Review Desregulación de Insulina

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Equine Veterinary Journal ISSN 0425-1644

DOI: 10.1111/evj.12169
Review Article
Insulin dysregulation
N. FRANK* and E. M. TADROS
Department of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, North Grafton, Massachusetts, USA
Division of Veterinary Medicine, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire, UK
Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, USA.
*Correspondence email: nicholas.frank@tufts.edu; Received: 24.01.13; Accepted: 02.08.13
Summary
Abnormalities of insulin metabolism include hyperinsulinaemia and insulin resistance, and these problems are collectively referred to as insulin
dysregulation in this review. Insulin dysregulation is a key component of equine metabolic syndrome: a collection of endocrine and metabolic abnormalities
associated with the development of laminitis in horses, ponies and donkeys. Insulin dysregulation can also accompany prematurity and systemic illness in
foals. Causes of insulin resistance are discussed, including pathological conditions of obesity, systemic inammation and pituitary pars intermedia
dysfunction, as well as the physiological responses to stress and pregnancy. Most of the discussion of insulin dysregulation to date has focused on insulin
resistance, but there is increasing interest in hyperinsulinaemia itself and insulin responses to feeding. An oral sugar test or in-feed oral glucose tolerance
test can be performed to assess insulin responses to dietary carbohydrates, and these tests are now recommended for use in clinical practice. Incretin
hormones are likely to play an important role in postprandial hyperinsulinaemia and are the subject of current research. Insulin resistance exacerbates
hyperinsulinaemia, and insulin sensitivity can be measured by performing a combined glucose-insulin test or i.v. insulin tolerance test. In both of these tests,
exogenous insulin is administered and the rate of glucose uptake into tissues measured. Diagnosis and management of hyperinsulinaemia is recommended
to reduce the risk of laminitis. The term insulin dysregulation is introduced here to refer collectively to excessive insulin responses to sugars, fasting
hyperinsulinaemia and insulin resistance, which are all components of equine metabolic syndrome.
Keywords: horse; insulin; glucose; insulin dysregulation; insulin resistance; laminitis; diabetes
Equine metabolic syndrome

Equine metabolic syndrome (EMS) is a collection of endocrine and
metabolic abnormalities associated with the development of laminitis in
horses, ponies and donkeys [1]. Insulin dysregulation, hyperleptinaemia,
increased adiposity and hypertriglyceridaemia are components of EMS,
and are risk factors for laminitis [2]. Hyperinsulinaemia is a particular
concern because laminitis has been experimentally induced in healthy
ponies and horses by infusing exogenous insulin with glucose i.v. [3,4].
Generalised obesity and/or regional adiposity accompany insulin
dysregulation in many equids with EMS. Horses and ponies with EMS
should also be evaluated for evidence of laminitis, including divergent hoof
growth rings (founder lines) or third phalanx rotation. Mild laminar
pathology does not always cause overt lameness and can go unrecognised
by horse owners. Increased adiposity is evident before laminitis in most
animals, but a lean EMS phenotype also exists, with insulin dysregulation
and laminitis occurring in horses and ponies with normal appearance.
Other terms used in the past to describe EMS include prelaminitic
metabolic syndrome, syndrome X, insulin resistance syndrome,
obesity-associated insulin resistance (IR) and prediabetes mellitus [5,6].
Hyperinsulinaemia
The discussion of hyperinsulinaemia in equids has been complicated by
the different approaches used in the past to assess glucose and insulin
dynamics. Insulin concentrations have been measured in the fed state in
several studies [2,710]. In others, horses have been fasted [1113], and
fasting prior to sample collection was recommended in the 2010 American
College of Veterinary Internal Medicine consensus statement [1].
Fasting hyperinsulinaemia results from persistent stimulation of
pancreatic cells, and in obese human individuals increased insulin
secretion during the interprandial period is attributed to elevated fatty acid
concentrations [14]. Hyperinsulinaemia has also been associated with
obesity in equids and higher fatty acid concentrations were detected in
obese insulin-resistant horses in one study, although hay was available at
the time of sampling [10]. Beta-cell hyperplasia is also a potential cause of
fasting hyperinsulinaemia. Several hormones and nutrients act as insulin
secretagogues and increase insulin concentrations, including incretin
Equine Veterinary Journal 46 (2014) 103112 2013 EVJ Ltd
hormones [15], glucagon, glucose, fatty acids and arginine. Insulinomas

can be accompanied by hypoglycaemia and an increased insulin:glucose
ratio, and are a rare cause of hyperinsulinaemia in other animals [16,17].
Only one case of insulinoma has been reported in equids, in a 12-year-old
Shetland pony that developed seizures [18]. Hypoglycaemia and
hyperinsulinaemia were detected during seizures and increased insulin
secretion was demonstrated during an oral glucose tolerance test and an
i.v. glucagon tolerance test.
Postprandial hyperinsulinaemia is a concern in equids because feeding
occurs on an almost continuous basis when horses and ponies are grazing
on pasture. Even when fasted, digestion continues for many hours within
the equine caecum and large intestine, with production of the
gluconeogenic substrate propionic acid and amino acids [19]. Testing
horses in the fed state allows for better assessment of insulin
dysregulation, but feeds vary in composition and this makes it difcult
to establish reference ranges. Standardised tests are therefore
recommended to diagnose hyperinsulinaemia in horses. The rst option is
an oral sugar test that is gaining acceptance in the USA, where corn syrup
is readily available for purchase [20], and the second is an in-feed oral
glucose test that is used in the UK, performed by mixing glucose powder
into a chaff-based feed in an amount equivalent to 1 g/kg bwt, with
samples collected 2 h later [21].
Hyperinsulinaemia is caused by increased insulin secretion or delayed
insulin clearance, and this problem may be a cause or a consequence of
IR (Fig 1). The accepted explanation for hyperinsulinaemia is that
insulin secretion increases as a consequence of decreased tissue insulin
sensitivity and this is referred to as compensated IR [8]. Decreased hepatic
insulin clearance is also associated with IR and can contribute to
hyperinsulinaemia because >70% of insulin secreted from cells is normally
cleared from the portal blood before reaching the peripheral circulation in
horses [22]. Low connecting (C)-peptide/insulin ratios have been detected
in horses with EMS and provide evidence of decreased insulin clearance
[22]. Connecting-peptide is a component of the proinsulin prohormone,
and is cleaved prior to secretion of the mature insulin peptide from
pancreatic cells. Since C-peptide is released in equal amounts to insulin,
concentrations reect insulin secretion. Unlike insulin, which has a plasma
half-life of only 58 min in humans, C-peptide does not undergo rapid
clearance from the blood by the liver, so blood concentrations reect
pancreatic function and can be used to evaluate hepatic insulin clearance.
103
N. Frank and E. M. Tadros
Excessive insulin
response to sugars
and/or amino acids
Postprandial
hyerinsulinaemia
Tissue insulin
resistance
Obesity has been a component of EMS since the syndrome was

