OBESITY INSULIN RESISTANCE CUSHINGS DISEASE LAMINITIS

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Isabel Griffin
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1 OBESITY INSULIN RESISTANCE CUSHINGS DISEASE LAMINITIS

IN HUMAN MEDICINE METABOLIC SYNDROME AFFECTS AT LEAST 27% OF ADULTS IN U.S. AND CONTINUES TO INCREASE AS OBESITY AND LACK OF EXERCISE IS A PART OF MODERN LIFE.

2 IN HUMAN MEDICINE METABOLIC SYNDROME AFFECTS AT LEAST 27% OF ADULTS IN U.S. AND CONTINUES TO INCREASE AS OBESITY AND LACK OF EXERCISE IS A PART OF MODERN LIFE. MORE RESEARCH IS DONE ON THE HUMAN SIDE BUT SIMILARITIES CAN BE SEEN IN EQUINE METABOLIC SYNDROME WITH HUMAN METABOLIC SYNDROME.

3 OBESITY AND IR REPRESENT THE CORNERSTONE OF BOTH METABOLIC SYNDROMES. ALTHOUGH LONG RECOGNIZED AS BEING ASSOCIATED WITH OBESITY, IT HAS MORE RECENTLY BECOME APPARENT THAT EXCESSIVE VISCERAL FAT RATHER THAN TOTAL FAT IS THE PRINCIPLE RISK.

4 Horses are herbivores and evolved to rely on grass forage for their nutritional requirements. In nature in the fall they ingest increasing quantities of grass and gain weight in preparation for the winter. Increased appetite, fat deposition, and thickening hair coat are hormonally driven by the hypothalmicpituitary axis. These survival mechanisms evolved for winter survival in nature.

5 If left alone, in nature the environmental harshness ends but the fat stores should be depleted by Spring before the onset of fresh green grass. In nature therefore, acquiring fat is a survival mechanism evolving over centuries but in excess and its chronic persistance cause serious adverse health risks.

6 Due to natural selection, some breeds have developed thrifty genes for survival in harsh climates (easy keepers). A human example is the Pima Indian tribe. Historically lean and active, now in the modern world inactive and obese have the highest incidence of type-2 diabetes in the world.

7 Some pony breeds, being more insulin resistant than horses, may represent equinespecific examples of this phenomenon.

8 FAT TISSUE ACTS LIKE GLAND Adipose tissue (fat) is no longer regarded as simply storage tissue for energy or to fill space. In 1994, leptin was discovered. It is secreted by adipocytes and involved in the pathogenesis of disease in obese individuals.

9 The results of this study have resulted in the new field of study called adipobiology. Adipose tissue has remarkable traits in that it can expand easily (to provide storage to stave off starvation in nature under harsh conditions). However, when perisistant this trait increases the risk of obesity-associated conditions such as vascular disease and diabetes (humans) and IR in horses.

10 It is now recognized that adipose tissue releases a plethera of adipokines responsible for increasing the risk of adipose-associated diseases. Adipokines now represent the missing link between IR and cardiovascular disease in humans.

11 Recent findings show what is secreted from adipose tissue depends on where that adipose tissue is located (SQ vs visceral). It is now becoming increasingly clear that adipose tissue secretes bioactive substances (adipokines) that influence insulin sensitivity and cause vascular injury.

12 TAKE HOME MESSAGE: It is the secretion of inappropriate quantities of adipokines over time that represents the basic pathophysiological foundation of many (if not most) of the health consequences of obesity. Obesity Paradigm: An Introduction to the Emerging Discipline of Adipobiology, Johnson, Philip J. et al. AAEP Proceedings Vol. 52 p41-49.

13 DEFINITION: IR is a condition in which there is a failure of tissues to respond appropriately to insulin. WHAT IS IR? Insulin is a hormone produced and secreted by the pancreas in response to glucose absorption into the bloodstream after eating.

14 Insulin binds to receptors on cell surfaces triggering events that allow glucose to be taken into the cell from the bloodstream.

15 Insulin facilitated uptake of glucose is done primarily in muscle and adipose tissue where it is used for energy or storage (glycogen or fat). Another very important and fascinating location dependant on insulin fascilitated uptake of glucose is the equine hoof-lamellar interface.

16 TWO THEORIES EXIST ON THE RELATIONSHIP BETWEEN IR AND LAMINITIS: THEORY #1: IR decreases the uptake of necessary glucose uptake into keratinocytes in the hoof starving them and compromising their attachment.

