EMS

• EMS = equine metabolic syndrome
• Equine metabolic syndrome (EMS) is not a single disease, but rather a collection of risk factors for endocrinopathic laminitis. These risk factors include…

  1. Insulin dysregulation
  2. Obesity - However, there are lean animals with EMS. These animals carry a lot of fat around their organs but do not appear to have fat build-up from the outside. Hence do not exclude EMS from your differentials just because the horse has an okay BCS.
  3. Laminitis
• Below is a flow diagram of the components of insulin dysregulation and how these features interact.

  A) hyperinsulinaemia

  B) hyperglycaemia

  C) hypertriglyceridemia

  D) insulin resistance

  
• Hyperinsulinemia is concerning as it is causative and predictive of laminitis. Hence, reducing insulin concentration is key and this can be done via diet, exercise and medication if needed.

  • Dietary management is the most important! Exercise is limited as they have bouts of laminitis but exercise can be increased when the horse is stable from episodes.

  There is no set insulin concentration that is known to cause laminitis this is due to other factors playing a part such as genetics, age, body weight and previous bouts of laminitis.
• EMS is NOT equine diabetes. However, prolonged high insulin can cause pancreatic beta cell exhaustion which mimics diabetes. This is not common but should be considered in the hyperglycaemic horse that is PU/PD, has weight loss and a normal insulin concentration
• Obesity rates vary and doesn’t mean that a horse is hyperinsulinaemic as these features are not co-dependant on each other but are commonly associated with each other.

  • This also applies in the opposite direction. A horse with hyperinsulinemia does not have to be obese
• Adiponectin can be tested for and is commonly low in EMS cases. This negatively impacts insulin sensitivity
• High leptin is associated with laminitis risk. Leptin expression is higher in nuchal fat which shows the importance of regional adiposity as not all adipose tissue has the same level of metabolic activity. We cannot test for leptin.
• regional adiposity = lean but have lots of fat on their neck
• There are genetically predisposed breeds such as native breed ponies, Spanish-derived breeds and warmbloods. There are other risk factors such as horses that are obese or have regional adiposity. There is also pregnancy associated insulin dysregulation (With or without hyperinsulinemia)

  • It is important to consider the risk factors as these highlight who to test.
• Classic presentations are the obese patients especially those with bigger fat pads. In some cases, you need to shave/clip their hair to better see their fat pads. They are also prone to developing swelling near the sheath and mammary glands

  • NOTE - crest fat can be very bad and become fibrosed despite weight loss

  These animals are often an ‘Easy keeper’/’good doer’ so are very thrifty. They may already have laminitis or you may be able to identify divergent hoof rings.
• There is a vast array of tests to choose from but the important ones are…

  • Basal tests (can be done in the yard)
  • Basal insulin concentration
  • Adiponectin (Adipose derived, insulin-sensitising hormone)
  • Dynamic tests (these require planning and hence take longer)
  • Oral sugar test (OST - this has replaced the oral glucose test
  • Combined glucose insulin test (CGIT)
• the basal insulin concentration test can be used to assess response to diet change (as well as diagnosis for EMS)

  • Do not fast beforehand as this is inaccurate
  • Perform this test 1-3 hours after coming off pasture not after big feed to see if they have high insulin during their resting state
  • This is not sensitive so a negative test doesn’t rule it out.
• Low concentrations of Adiponectin are associated with laminitis risk. This test has a place (assessing a ponies risk for laminitis done alongside the basal insulin test) but not everyone finds it useful
• • Ingestion of glucose stimulates the release of incretins which stimulates insulin release. There are many incretins and in horses the important ones include…
  • Gastric inhibitory peptide (GIP)
  • Glucagon-like peptide one - GLP-1 -MOST IMPORTANT despite uncertain mechanism
  • GLP-2 - doesn’t stimulate insulin release but does seem to increase glucose bioavailability
  • A diet high in non-structural carbohydrates (NSCs) causes a decrease in both insulin sensitivity and adiponectin.
  • Hepatic clearance is important for insulin concentration but this is not fully understood
• To perform the oral sugar test

  • Collect baseline insulin –optional due to the high validation
  • Administer oral Karo Light syrup (45 ml/100kg is the most sensitive and know that there are different doses of Karo Light) then 60-90 min later collect blood to test for insulin and glucose.
  • This test is well-validated and relatively inexpensive and doesn’t require a lot of labour.
  • This test includes the whole entero-insular axis which represents reality (their true response) better than IV administration. You can get false negatives and hence the CGIT should be used
• To perform a combines glucose insulin test, fast overnight to collect baseline insulin and glucose. Then administer IV glucose and insulin and take frequent glucose sampling, insulin at 45min. Glucose should be at baseline by 45min, insulin <100 iu/ml
• the combined glucose insulin test looks at tissue insulin sensitivity rather than mimicking what happens in real life as the guts response is not involved. Hence has fallen out of favour.