rst proposed in 2002 [28], but hyperinsulinaemia is also detected in lean
horses and ponies [21] and some obese animals have normal insulin
concentrations [11,12]. These inconsistencies can be explained by
considering obesity as modifying factor, with the genetics of the individual
animal determining the magnitude of insulin dysregulation.
Hyperinsulinaemia itself might even promote obesity through the anabolic
effects of insulin on lipid metabolism [14] and contribute to the easy
keeper or good doer phenotype. Horses and ponies with this phenotype
readily become obese when overfed, and obesity can develop when grass
is the only source of energy. A recent study performed with knockout mice
conrmed that hyperinsulinaemia alters lipid metabolism and promotes
obesity [29]. Genetic manipulations affecting the brain and pancreas
generated mice that were incapable of diet-induced hyperinsulinaemia,
and these animals were also protected from obesity and hepatic lipid
inltration. Hyperinsulinaemia, obesity and hepatic IR might therefore
represent a vicious cycle in equids if lipid inltration of the liver slows
insulin clearance and higher fatty acid concentrations induce fasting
hyperinsulinaemia.
Relative hypoinsulinaemia and

diabetes mellitus
Fig 1: The cause-and-effect relationship between insulin resistance and
hyperinsulinaemia.
Although the cause-and-effect relationship between IR and

hyperinsulinaemia appears straightforward, the authors have encountered
horses and ponies with postprandial hyperinsulinaemia that have normal
glucose and insulin responses during the combined glucose-insulin test
(CGIT), which is a test for insulin sensitivity. Other causes of postprandial
hyperinsulinaemia following ingestion of sugars should therefore be
considered, including increased stimulation by incretin hormones,
including glucagon-like peptide 1 and glucose-dependent insulinotropic
peptide [15]. These incretin hormones are secreted from L and K cells,
respectively, within the small intestine in response to ingestion of sugars,
amino acids and fats, and the activity of both hormones is regulated
through degradation by the enzyme dipeptidyl peptidase 4. Both
hormones have been identied in equine plasma after oral administration
of glucose [23,24]. Incretins stimulate pancreatic cell insulin secretion
and slow gastric emptying, thereby minimising postprandial
hyperglycaemia. Postprandial hyperinsulinaemia in horses with EMS might
therefore reect increased incretin hormone secretion or decreased
degradation by dipeptidyl peptidase 4. Furthermore, incretin hormones
increase pancreatic islet mass in rodents by stimulating cell proliferation,
induction of islet neogenesis, and inhibition of cell apoptosis [25]. It is
conceivable that chronic incretin hormone stimulation contributes to cell
hyperplasia and hyperinsulinaemia in horses with EMS. In humans, fasting
glucagon-like peptide 1 concentrations increase in association with greater
clustering of metabolic syndrome components [26].
If the rst manifestation of insulin dysregulation in genetically
predisposed horses is postprandial hyperinsulinaemia, then IR would raise
insulin concentrations even further. These relationships are illustrated in
Figure 2. Obesity, systemic inammation and concurrent endocrinopathies
such as pituitary pars intermedia dysfunction (PPID) are potential causes of
IR that can exacerbate hyperinsulinaemia by slowing insulin clearance.
Hyperinsulinaemia might even induce IR itself through the process of
homologous desensitisation, a process by which tissue sensitivity to
insulin decreases as blood hormone concentrations increase [14]. Acute
increases in insulin concentrations can still stimulate glucose uptake, but
chronic hyperinsulinaemia results in downregulation of the insulin receptor
and downstream signalling. This is the mechanism by which insulinomas
induce IR and is referred to as the Somogyi effect, when higher doses
of exogenous insulin have a diminished effect on blood glucose
concentrations [14]. Evidence for hyperinsulinaemia inducing IR was
provided by a recent study in mice [27]: a high-fat diet induced obesity and
IR, and streptozotocin was administered to one group of mice to lower
insulin concentrations. Insulin resistance was only detected in mice that
developed hyperinsulinaemia.
104
The term hypoinsulinaemia is rarely used because lower limits are not
provided for insulin reference ranges. However, the concept of relative
hypoinsulinaemia is a key component of diabetes mellitus. Type 1 diabetes
mellitus is most commonly caused by immune-mediated destruction of
pancreatic cells, resulting in inadequate insulin secretion, and a rarer
idiopathic form is also recognised in humans. In contrast, type 2 diabetes
mellitus develops when insulin production by cells decreases following
a prolonged period of hyperinsulinaemia. The term pancreatic insufciency
or pancreatic exhaustion are used to describe this process of
decompensation, and Treiber et al. [8] adopted the term uncompensated
insulin resistance to describe horses and ponies with high blood glucose
concentrations that are inadequately controlled by insulin. In diabetes
mellitus, pancreatic insulin secretion decreases as a result of direct
damage to the pancreas and loss of cell mass, whereas inhibition by
hormones such as somatostatin and catecholamines can suppress insulin
Equine metabolic syndrome (EMS)
[Genetic predisposition]
Postprandial
hyperinsulinaemia
Anabolic effects:
Obesity and regional
adiposity
(+)
PPID
Inflammation
Pregnancy
Tissue insulin resistance
At-risk
Disease:
LAMINITIS
Fig 2: Putative relationships among hyperinsulinaemia, obesity, insulin resistance and