17 THEORY #2: IR affects blood flow to the foot. Studies that support this theory have not been done in horses, but it is known in humans that insulin is a vasodilator and IR has been associated with decreased peripheral circulation.

18 SO IF IR INCREASES THE RISK OF PASTURE ASSOCIATED LAMINITIS, WHAT IS THE TRIGGER TO THE LAMINITIC EPISODE? NSC: non-structural carbohydrates within pasture grasses seem to play an important role.

19 NSC: simple sugars, starch and fructans vary in grasses considerably according to geographical location, soil, weather, and time of day. NSC affect susceptible horses in two ways: High sugar intake exacerbates IR like it does in humans High sugar intake alters the bacterial flora in the large intestine.

20 Alterations in hind gut flora then trigger production of exotoxins, endotoxins, and vasoactive amines believed to be triggering factors in laminitis. Which are involved in triggering the event is yet to be identified, but alterations in hind gut flora is inducible by oral administration of oligofructose (a fructan).

21 DIAGNOSIS: Resting serum-insulin concentrations. Horses should be fasted or fed only grass hay overnight and stress should be avoided at collection. Leptin. A hormone produced and secreted by adipose tissue. Used to differeniate hyperinsulinemia due to IR (EMS) and other causes such as pain associated with laminitis, stress, or samples collected in the nonfasted animal.

22 TWO STRATEGIES TO ADDRESS: DIET EXERCISE

23 OBESE HORSES WITH IR: PUT ON A DIET TO LOSE WEIGHT! sweet feeds eliminated if no laminitis: allow to graze easy keepers: limit grazing if still too heavy (1-2 hours/day; muzzle) Hay should be primary dietary component

24 HAY ANALYSIS IS STRONGLY RECOMMENDED: NSC <12% If not, soak the hay. Protein and trace mineral supplements, OK.

25 EXERCISE: Encourage exercise as consistently as possible Lunge or in hand daily to bring to ideal weight.

26 NON-OBESE HORSES WITH REGIONAL FAT DEPOSITS: Typically these are horses with Cushings disease Diet and exercise similar to previous but with more calories. No sweet feed: replace with fat and fiber. Up to 20% of calories can be fat in the form of vegetable oil or rice bran. Low- carb commercial feeds ok.

27 HORSES WITH IR AND LAMINITIS: OFF PASTURE GRASS HAY WITH LOW NSC CONCENTRATES OF FAT AND FIBER UNTIL LAMINITIS SUBSIDES

28 AFTER ACUTE PHASE PASSES: PUT ON A REDUCTION DIET HAY WITH LOW NSC THYRO-L CAN BE USED TO ACCELERATE WEIGHT LOSS: shown to reduce body-fat mass and improve insulin sensitivity.

29 SOME HORSES WITH CHRONIC LAMINITIS, IR AND/OR CUSHINGS HAVE TO BE TAKEN OFF PASTURE INDEFINITELY.

30 EQUINE CUSHINGS DISEASE, PPID OR PITUITARY PARS INTERMEDIA DYSFUNCTION, IS ONE OF THE MOST COMMON DISEASES OF HORSES AND PONIES OVER 15 YEARS OLD. 1 out of 7 horses over 15 years of age are estimated to suffer from PPID and as young as 7 years old.

31 Up to 70% of clinical laminitis cases have equine cushings (PPID) as the underlying cause. All breeds and types can be affected although Morgans and ponies have an increased risk. No gender predilection; age of onset of clinical signs is generally, although it is seen as early as 7 years old.

32 PATHOGENESIS: Recent studies support the cause is a primary hypothalamic disease: Oxidative injury and degeneration of dopaminergic neurons in the hypothalamis that have inhibitory effects on the par intermedia occurs. Loss of inhibitory control leads to proliferation of the pars intermedia. Horses with PPID develop pituitaries up to 5 times normal weight.

33 CLINICAL SIGNS: HIRSUTISM: long, sometimes curly hair coat that fails to shed. HYPERHIDROSIS: excessive sweating is observed in up to 2/3 of horses with PPID. LETHARGY. MUSCLE WASTING: Loss of epaxial and rump muscle (top line).

34 CLINICAL SIGNS: WEIGHT LOSS: Also due to dental issues in these older horses. ABNORMAL FAT DEPOSITION: cresty neck, over the tail head, behind the eyes and in the sheath of male/gelded horses. CHRONIC INSIDIOUS-ONSET LAMINITIS: Major clinical complication in more than 50% of horses with PPID. Chronic pain from laminitis and associated foot abscesses is the most common reason for euthanasia.

