Diagnosing equine metabolic syndrome

Equine metabolic syndrome (EMS) is also known as atypical Cushing’s disease or peripheral Cushing’s disease. It results in significant peripheral insulin resistance, but the exact aetiology is unknown. It tends to be seen in horses under 10 years of age; however, it can be seen in older horses. EMS is a syndrome of obesity, laminitis and insulin resistance (IR). IR is now more commonly called insulin dysregulation (ID).

Obesity is not a significant factor on its own and appears to be strongly linked to genetic predisposition, especially in some of the susceptible British pony breeds. Clinical signs include recurrent laminitis that is often seasonal, polyuria/polydipsia and abnormal weight distribution (including “cresty” neck). Hirsutism, abnormal coat shedding and sweating are not usually found in EMS, and this helps to differentiate EMS from equine pituitary pars intermedia dysfunction (PPID).

How is EMS diagnosed?

Basal cortisol levels may be significantly increased above the reference range, which results in high glucose levels in many cases. Insulin levels are frequently raised, but there is considerable variation over 24 hours. Endogenous ACTH (eACTH) is expected to be within the normal range or borderline high. There are some cases, however, that have values considered consistent with PPID. EMS cases tend to test negative on an overnight dexamethasone suppression test, so this can be a useful test to differentiate EMS and PPID.

EMS cases tend to test negative on an overnight dexamethasone suppression test, so this can be a useful test to differentiate EMS and PPID

In EMS, there are some factors present that can be assessed. These consist of obesity, ID and dyslipidaemia as the most readily available. Further components such as blood pressure, uric acid or adipokines may also be helpful, and further investigation will establish whether these are of significant value.

Obesity estimates/measurements

In most cases obesity estimates and measurements, through visual assessment or body condition scoring, are subjective. More objective measurements may be obtained by ultrasonography or morphometric measures of, for example, girth and rump width.

Dyslipidaemia

Increased serum triglycerides are suggestive of obesity and ID. However, some studies suggest that these are not any more accurate than the tests listed above when diagnosing EMS (Frank et al., 2010). Treiber et al. (2006) provides interesting opinions on the use of insulin to glucose ratios and derivatives when diagnosing EMS.

High resting glucose is not a common finding in cases of EMS; however, it is advisable to record this in all cases to help pick up the occasional type II diabetes mellitus occurrence

EMS or ID usually occurs in a subset of animals with PPID and appears to be associated with an increased risk of laminitis and a worse prognosis. It is worth noting that high resting glucose is not a common finding in cases of EMS; however, it is advisable to record this in all cases to help pick up the occasional type II diabetes mellitus occurrence.

Testing for insulin dysregulation

Hyperinsulinaemia

Insulin levels may be raised on a basal sample. But if there is doubt, a dynamic test of insulin resistance can be used, for example, oral sugar/glucose test or insulin resistance test.

Insulin measurement

Ensure the patient has not been fed any carbohydrate for 12 hours before collecting samples and that the horse has not exercised that day.

Elevated insulin values over 50IU/ml without having a carbohydrate meal are likely to be caused by insulin resistance or ID. However, there are numerous factors that influence insulin concentrations, and the sensitivity and specificity of these cut-off values have not been determined. Although high insulin suggests ID, low insulin does not rule it out. Many ID cases are only detected when excessive endogenous insulin is secreted in response to oral or intravenous glucose and/or delayed return to normal glucose levels following a glucose challenge (consistent with glucose intolerance).

Resting basal insulin may be used to assess the insulinaemic effect and, therefore, the laminitis risk of the current diet (forage or pasture).

In-feed oral sugar and glucose tests

An in-feed oral sugar test… can be performed at the stable premises and is useful in suspected IR/ID cases with normal fasted insulin concentrations

An in-feed oral sugar test (OST) or an oral glucose test (OGT) can be performed at the stable premises and is useful in suspected IR/ID cases with normal fasted insulin concentrations.

Protocol

• Fast the patient from three to eight hours or perform at pasture
• Request owner to give a non-glycaemic feed (chaff) containing light corn syrup (0.15ml/kg to 0.45ml/kg) or glucose or dextrose powder (0.5 to 1g/kg). You should also wet the feed to facilitate mixing and ingestion. It is also possible to give the sugar directly but you may be met with some resistance
• Serum insulin is measured between 60 and 90 minutes after feeding for an OST, or after 180 minutes for an OGT

Interpretation

Serum insulin over 60IU/ml (0.15ml/kg OST), over 110IU/ml at 60 minutes (0.45ml/kg OST) or 85μIU/ml at 180 minutes (1g/kg OGT) is considered consistent with ID.

