick, M.M., Sessions, D.R., Murphy, B.A., Kennedy, E.L., Reedy, S.E., Fitzgerald, B.P.,
2006. Obesity is associated with altered metabolic and reproductive activity in
the mare: effects of metformin on insulin sensitivity and reproductive cyclicity.
Reproduction, Fertility and Development 18, 609–617.