the exacerbating factors of pregnancy, inammation and pituitary pars intermedia
dysfunction (PPID).
secretion during stress or illness [30]. In veterinary medicine, type 1

diabetes mellitus is most commonly observed in dogs, whereas type 2
diabetes mellitus is more often detected in cats. Transient Type 1 diabetes
mellitus has recently been reported in a foal [31], and there are reports of
type 2 diabetes mellitus in mature horses in association with pancreatitis
[32], PPID [33,34], granulosa cell tumour [35], and presumed autoimmune
polyendocrine syndrome [36].
Increased understanding of glucose and insulin dysregulation in
horses has led to more frequent recognition of diabetes mellitus,
particularly in horses with PPID [33]. Horses with advanced PPID can
develop transient diabetes mellitus when stress and systemic disease are
encountered, so it is important to monitor blood glucose and triglyceride
concentrations in hospitalised patients. Hyperglycaemia is marked
(>11 mmol/l [2.0 mg/l]) in some horses and accompanied by glucosuria.
Severe hypertriglyceridaemia is also a concern in horses with diabetes
mellitus, and insulin therapy is required to manage hyperglycaemia and
suppress hormone-sensitive lipase. This condition appears to involve cell
insufciency because horses are very sensitive to exogenous insulin and
return to adequate glycaemic control when the primary problem resolves,
or when pergolide treatment is initiated or increased. Hyperglycaemia
alters the amino acid lysine and this leads to the formation of fructosamine,
which alters other amino acids and creates advanced glycosylation
end-products that damage tissues. Higher fructosamine concentrations
have been detected in laminitic horses [37] and are likely to reect the
accompanying stress- and pain-associated hyperglycaemia.
Insulin resistance
Insulin resistance refers to the failure of insulin-sensitive tissues to respond
to insulin, and skeletal muscle, adipose, and liver are primarily affected.
Consequences of IR include impaired glucose uptake into tissues,
increased glucose synthesis in the liver via gluconeogenesis, and
increased lipolysis resulting in higher circulating free fatty acid
concentrations. Insulin resistance is associated with glucose transporter 4
dysfunction within skeletal muscle and adipose tissues [38,39].
Insulin resistance and glucose

Resting glucose concentrations are often towards the higher end of
reference range in horses and ponies with EMS [10], and it is reasonable to
assume that both hyperglycaemia and hyperinsulinaemia are encountered
when these animals are grazing on pasture (Fig 3). Glucotoxicity is a
Interaction: Pasture
January
April
Increase in
starch, sugars, and
amino acids
Insulin
Exacerbation of
hyperinsulinaemia
Jan
Apr
Increased risk of
LAMINITIS
Fig 3: The effect of pasture on hyperinsulinaemia as a risk factor for laminitis.

Postprandial blood glucose and insulin concentrations respond to changes in pasture
grass composition and abundance across different seasons of the year. Starches,
sugars and amino acids raise insulin concentrations and exacerbate preexisting
hyperinsulinaemia in genetically susceptible horses.
consequence of persistent hyperglycaemia in human diabetes mellitus

patients, and hyperglycaemia can result in glycosylation of amino acids
within tissues and the formation of advanced glycosylation end-products.
Tissues become damaged as a result of glycosylation and this process
contributes to the development of diabetic angiopathy [40]. Endothelial
dysfunction is also induced as hyperglycaemia stimulates diacylglycerol
synthesis and activation of protein kinase C. Hyperglycaemia might
therefore contribute to the development of laminitis in horses, and this
hypothesis has been tested in 2 studies. Hoof lamella changes suggestive
of laminitis were induced in healthy Standardbred horses by infusing
glucose i.v. for 48 h [41]. However, in a related study using the
hyperinsulinaemia model [42] advanced glycosylation end-products were
not detected in hoof tissues collected after laminitis was induced. Glucose
might therefore play a role in the development of acute laminitis by
inducing endogenous insulin secretion or altering endothelial function, but
not through glycosylation of amino acids.
Insulin resistance and obesity