In one study, the OST and OGT agreed – with respect to a binary classification of animals – as ID or insulin-sensitive in 85 percent of animals (Smith et al., 2015). However, in another study, the repeatability of the OST was poor, with the within-subject coefficient of variation (CV) of the OST at any single time point being 32 percent when animals remained at pasture or 40 percent when animals were starved (Knowles et al., 2017). The repeatability of the OGT was fair, with the median CV of the insulin concentration at 120 minutes being 19 percent (de Laat and Sillence, 2017).

Additionally, the OST and OGT are affected by season, with greater OST insulin responses occurring in summer compared to winter and greater OGT insulin responses occurring in autumn and winter compared to spring and summer. It should, however, be remembered that the sensitivity and specificity of these cut-off values have not been reported, and these cut-off values are specific to the assays used in the studies to measure serum insulin concentrations.

Insulin resistance test

Protocol

• Fasting is not required; however, grain-based food should be withheld
• Measure basal glucose
• Give 0.1IU/kg regular (soluble) insulin intravenously
• Measure glucose after 30 minutes

Interpretation

In the single study reporting its use, blood glucose concentrations decreased by more than 50 percent from baseline in all six normal horses, while the decrease was less than 50 percent in all six horses with tissue insulin resistance (Bertin and Sojka-Kritchevsjy, 2013).

Horses should not be fasted when performing an IRT as fasting decreases the response to insulin. It should be acknowledged that the IRT sensitivity and specificity are unknown, and its repeatability has not been reported. A small amount of grain may be fed or IV dextrose administered immediately after the 30-minute sample is collected to reduce hypoglycaemic risk (though this is unlikely to occur in horses where there is a suspicion of ID).

Combined insulin-glucose tolerance test

The combined insulin-glucose tolerance test (CGIT) is no longer recommended for use in clinical practice as it is considered too complex and expensive for routine clinical use, although it can provide relevant information in research settings. CGIT is not, however, an appropriate substitute for the OST/OGT or IRT to diagnose EMS.

Protocol

• Fast the patient overnight
• Measure basal glucose and insulin
• Give 150mg/kg 40 to 50 percent glucose solution intravenously immediately followed by 0.1IU/kg soluble insulin
• Collect samples for glucose at 1, 5 and 15 minutes, then every 10 minutes up to 45 minutes, then every 15 minutes up to 2.5 hours
• Test the 45-minute sample for insulin

Interpretation

The Equine Endocrinology Group has reported that the dynamic tests (ie OST/OGT) cause only transient alterations in glucose and insulin concentration and do not induce laminitis

In a normal horse, the peak blood glucose occurs at around 1 to 5 minutes and reaches 2 to 2.5 times the baseline. The blood glucose usually remains above the baseline for between 30 and 45 minutes, followed by a negative phase for a further 1 to 2 hours where the blood glucose is below the original baseline. In a case of ID, this is expected to have a higher peak and a longer positive (over 45 minutes) and shorter negative phase, or sometimes there is no negative phase. A 45-minute insulin concentration of over 100IU/ml also implies ID.

Note that the Equine Endocrinology Group has reported that the dynamic tests (ie OST/OGT) cause only transient alterations in glucose and insulin concentration and do not induce laminitis.

Reasons for reduced sensitivity and specificity of tests for PPID and EMS

The effect of season is well documented, resulting in variable output of hormones from the equine pituitary pars intermedia or PIA. Other reasons for the reduced sensitivity and specificity of the available tests for EMS may include the facts that:

1. There is a lack of histological diagnosis consensus for PPID. As a result, no gold standard exists to validate antemortem tests
2. PPID is a progressive disease and diagnostic tests appear to have greater accuracy when applied to cases with more advanced clinical signs. Their sensitivity and specificity in early cases that do not include hypertrichosis as a clinical sign have yet to be adequately determined
3. ACTH is not one of the main products of the equine PIA. Therefore, greater diagnostic accuracy may be achieved by measuring alternative, as-yet undetermined, hormones, or even the plasma POMC peptide signature

Conclusion

In conclusion, a diagnosis of EMS requires a combination of detailed history, clinical signs and a combination of diagnostic tests. The effect of season and the current health status of the individual should also be taken into account. For further information on EMS please refer to the Equine Endocrinology Group.