Equine Cushing’s Disease (ECD), Insulin Resistance (IR) and Equine Metabolic Syndrome (EMS)

1. Equine Cushing’s Disease (ECD), Insulin Resistance (IR) and Equine Metabolic Syndrome (EMS) Amy M.Gill, Ph.D.

2. Excessive Weight or Obesity leads to: • Increased stress on heart and lungs • Greater risk of laminitis/ founder • Increased risk of developmental orthopedic problems in growing horses • Increased strain on feet, joints, and bone • Accentuated pain from arthritic conditions • Reduced reproductive efficiency • Lethargy/easily fatigued when exercised

3. Excessive Weight or Obesity leads to: • Development of lipomas • Increased risk of hyperlipidemia • Increased insulin resistance • Difficulty regulating body temperatures • Fatty tissue accumulated around key organs –can impair function • Development of Equine Cushing’s(EMS), Equine Metabolic Syndrome(EMS) and/or Insulin Resistance(IR)

4. To reduce weight: • Reduce caloric intake! • Eliminate “grain” rations • Feed grass hay low in NSC, small amounts several times daily • Supplement with vit/min mixture or “lite” supplement • Increase exercise • Limit pasture intake w/muzzle

5. Why are horses developing these disorders? • ECS – older population? Living longer, advanced vet care?...or daily stress/starch affects normal endocrine profiles? • EMS – overweight population – “pear or apple shape” – similar to human phenotype – elevated cortisol from the omentum • IR – why foals??? – survival mode – conserve body stores of energy….

6. Why are horses developing these problems? • IR - Mares – efficient placental transfer of glucose…… • IR - Horses in training…too much stress (cortisol + starch..) • Excitable behavior – starch/confinement – “sugar buzz” - RER • “Horses are not tolerant of changes in blood glucose and insulin levels”

7. Horses with ECD, EMS and IR: • All have insensitivity to insulin & aberrant carbohydrate metabolism • Cannot tolerate starches, sugars, fructans • Untreated horses eventually suffer laminitis

8. Performance – requires supplementation • Fermentable fiber, NSC and fat are main energy sources • Supply dietary energy which is converted into Adenosine Tri Phosphate (ATP) for metabolism, exercise, milk production etc. • Glucose used metabolically several ways – predominant pathways - aerobic and anaerobic • Fats – used only aerobically • Horses in heavy training need some NSC in diet for rapid glycogen repletion but all other classes fair better with low inclusion rates in the total diet (gluconeogenic).

9. Problem: Starch not easily digested • Can metabolize starches/sugars to glucose in sm. intestine via mammalian enzymes but produce small amounts of salivary and pancreatic amylase • Easy to exceed capacity of SI. • Critical capacity of small intestinal digestion about 0.4% of body weight “sweet” feed • May be only 0.2% depending on starch (resistant corn starch vs. oat) • Individual sensitivity must be considered

10. Problem: Glucose absorption is not simple in the horse • Regulated by two classes of carrier proteins: • 1st -Na+/glucose co-transporter type (SGLT1) – moves glucose from lumen into cells in intestinal wall • 2nd -Facilitative glucose transporter (GLUT) –moves glucose from wall into bloodstream • Both become sluggish with chronic sugar loading over time • Both are slow to respond to abrupt dietary changes

11. Problem:Resistant starches and fructans • Other non fiber carbohydrate (NFC) such as resistant starches (corn), fructans and galactans are not subject to mammalian enzymes • Rapidly fermented in hindgut – shifting ratios of VFA in favor of more lactate and propionate

12. Pasture grass and harvested forages:Can have high NSC and NFC! • Drought, climate, time of day can affect amount of starch, sugar and fructan in grass • Overgrazed pasture – more fructans • Lush, normal growth pasture lowest in fructans (high energy) • Freezing – thawing – concentrates sugar – “survival” for grasses • Bran, weeds can be high in NSC • Dead, brown grass in dry areas (drought stressed) • Limiting fertilizer - smaller plants, more conc. NSC

16. Exotoxins “Trigger Factors” Laminitis Gas Colic Dehydration Events leading to Metabolic Disorders Starch, fructan overload or organ failure Gastrointestinal disturbance Lactic Acid Blood Flow altered in hoof pH Matrix Metalloproteinases(MMP’s) Kills Cecal “good” Bacteria Lactobacillus, Streptococcus Bovis increase Gut Motility Slows (Fermentation Continues)

17. ECD • Adenoma or enlargement in pituitary gland (insufficient dopamine - neurotransmitter?) “In horses with ECD, there appears to be insufficient DOPamine being released from the hypothalamus. DOPamine inhibits the pars intermedia of the pituitary gland. Therefore when there is less DOPamine there is less inhibition of the pars intermedia which then increases in size”

18. ECD • What causes hyperplasia? • Theory: “chronic stress” decreases dopamine secretion by hypothalamus, causing loss of control of intermediate lobe of pituitary gland and leading to the development of hyperplasia in the pituitary gland.