Obesity is a pathological condition associated with altered adipokine
production and IR, and inammation plays an important role in obesity in
other species [4346]. As adipocytes reach their maximal storage capacity,
events leading to energy failure, inammation and cellular stress are
initiated [47]. Hypoxia is a factor in adipocyte stress because oxygen only
diffuses approximately 100 m from capillary beds, and adipocyte
diameter expands beyond this limit in obesity [47,48]. The endothelium of
vessels within adipose tissues can also become unresponsive to nitric
oxide-induced vasodilation, and this further contributes to hypoxia [47,49].
Hypoxia leads to a reduction in mitochondrial function and stimulation of
hypoxia-induced genes that promote inammation. Stressed adipocytes,
and those that have become necrotic as a result of hypoxia, release
cytokines such as macrophage chemoattractant proteins that recruit new
macrophages to adipose tissues [47,5052]. Resident tissue macrophages
within adipose tissue tend to be anti-inammatory in prole, whereas
those recruited by stressed cells have a more proinammatory prole [47].
Resident macrophages can also convert to a proinammatory prole
under conditions of adipose tissue hypoxia or when inuenced by
recruited proinammatory macrophages [53,54].
In addition to suffering from hypoxia, adipocytes that are laden with
triglyceride lose their ability to buffer lipid uxes within the body [47,55].
Ectopic lipid deposition and lipotoxicity ensue, contributing to the
development of IR in adipose and other tissues. Lipid accumulation in liver,
muscle, pancreas and other tissues has a negative impact on insulin
metabolism throughout the body [5558]. Insulin normally induces nitric
oxide-dependent vasodilation in certain capillary beds, so loss of insulin
sensitivity further impedes postprandial capillary recruitment and the
delivery of lipids to appropriate storage depots, promoting ectopic
deposition [47]. Accumulation of intermediate lipid metabolites such as
diacylglycerol, long-chain fatty acyl CoA, and ceramide exacerbates cell
stress and incites inammation, and this leads to IR [5961].
Inammatory mediators secreted from adipose tissue act locally and at
distant locations, which may be relevant to equine laminitis because the
vascular endothelium is targeted [62,63]. In obese human individuals and
rodents, increased adipose tissue secretion of inammatory mediators
and adipokines is well described [45], but studies on associations between
obesity and inammatory cytokines have yielded conicting results in
horses. Vick et al. [13] detected positive correlations among body
condition score, blood mRNA expression of tumour necrosis factor
(TNF) and interleukin (IL)-1, and blood TNF protein concentrations in
light breed mares. Regional adiposity, assessed using the cresty neck score
[64], has also been associated with increased plasma TNF protein
concentrations in ponies [2]. Previously laminitic ponies had signicantly
higher plasma TNF protein concentrations than nonlaminitic ponies, and
the same animals had higher neck scores and insulin concentrations.
Detection of hyperinsulinaemia in horses and ponies with regional
adiposity and laminitis raises the question of whether insulin affects
inammatory cytokine concentrations in horses. This has been
demonstrated in horses using an experimental model, with signicantly
higher plasma TNF and IL-6 protein concentrations detected during i.v.
infusion of insulin for 6 h [65]. Average TNF concentrations were 16% and
20% higher than baseline at 4 and 6 h, respectively, in the insulin group.
105
Not all studies have supported the development of a basal

proinammatory state in obese and hyperinsulinaemic horses.
Holbrook et al. [66] demonstrated lower endogenous gene expression of
IL-1 and IL-6 in peripheral blood mononuclear cells from hyperinsulinaemic
obese horses than in controls, and comparable cytokine responses in
both groups following peripheral blood mononuclear cell stimulation.
However, neutrophil oxidative burst activity was signicantly higher in
obese horses, suggesting that immune function is altered by obesity and
hyperinsulinaemia. Suagee et al. [7] were unable to associate obesity with
plasma concentrations of TNF, IL-1 or IL-6 protein in a larger population
of 110 horses. Of the variables examined, only serum amyloid A
concentrations were positively correlated with insulin concentrations and
body condition score. When insulin-resistant and insulin-sensitive horses
were compared by Burns et al. [67], no differences in TNF, IL-1, IL-6 or
macrophage chemoattractant protein-1 mRNA expression were detected
within adipose tissues collected from multiple sites. This study revealed,
however, that expression of IL-1 and IL-6 was signicantly higher in nuchal
ligament adipose tissue, than in other depots, suggesting that regional
adiposity contributes to the increased risk of laminitis in insulin-resistant
horses. It therefore remains challenging to separate the effects of adiposity,
hyperinsulinaemia and IR on inammatory cytokine proles in equids.
Hepatic insulin resistance

Hepatic lipid inltration accompanies obesity in man and can lead to the
development of nonalcoholic fatty liver disease [6870]. Increased plasma
gamma glutamyl transferase activity and post mortem evidence of hepatic
lipidosis have also been detected in obese horses (N. Frank, unpublished
data). Enhanced peripheral lipolysis secondary to IR represents the major
cause of lipid accumulation in the steatotic liver, with a smaller
contribution by de novo lipid synthesis within hepatocytes [71].
Intermediates of fatty acid metabolism are agonists for Kupffer cell pattern
recognition receptors and therefore trigger an inammatory cascade
[56,72], which induces hepatic IR and contributes to systemic inammation
[73]. Recent studies suggest that IL-6 plays an important role in hepatic IR
by suppressing insulin receptor autophosphorylation and tyrosine
phosphorylation of insulin receptor substrate 1 [74].
Hepatic IR may also lead to the development of hypertriglyceridaemia in
horses and ponies. Although plasma triglyceride and very low-density
lipoprotein (VLDL) concentrations are only mildly increased in horses and
ponies with obesity and hyperinsulinaemia [2,10], they are potential
indicators of hepatic IR. Insulin secreted from the pancreas arrives at the
liver via the portal blood and normally suppresses VLDL secretion after
eating, so that triglycerides are stored at times of positive energy balance.
Pathways involved in insulin-mediated suppression of VLDL secretion are
affected by hepatic lipidosis and IR, and lipoprotein secretion increases as
a result [75]. Increased ferritin concentrations are also detected in human
nonalcoholic fatty liver disease patients, and serve as a predictor of liver
damage [76]. Ferritin concentrations were recently measured in obese
horses and a positive correlation existed between ferritin concentrations
and insulin area under the curve values after oral dextrose administration
and corn ingestion [77].
Insulin resistance and adipokines