  • Oral glucose is affected by other factors such as gastric emptying/gut transit and absorption etc. This test does not account for this
• The reason behind these tests are that EMS involves insulin dysregulation…

  • A prolonged hyperinsulinaemic response can be assessed via OST or CGIT
  • Basal hyperinsulinemia +/-hyperglycaemia can be assessed via basal insulin concentration
  • Tissue insulin resistance can be assessed via the CGIT
  • Only reliably tested by the IV glucose routes)
• the insulin tolerance test (ITT) is not a preferred test as can cause hypoglycaemia
• To assess the risk of laminitis you can…

  • Identify hyperinsulinemia
  • Perform dynamic tests
  • Look for decreased adiponectin concentration
  • Assess for concurrent risk factors
  • It is possible to have more than one endocrinopathy at once so if have both risk factors look for both E.g. PPID
  • Look for evidence of previous episodes
  • A bit ‘Footy’ indicates subclinical laminitis
  • Pottering gait and don’t turn corners well
  • Divergent hoof rings
• Hyperinsulinemia leads to laminitis as it causes the lengthening/stretching of secondary epidermal lamellae. The mechanism of how it causes this is unsure.

  • This is different to sepsis related laminitis as there is no destruction of the basement membrane. Hence both these causes of laminitis present the same (pottering gait and struggling to turn the corner) but they are different histopathologically
• Ingestion of glucose stimulates the release of incretins which stimulates insulin release. These incretins are important targets for drugs and hence testing should involve the entero-insular axis
• what is the most important incretin?

  glucagon-like peptide one (GLP 1)
• The management of EMS involves...

  1. Diet - THE MOST IMPORTANT (reduction of carbohydrate intake and management of obesity)
  2. Exercise - this can be increased when the laminitis is stable (Increases insulin sensitivity and helps manage obesity to a degree)
  3. Medication (up and coming)
• what is the common way to reduce the carbohydrate intake in an EMS pony?

  soaking the hay
• Possible medications include...

  • SGLT2 inhibitors (ertugliflozin, canagliflozin) cause them to urinate more glucose out.
  • This can cause hyperlipidaemia (no UTI risk seen in horses). It also seems to be pain relieving as the horses tend to be more comfortable on their feet.
  • levothyroxine
  • this makes them very hungry with a high amount of energy but this is not liked by some practitioners
• Regional adiposity is the accumulation of fat in certain areas such as around the nuchal ligament in the neck (causing cresty neck), tail head fat pads, supra-orbitally, behind the shoulder or the prepuce (Sheath) or mammary gland region. Hence fat is not evenly deposited around the body.
• To classify an animal as obese we need to look at the body condition score.

  • Anything above 5 /9 is overweight
  • Anything above 7 /9 is obese
• Additional components involved in EMS include…

  • Dyslipidaemia (hypertriglyceridaemia)
  • Hypertension
  • Hyperleptinemia
  • Altered reproductive cycling
  • Increased systemic markers of inflammation
• The age range is 5-15 years for affected horses however the pathophysiology may start younger (need to be obese for several years before insulin resistance occurs).

  • Being overweight at a younger age is a risk factor
• there also appears to be a seasonal pattern (Spring-Summer) as there is lush pasture in spring-summer which is rich in sugar and consequently means there is a greater risk of laminitis.
• not all cases of EMS will get laminitis but the risk is very high.

  • The horse may be fine now but they are heading down the route of laminitis. Hence this is a risk not a certainty but the risk commonly develops into a laminitis case
• The pathophysiology is that adiposity leads to insulin resistance which then causes laminitis. However, there are other factors at play…

  • Inflammation and oxidative stress
  • Adiposity will produce pro-inflammatory cytokines that will also induce oxidative stress
  • This is linked to the development of PPID as well as other problems
  • Altered adipocyte function
  • Altered endothelial function
  • Affects the vessels in the foot
  • Pro-thrombotic state
• There are three stages of insulin resistance…

  1. Compensated insulin resistance
  2. Uncompensated insulin resistance
  3. Type 2 diabetes mellitus (end-stage)
• In the compensated insulin resistance stage (the first stage of insulin resistance) there are normal glucose concentrations are maintained by increased insulin output (hyperinsulinemia)

  • This is common in the first 5 years of obesity
• in uncompensated insulin resistance (stage two of insulin resistance) glucose concentrations are increasing. There is also increased insulin concentration (but the quality of the insulin is poor hence the high glucose). This is represented as hyperglycaemia with hyperinsulinemia.

  • This is represented as hyperglycaemia with hyperinsulinemia.
• In the end stage of insulin resistance, there is persistent hyperglycaemia because of inadequate insulin output (pancreatic β-cell exhaustion). Hence you have hyperglycaemia (which can be quite extreme and lead to glucosuria) with hypoinsulinemia.
• insulin resistance can then lead to laminitis but this relationship is complex and only partially understood.

  1. Hyperinsulinemia which then causes…
  2. Endothelial cell dysfunction which then causes…
  3. Digital vasoconstriction. Hence there is…
  4. Impaired glucose uptake from epidermal laminar cells
  5. Altered epidermal cell function or mitosis
  6. Matrix metalloproteinase activation
  7. Pro-inflammatory/pro-oxidative state also in lamellar tissue
• There are many diagnostic tests available which vary in their sensitivity and specificity…

  • Basal glucose/insulin
  • There is a lot of fluctuation during the day and hence is not that useful
  • Oral sugars test (OST) (Karo light)/oral glucose tolerant test (OGTT)
  • This can be done on the road. The owners need to give the horse some sugar syrup and then you take a sample within a couple of hours and measure the insulin levels.
  • Combined glucose and insulin test (CGIT)
  • Often done in referral centres as you need multiple blood samples to be taken over several hours