19. Pathophysiology of ECD • Pituitary gland contains cells (melanotropes) that normally use dopamine to process beta-endorphin hormones • Cushing's horse - because dopamine is not present- melanotropes produce small amount of corticotrophin – this stimulates cortisol production from adrenal glands.

20. Hypothalamic-pituitary axis • Normal negative feedback to decrease cortisol production does not work since melanotropes have no cortisol receptors. • Cortisol release continuously Low Dopamine Enlarged X

21. ECD • Generally in horses over age 15 years • 70 % over 20 years may be affected • Obese at first, prone to laminitis,colic extreme hair growth, fat deposits • Overtime lose muscle, supra-orbital swelling, runny eyes, lethargic, immuno-suppressed

22. EMS • Previously Peripheral Cushing’s – inactive cortisone converted to active cortisol by enzyme activity in fat cells (adipocytes) in liver or surface of bowel • Symptoms similar to ECD- may not have shed out problem, fat in sheath, rump and neck, seen in younger horses

23. Fat over tail head Fatty sheath

24. Classic EMS Phenotype

25. IR in Performance Horses • Horses can be IR without ECD or EMS • Have normal blood glucose levels but show elevated resting insulin levels VERY FIT HORSES CAN BE IR!!

26. Diagnosis for ECD • Dexamethasone Suppression Test (DST)– measure base cortisol, inject corticosteroid – normal horse decreases ACTH, cortisol • ECD horse – not responsive to corticosteroid. ACTH and cortisol stay high. – can induce laminitis if in acute stage • Can also measure *ACTH* but hormone unstable in tube– can get low values (time of day/year)

27. Other diagnosis for ECD • Blood glucose – high values good indicator so long as no stress • Blood cortisol – two samples 8 h/apart – if no change – good diagnosis – no stress • Blood insulin – good indicator if no stress • DST best definitive diagnosis…

28. Pharmacological Treatment for ECD CYPROHEPTADINE (seratonin blocker) PERGOLIDE(dopamine agonist) TRILOSTANE, inhibitor of adrenal cortisol synthesis, used in dogs

29. Diagnosing EMS • DST not definitive - no problem with pit-adrenal feedback loop • Resting Blood glucose/insulin – must fast 5 hours – severe cases usually have high resting levels • Less severe cases - Oral or IV Gluc. Tolerance Test – measure rise in blood glucose and insulin – slow return to normal indicates disorder

30. Diagnosing IR • *IV Glucose* - Higher resting glucose + delayed return of glucose and insulin to normal levels VISUALLY!!!!!

31. Managing horses with Metabolic disorders • MUZZLE • EXERCISE • Avoid starch in diet – pasture, forage concentrates • More soluble fibers, moderate fat, mixed lower quality hay (check NFC, NSC) • Biguenides (metformin, glucophage) : gluconeogenesis, SI absorption, sensitivity to insulin • Byetta: Insulin secretion

32. Increasing fat/digestible fiber in concentrates maintains the ENERGY content of the feed but reduces the percentage of starch in the total ration

33. Calorie Density - Fat vs. Oats 3 2.5 2 Relative 1.5 Calorie Oats Concentration 1 Fat 0.5 0 Ingredient Maintaining Body Condition in the Performance Horse Fat has 2.5 times as much calories per gram as oats

34. Vegetable fats • Highly digestible/palatable – vegetable highest, animal least (not recommended for horses) • Easily absorbed from small intestine, hard to bypass • Bile from liver – adequate for emulsification • Fats do not produce glycemic response • Reduce excitability

35. Soluble Fiber – “Super Fibers” • Higher in energy than most long-stemmed forage, equal to that of oats • Very palatable • Enhance microbial fermentation rate, improving digestion of other fiber, even mature (poorer quality) hay • Allows reduced long stem forage feeding safely if necessary