Leptin is an adipocyte-derived hormone that is produced almost
exclusively by white adipose tissue, and concentrations increase in obese
and insulin-resistant horses as a result of increased fat mass and leptin
resistance [2,10,7880]. Leptin acts as an adiposity signal to keep other
systems in the body apprised of the adipose depot size, and interaction
between leptin and its long-form receptor in the hypothalamus modulates
satiety [81,82]. Intact leptin signalling results in appetite suppression [81]
and might also enhance energy expenditure and reduce hepatic fatty acid
synthesis [83]. In humans, leptin resistance is implicated in overeating and
obesity [84]. Leptin concentrations are positively correlated with body
condition score in horses, ponies and donkeys [78,85], although
hyperleptinaemia is also detected in equids with normal body condition
scores. Hyperinsulinaemia and tissue IR are both associated with
hyperleptinaemia in mares [86]. Leptin might therefore serve as an indirect
measure of adipocyte pathology and insulin dysfunction, and leptin
106
concentrations are included on a diagnostic panel for EMS, with a cut-off

value of 4 g/l for hyperleptinaemia.
Adiponectin is an insulin-sensitising hormone with pleotropic effects
that include enhancement of fatty acid oxidation and improvement of
glucose tolerance [87]. This adipokine also possesses anti-inammatory
properties and counteracts IR caused by cytokines such as TNF [88].
Adiponectin circulates in the form of trimers, hexamers and high molecular
weight multimers [89], and lower concentrations of total [80] and high
molecular weight [90] adiponectin have been detected in obese horses.
High molecular weight adiponectin concentrations were negatively
correlated with insulin concentrations [90].
Leptin and adiponectin are important to the discussion of EMS and
laminitis because both adipokines have direct effects on the vascular
endothelium, as well as indirect effects via modulation of insulin sensitivity
and inammation [9193]. Adiponectin has anti-inammatory actions and
can therefore counteract the effects of cytokines such as TNF on the
endothelium [81,9497]. In contrast, leptin is generally proinammatory
and exacerbates endothelial activation and the generation of free radicals
that damage the endothelium [98,99]. Obese people with adiponectin
deciency have a higher risk of mortality during sepsis, and loss of
adiponectins immunomodulatory effects and protective actions on the
endothelium is believed to be a contributing factor [94].
Insulin resistance and PPID

It is often assumed that PPID predictably causes IR, but this assumption
must be challenged on the basis of clinical experience and the detection of
hyperinsulinaemia in only 32% of horses with PPID [100]. There are a
number of mechanisms that might link PPID with hyperinsulinaemia and IR
in horses. Cortisol antagonises the actions of insulin and causes IR, with
accompanying hyperinsulinaemia, as is readily demonstrated in the rat by
administering dexamethasone [101]. Administration of dexamethasone to
healthy horses also increases plasma insulin concentrations and lowers
insulin sensitivity [102,103]. Hyperinsulinaemia and decreased insulin
sensitivity are recognised consequences of hyperadrenocorticism in dogs,
and diabetes mellitus is commonly detected [104]. Higher C-peptide
concentrations are also detected following glucagon infusion in dogs
with hyperadrenocorticism and provide evidence of increased insulin
secretion [105]. Corticotropin-like intermediate peptide is a derivative
of pro-opiomelanocortin and adrenocorticotrophic hormone (amino
acids 1839), and concentrations increase in horses with PPID [106,107].
This hormone acts as an insulin secretagogue when added to the media
of pancreatic explants [108], and might therefore contribute to the
development of hyperinsulinaemia in equine PPID. Alpha melanocytestimulating hormone (MSH) concentrations are also increased with PPID
[109] and this hormone, along with leptin, plays an important role in energy
metabolism. Under normal conditions, MSH stimulates neural
melanocortin receptors 3 and 4 within the hypothalamus, opposes
the action of leptin, and reduces body fat mass [110]. However,
downregulation of this system as a result of increased MSH
concentrations might have the opposite effect and raise insulin
concentrations through increased visceral adiposity and hepatic IR.
One explanation for the variability in insulin concentrations detected in
horses with PPID is that the condition itself is less predictable than other
forms of hyperadrenocorticism. Adrenal hyperplasia is a common
manifestation of hyperadrenocorticism caused by pars distalis tumours
in dogs, whereas only approximately 20% of horses with PPID develop
this problem [111]. Polyuria and polydipsia are also common features of
canine hyperadrenocorticism, but are only reported in 30% of horses with
PPID [112].
Convergence of PPID and EMS

An alternative explanation for the variability in insulin concentrations
detected in equids with PPID is that this endocrinopathy acts only as a
modifying factor (Fig 2). If hyperinsulinaemia is a genetically determined
trait in equids, then PPID exacerbates the problem by stimulating
insulin secretion via increased corticotrophin-like intermediate peptide
concentrations or by inducing IR though hyperadrenocorticism. When
viewed from this perspective, it is not surprising that in the study by
van der Kolk et al. [113] hyperinsulinaemia had 92% sensitivity as a
diagnostic test for PPID because ponies were over-represented.

Hyperinsulinaemia occurs independently of PPID in ponies [115] and
is detected at all ages [2,9]. If PPID is an exacerbating factor for
hyperinsulinaemia, even as pituitary dysfunction is rst developing, then
early diagnosis of this endocrine disorder is essential. Detection of higher
insulin concentrations at noon, rather than 08.00 h, in horses with PPID fed
hay and chaff the morning of testing also suggests that postprandial
hyperinsulinaemia is exacerbated by PPID [115], and this could increase
the risk of hyperinsulinaemia-induced laminitis.
Systemic inammation and the stress response

to illness
Insulin resistance can develop as a result of mediators released during the
systemic inammatory response (Fig 2). A number of the inammatory
mediators upregulated by nuclear factor B signalling, as well as the
counter-regulatory hormones cortisol, epinephrine, glucagon and growth
hormone, can induce IR [117118]. Transient IR has been induced in
healthy horses by administering lipopolysaccharide i.v., and this is
presumed to occur through increased production of proinammatory
cytokines [119,120]. Cross-talk between the insulin signalling cascade and
inammatory signalling cascades occurs on many levels, and IR results
from inappropriate serine phosphorylation of insulin receptor substrates
and the insulin receptor itself [121]. Cortisol downregulates the expression
of proteins involved in the phosphoinositide 3-kinase signalling cascade
[122,123], including the p85 regulatory subunit [124]. Glucocorticoids also
reduce cellular insulin receptor substrate-1 concentrations in adipocytes
[122,123] and inhibit translocation of glucose transporter 4 to the plasma
membrane [125].
The overall goal of these counter-regulatory mechanisms is to ensure
the provision of adequate energy in the form of carbohydrates, proteins
and lipids to meet the bodys requirements while responding to infection
[126]. Inducing a state of peripheral and hepatic IR tips the balance in
favour of glucose liberation from tissue stores and glucose synthesis via
gluconeogenesis in the liver [127]. However, stress-associated inhibition of
insulin secretion by catecholamines and relative hypoinsulinaemia might
also exacerbate hypertriglyceridaemia in hospitalised horses [128].
Hyperadrenocorticism increases lipolysis and ketogenesis in horses [129],
although exogenous corticosteroid administration did not exacerbate
hypertriglyceridaemia in one study of ponies [130]. Although the
effects of catecholamines on fat metabolism have not been extensively
studied in equids, in other species plasma triglyceride concentrations
increase in response to administration or endogenous release of
catecholamines [131,132].
Alterations in insulin metabolism in the foal

The endocrine system of the foal undergoes many adaptations in the
perinatal period and this subject was recently reviewed by Fowden et al.
[133]. Insulin sensitivity decreases in foals during the rst 24 h of life and
this is attributed to increased circulating cortisol and catecholamine
concentrations. Clearance of exogenous glucose is slower during the rst
1224 h after birth, despite appropriate insulin responses [134]. This may
be part of the adaptation to intermittent nursing, rather than continuous
delivery of glucose via the placenta. Relative hypoinsulinaemia may be
observed in normal foals during the immediate post partum period, and
glucose-stimulated insulin secretion from pancreatic cells is signicantly
lower in healthy foals 2 h after birth, compared to one week of age
[135,136]. It has been suggested that perinatal alterations in the
abundance of insulin receptors and intracellular signalling proteins affect
insulin sensitivity in foals, as has been noted in other species [133].
Survival of premature and dysmature foals is inuenced by the degree of
maturity of several key endocrine systems [133,137]. In particular,
immaturity of the hypothalamic-pituitary-adrenal axis is associated with
impaired stress responses and increased mortality in the face of sepsis
[138140]. Hypoglycaemia and hyperglycaemia can both occur in critically
ill foals [141,142], as in human neonates [143,144]. Premature human
infants and those born small for gestational age because of impaired
placental function are at risk for neonatal hyperglycaemia [144]. Both
peripheral and hepatic IR are demonstrated in preterm human

infants [143,145], and IR can be further exacerbated by sepsis and other
inammatory conditions [144,146]. Relative hypoinsulinaemia also
contributes to the development of hyperglycaemia because pancreatic
cells are immature in premature infants and fail to efciently process
proinsulin to biologically active insulin [145]. As in humans, normal
physiological processes, including transient reduction in insulin sensitivity
within 24 h of birth and relative insulin deciency caused by inefcient
cell secretory function, render neonatal foals susceptible to
hyperglycaemia and other metabolic derangements in the face of
prematurity or critical illness.
Insulin concentrations are low after birth in premature foals delivered via
induced parturition before 320 days, and pancreatic cell responses to
exogenous glucose at age 2 h are also blunted in comparison to full-term
foals [135]. These ndings are attributed to the inhibitory effects of
increased catecholamine concentrations in premature foals. In contrast,
increased cell responsiveness to exogenous glucose, without an
accompanying change in glucose clearance, has been observed in foals
born 2448 h premature after induced parturition [147]. It is assumed that
pancreatic compensation is occurring in response to decreased peripheral
insulin sensitivity as a result of hypercortisolaemia. Studies examining
insulin sensitivity in healthy, full-term human infants born small for
gestational age have yielded mixed results, with both increased and
decreased insulin sensitivity documented over the rst 23 days of life
[148,149]. Relative insulin deciency resulting from reduced pancreatic
cell mass has also been suggested as a contributing factor to
hyperglycaemia [144], which is associated with increased morbidity and
mortality in human neonates [150,151].
Sepsis is a leading cause of death in neonatal foals [152156]. Septic
foals have lower glucose and insulin concentrations and higher triglyceride
and glucagon concentrations than healthy foals, and higher insulin and
lower leptin concentrations are associated with mortality [142].
Hyperglycaemia is associated with increased mortality in critically ill
foals [138,141] and is likely to result from increased production of
inammatory cytokines and stress hormones [116,157]. Sepsis-associated
hyperglycaemia develops as stress hormones such as epinephrine
and cortisol induce gluconeogenesis and IR, and toxins including
lipopolysaccharide bind to Toll-like receptor 4 and impair insulin signalling.
Although some septic foals experience relative adrenal insufciency,
circulating concentrations of cortisol and other stress hormones such
as catecholamines can still be markedly increased and contribute to
IR [138,139].
Pregnancy
In addition to pathological causes of IR, such as obesity, systemic
inammation, hyperadrenocorticism and acromegaly, there are
physiological causes such as pregnancy and stress. Pregnancy is
associated with IR in people and horses (Fig 2), and represents a normal
physiological adaptation [158]. In women, insulin action is 5070% lower
than normal during late pregnancy, and both basal and 24 h mean insulin
concentrations show a 2-fold increase [158]. Postprandial glucose
concentration, basal endogenous hepatic glucose production and total
gluconeogenesis are also increased during late pregnancy. These
alterations are attributed to rising concentrations of prolactin, cortisol and
glucagon, and ensure continuous delivery of nutrients to the growing fetus
[158]. Hyperinsulinaemia, enhanced cell sensitivity to endogenous and
exogenous glucose, increased degradation of insulin, and decreased
insulin sensitivity have all been demonstrated in pregnant mares [159].
George et al. [160] also used the frequently sampled i.v. glucose tolerance
test (FSIGTT) and minimal model analysis to demonstrate that pregnant
Thoroughbred mares had slower glucose clearance and greater insulin
secretion at 28 weeks of gestation than nonpregnant mares. These mares
developed higher glucose and insulin concentrations after meals,
consistent with lower insulin sensitivity and increased insulin secretion.
Assessment of insulin sensitivity