36. Safe grazing and forages • Graze overnight, or in the morning when fructan levels are lower, rather than late afternoon or early evening • Soak hay in hot water 30 minutes • Grazing muzzles • Rotate pasture, prevent overgrazing • Fertilize, mow • Test hay before buying (NSC 10% or below)

37. Chromium and Magnesium Chromium is aka “Glucose Tolerance Factor (GTF)” may be useful in increasing receptors for insulin thus reducing insulin resistance. Magnesium deficiency interrupts insulin secretion from the pancreas and increases insulin resistance in body tissues

38. Dosage • Magnesium (Mg) – 6 g/500 kg bw/d • Magnesium oxide – 56% Mg = .56 X 6= 10.7 g/d • Chromium (Cr) – 5 g/d as chromium yeast/500 kg bw

39. Disorders related to ECD, EMS and IR

40. Laminitis/Founder Failure of the attachment between the distal phalanx (coffin bone) and the inner hoof wall

41. Exotoxins Laminitis Gas Colic Dehydration Events leading to Laminitis Starch, fructan overload or organ failure Gastrointestinal disturbance Lactic Acid pH Blood Flow altered in hoof Matrix Metalloproteinases(MMP’s) Kills Cecal “good” Bacteria Lactobacillus, Streptococcus Bovis increase Gut Motility Slows (Fermentation Continues)

42. Laminitis - three phases: • Developmental - 8- 40 h, no pain, lamellar disintegration • Acute - Onset of hoof pain • Chronic - lameness, sloughing of hoof • MMP’s (Matrix Metalloproteinases) – enzyme responsible for normal growth of hoof • When inhibiting factors are suppressed by trigger factors - MMP’s cause epidermal cells to detach from basement membrane • Hoof separates from the distal phalanx

43. Normal BM Epidermal cells detached from BM

44. Prevention – during developmental stage: • Key is to prevent MMP activator from reaching hoof (Streptococcus bovis ssp. – “trigger factor”?) NSAIDS – “Leaky gut” • Digital blood vessels dilate during developmental phase - Use ice to restrict dilation – “shut down” metabolism • Cold - prevents stimulation of macrophages and hence expression of tumor necrosis factor along with other cytokines, which may be a stimulus for MMP activity.

45. Standing in ice……..helps • (Arteriovenous anastomoses) AVA Shunts – normally open and close periodically to warm hoof during freezing temps • With laminitis - Stay open • Blood bypasses caps – no perfusion - die • Bounding pulse • Constant cold shuts down cellular metabolism • Summary – want to prevent activation of MMP’s and damage to capillaries

46. Management:Laminitis • Limit starch/sugar intake • Use alternative “energy” sources • Hay w/ protein/vitamin/mineral supplement • Muzzle at risk horses on pasture • Turn out, trim hooves regularly • Physical therapy • Biguenides, Byetta, ECD meds.. • Chromium/magnesium supplementation? • Sterile Bovine Colostrum

47. Sterile Bovine Colostrum • SBC - Rich Source of Growth Factors • IGF-I, IGF-II, TGF-β and epidermal growth factor (EGF) stimulate growth and repair processes in the gastro-intestinal tract

48. Developmental Orthopedic Disease (DOD) • Foals 3-12 month may be IR, mechanism to store fat • DOD risk may be increased with high intake of starches/sugars, particularly Osteochondritis Dissecans (OCD) at this time • Meal feeding starch increases insulin, growth hormone, insulin-like growth factor (IGF-1) and decreases thyroxine (T4) for 4 hours post feeding • IGF-1 responsible for production of articular cartilage • T4 cartilage into chondrocytes • Halted conversion of cartilage to chondrocytes following starch meal

49. Pregnancy • Progressive insulin resistance • Mare shifts utilization of substrate from glucose to fatty acids: Improves placental transfer of glucose to fetus • Condition: Macrosomia • Large foals – storing glucose as fat • Produce high insulin • Dystocia • Humans: newborns problems regulating blood glucose, jaundiced (immature liver, high RBC)

50. Pregnancy • Insulin Resistance – post foaling and re-breeding complications? • Humans: higher incidence of spontaneous abortion and congenital deformities • Long term effects of starch feeding on mare hormone profiles and subsequent effect on developing fetus?