Tissue insulin sensitivity is most accurately assessed by performing
dynamic tests such as the hyperinsulinaemic-euglycaemic clamp (HEC)
107
procedure and FSIGTT with minimal model analysis [161]. The HEC
procedure involves i.v. infusion of soluble (regular) insulin and concurrent
infusion of dextrose solution to maintain glucose concentrations at the
preinfusion euglycaemic level. Because blood glucose concentrations are
held constant during the insulin infusion, the glucose infusion rate
represents insulin sensitivity in muscle and adipose tissues. Vick et al. [13]
evaluated a population of 60 mixed light horse breed mares on pasture
using this test and found that body condition scores were signicantly and
positively correlated with resting insulin concentrations (Spearmans rho =
0.53), and negatively correlated with insulin sensitivity (Spearmans rho =
-0.57) at the time of testing. To perform the FSIGTT procedure, an i.v. bolus
of dextrose is administered rst, followed several minutes later by an i.v.
insulin bolus. While these tests provide the most information about
glucose and insulin metabolism, the time and equipment required to
perform them largely restrict their utility to the research setting.
An insulin tolerance test (ITT) can also be used to measure tissue insulin
sensitivity, and this procedure involves i.v. injection of soluble insulin as a
bolus in amounts ranging from 20 to 125 iu/kg bwt, followed by serial
blood sampling over a 3 h period [86]. Area under the glucose curve is
calculated, or the dose of insulin required to cause a 50% decline in glucose
concentration can be recorded. The ITT has been simplied to a 2-step
insulin-response test consisting of an i.v. insulin injection of 100 iu/kg bwt
soluble insulin followed by blood glucose determination at 0 and 30 min
after injection [162]. Insulin-resistant horses fail to undergo a 50% reduction
in blood glucose concentration within 30 min. When 6 insulin-resistant
horses were compared with 6 controls, the 2-step ITT performed as well as
the conventional test that required 10 blood samples, and is therefore
practical to use in the clinical setting.
A CGIT can also be performed to assess insulin sensitivity, and involves
i.v. infusion of dextrose solution, followed immediately by soluble insulin
[10,163]. Blood glucose concentrations initially increase and then decrease
in response to exogenous (and endogenous) insulin. The time required for
blood glucose concentrations to return to baseline is recorded and the
insulin concentration is measured in blood collected at 45 min. The rate of
decrease in glucose concentrations caused by exogenous insulin reects
tissue insulin sensitivity, whereas the insulin concentration at 45 min is
affected by insulin clearance rate and pancreatic insulin output. Insulin
resistance is diagnosed when the blood glucose concentration fails to
return to baseline by 45 min. However, IR may also be present if normal
glucose results are accompanied by an increased (>100 iu/ml) insulin
concentration at 45 min. In these cases, compensated IR or cell
hyperplasia are suspected, with compensatory increases in insulin
secretion remaining sufcient to maintain normal glucose homeostasis.
Uncompensated IR, in contrast, results in higher glucose concentrations
after dextrose infusion with lower peak insulin concentrations.
Care must be taken when interpreting results of earlier studies that
assessed insulin sensitivity on the basis of resting insulin concentrations.
Factors such as stress or duration of fasting can affect resting insulin
concentrations and introduce variability. Since proxy measures of insulin
sensitivity, including the reciprocal of the square root of insulin (RISQI), are
calculated using resting insulin concentrations [8], hyperinsulinaemia
caused by factors other than IR could also affect these results. The same
concern can be raised with acute insulin response to glucose values
calculated from FSIGTT results [11], because enhanced insulin secretion
caused by increased cell function or hyperplasia might also raise acute
insulin response to glucose values. Proxy measures of insulin sensitivity
remain useful screening tests for detecting insulin dysregulation in larger
populations, but dynamic tests involving the administration of exogenous
insulin are preferred for the diagnosis of IR. Further studies are required to
determine the degree of agreement among FSIGTT, HEC, CGIT and ITT
results in the same horses.
Management of hyperinsulinaemia and

insulin resistance
Potential exacerbating factors for hyperinsulinaemia, including obesity,
high-sugar diets, inadequate exercise and concurrent PPID, must be
considered before establishing a management plan. If obesity is present,
the initial focus of management should be weight loss, and when PPID is
108
diagnosed, pergolide should be prescribed. A complete diet history should

be collected and assessed, and the diet adjusted to reduce the amount of
sugars available if hyperinsulinaemia is a concern. Horses should be
regularly exercised, as this is an integral part of weight management plans
when obesity is a factor.
Body fat mass can be reduced in obese horses and ponies by lowering
energy intake and increasing exercise [164]. Some horses with EMS are
being overfed by their owners, and removal of grain from the diet is
sufcient to induce weight loss. Other obese horses and ponies are
resistant to weight loss and require greater reductions in energy intake
[165]. Pasture access should be restricted in obese animals because
obesity often persists until grass intake is limited, and sugars and amino
acids contained in pasture grass contribute to hyperinsulinaemia.
Recommended strategies for limiting grass consumption include placing
the obese horse and a companion in a small grass paddock that is
0.130.2 ha in size (one-third to one half an acre), or the application of a
grazing muzzle during turnout. Responses to management should then be
reassessed and housing conditions adjusted over time. If removing grain
from the diet and limiting pasture access does not result in weight loss, the
amount of hay fed should be progressively reduced. Hay should initially be
fed in amounts equivalent to 1.5% of current bodyweight and then lowered
to 1.5% of ideal bodyweight. An obese horse or pony that is not losing body
mass after 4 weeks on this diet can be reduced to 1.25%, and then down to
the minimum level of 1.0% bodyweight after another month if there has
been no progress. A balanced vitamin/mineral supplement or ration
balancer should be provided to horses on a hay-only diet to maintain
adequate micronutrient and protein intake.
Attention must also be paid to the sugar content of the diet, and the
importance of this component of the management plan depends on the
severity of hyperinsulinaemia. Hay containing large amounts of simple
sugars and hydrolysable starches is a signicant concern for severely
affected horses. Analysis of the hay is recommended for these animals to
ensure that the nonstructural carbohydrate content of the forage is <10%
on a dry-matter basis [1]. Hay can also be soaked in cold water for one
hour to lower the nonstructural carbohydrate content, although results
vary according to the type of hay used [166]. A supplement containing
additional protein, vitamins and minerals should also be provided.
Hyperinsulinaemic horses with normal body mass are more challenging to
manage. The rst question to be addressed is whether the animal is
concurrently affected by PPID, so horses older than 10 years should
undergo testing for both PPID and IR [112,167]. Previously obese horses
that remain hyperinsulinaemic after weight loss must also be managed
carefully. If weight gain is required, feeds providing more energy
in the form of fat and bre should be selected.
Two medical treatments are also used to manage horses with EMS and
both have specic indications.
Levothyroxine sodium can be administered to accelerate weight loss
when severe insulin dysregulation is present in an obese horse that cannot
be exercised because of laminitis, or when obesity persists despite
intensive diet and exercise management. Levothyroxine sodium lowers
bodyweight and improves insulin sensitivity in horses [168], and can be
administered by mouth or in the feed at a dosage of 0.1 mg/kg bwt once
daily. A higher dosage of 0.15 mg/kg bwt can be selected if obesity persists
after 3 months of treatment. Levothyroxine is administered until the horse
reaches an ideal body condition score or until the end of a 6-month period.
When treatment is discontinued, the dosage is lowered to 0.05 mg/kg
bwt/day for 2 weeks and then 0.025 mg/kg bwt/day for 2 weeks.
Complications have not been associated with the administration of
levothyroxine to healthy horses for 12 months [168], although some horses
exhibit increased activity and mild hyperexcitability when treated. Pasture
access must be restricted when horses are treated with levothyroxine to
prevent the horse from increasing its own feed intake. Levothyroxine is
reasonably priced in the USA, but expensive in the UK.
Metformin hydrochloride is commonly administered to treat diabetes
mellitus in man and has also been reported to improve resting insulin
concentrations and proxy measures of insulin sensitivity in horses and
ponies [169]. However, studies evaluating metformin use in equids have
yielded conicting results, and insulin sensitivity did not improve in
nonobese insulin-resistant ponies when i.v. glucose tolerance tests were
performed to assess glucose and insulin dynamics [170]. This discrepancy
can be explained by the low oral bioavailability of metformin in horses [171]

and recent results indicating that metformin acts at the level of the
intestine to blunt blood glucose and insulin concentrations after feeding
[172]. Metformin therefore appears to be better suited to controlling
postprandial hyperinsulinaemia than to treating IR in horses. The current
recommendation for metformin is 30 mg/kg bwt per os q. 812 h, given
one hour before feeding or turnout.
Future directions
Looking forward, our understanding of insulin dysregulation in mature
horses will be further enhanced when results of studies examining the
genetic basis of EMS are completed and incretin biology is further
investigated in the horse. Insulin dysregulation in foals also requires
additional research so that glucose concentrations can be better managed
in premature foals and those with systemic illness. Relationships between
EMS and PPID also require further study, and evidence must be gathered to
establish links between insulin dysregulation and the development of
pituitary disease.
Authors declaration of interests

Dr Frank consults for Boehringer Ingelheim on research study design.
Source of funding
Dr Frank has received research funding in the past from Boehringer
Ingelheim Vetmedica.
Authorship
Manuscript prepared by Dr Frank with sections contributed by Dr Tadros.
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Equine Veterinary Journal ISSN 0425-1644

*Correspondence email: nicholas.frank@tufts.edu; Received: 24.01.13; Accepted: 02.08.13

Equine metabolic syndrome

hormones [15], glucagon, glucose, fatty acids and arginine. Insulinomas

N. Frank and E. M. Tadros

Obesity has been a component of EMS since the syndrome was

Relative hypoinsulinaemia and

Although the cause-and-effect relationship between IR and

Tissue insulin resistance

Fig 2: Putative relationships among hyperinsulinaemia, obesity, insulin resistance and

N. Frank and E. M. Tadros

secretion during stress or illness [30]. In veterinary medicine, type 1

Insulin resistance and glucose

Fig 3: The effect of pasture on hyperinsulinaemia as a risk factor for laminitis.

consequence of persistent hyperglycaemia in human diabetes mellitus

Insulin resistance and obesity

Not all studies have supported the development of a basal

Hepatic insulin resistance

Insulin resistance and adipokines

N. Frank and E. M. Tadros

concentrations are included on a diagnostic panel for EMS, with a cut-off

Insulin resistance and PPID

Convergence of PPID and EMS

N. Frank and E. M. Tadros

diagnostic test for PPID because ponies were over-represented.

Systemic inammation and the stress response

Alterations in insulin metabolism in the foal

peripheral and hepatic IR are demonstrated in preterm human

Assessment of insulin sensitivity

Management of hyperinsulinaemia and

N. Frank and E. M. Tadros

diagnosed, pergolide should be prescribed. A complete diet history should

N. Frank and E. M. Tadros

can be explained by the low oral bioavailability of metformin in horses [171]

Authors declaration of interests

N. Frank and E. M. Tadros

56. Carpentier, A.C. (2008) Postprandial fatty acid metabolism in the

N. Frank and E. M. Tadros

N. Frank and E. M. Tadros

Equine Veterinary Journal 46 (2014) 103112 2013 EVJ Ltd

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