35 CLINICAL SIGNS: PU/PD: Drinking and urinating excessively occurs in approximately 1/3 of cases. DELAYED WOUND HEALING/LOWERED IMMUNE RESPONSE: Results in secondary infections such as skin infections, subsolar abscesses, gum disease, sinus infections, conjunctivitis, and bronchopneumonia.

36 CLINICAL SIGNS: A DISASTROUS AND LESS COMMON COMPLICATION IS SUSPENSORY DESMITIS AND BREAKDOWN:

37 DIAGNOSIS: TESTS AVAILABLE INCLUDE: SCREENING TESTS: ACTH concentrations. DYNAMIC TESTS: i.e. DEXAMETHASONE SUPPRESSION TEST, assesses the response of the hypothalamic-pituitary axis.

38 DYNAMIC TESTS: DEXAMETHASONE SUPPRESSION TEST: Considered the GOLD STANDARD. The major limitation is the concern, although poorly documented at the dose for the test, of exacerbating laminitis with dexamethasone.

39 DYNAMIC TESTS: THYROTROPIN RELEASING HORMONE STIMULATION TEST: Unfortunately the results can be complicated. It was recently found over 30-50% increase in cortisol concentration in 10 out of 16 and 7 out of 16 normal horses. Therefore not the most reliable test for PPID.

40 DYNAMIC TESTS: COMBINED DEX-SUPPRESSION/TRH STIMULATION TEST: The combined DST/TRH test was more accurate (81%) than either the DST (71%) or TRH (71%) alone. Unfortunately all tests were less accurate than hirsutism alone (86%). Also, the combined test is both more expensive to the client and less practical for ambulatory practice. It has not gained much acceptance.

41 SINGLE SAMPLE SCREENING TESTS: ACTH: Problematic: sample handling can affect results as ACTH is absorbed onto glass and degraded enzymes in both whole blood and plasma. Seasonal variation: More than 90% of horses and ponies had above normal concentrations in September compared to less than 5% in January and May.

42 NOTE: Although less affected by season, as many as 26% of normal horses were positive with the DST in September. Recent findings have led to a decline in the popularity of using the ACTH concentration test alone for diagnosis.

43 SINGLE SAMPLE SCREENING TESTS: INSULIN: Unfortunately, hyperinsulinemia can accompany other disorders. Used alone, insulin concentrations are not specific for PPID. However, it is useful to know if concurrent IR is present as long term survival is poorer in PPID horses with concurrent hyperinsulinemia.

44 COMPLETE INITIAL DIAGNOSTIC WORKUP RECOMMENDED: PHYSICAL EXAM CBC, CHEMISTRY LATERAL HOOF RADIOGRAPHS DST/ACTH/INSULIN/LEPTIN

45 MANAGEMENT: Clipping Teeth, at least once/year Attention to nutrition Regular trimming of feet Treat secondary infections

46 MEDICATIONS: CYPROHEPTADINE: This drug may be of some benefit, although clinical improvement has been disputed. Adverse affects are minimal. Since there are anti-histamine effects, some drowsiness or mild sedation may be seen.

47 MEDICATIONS: PERGOLIDE MESYLATE: This drug has been shown to be more effective than cyproheptadine in three independent studies. Most common adverse effects include a mild decrease in appetite for the first few days of treatment in 5-10% of horses.

48 MEDICATIONS: EVITEX OR HORMONIZE: An herbal product made from chasteberry advocated for treatment of PPID. The claim was supported by case testimonials in which the diagnosis of PPID was poorly documented. In a field study presented at the 2002 AAEP Convention by Beech et al. it was shown that this herbal product was ineffective for the treatment of PPID.

49 RESPONSE TO TREATMENT: IMPROVED SHEDDING OF HAIR COAT, SEEN BEST IF TREATMENT INITIATED IN MARCH vs OCTOBER. IMPROVED ATTITUDE AND ENERGY DECREASED WATER CONSUMPTION DECREASED SWEATING

50 ONCE PRESENT, PPID IS A LIFELONG CONDITION. FOLLOW-UP ENDOCRINOLOGIC TESTING IS RECOMMENDED q/6 months (DST/ACTH) to monitor dosage. PPID can be effectively treated with management and medication. Prognosis for correction of the disorder is poor. Prognosis for life is guarded to fair.

51 THERE ARE LIMITED LONG TERM STUDIES OF HORSES WITH PPID HOWEVER IN ONE REPORT THE SURVIVAL TIME FROM INITIAL DIAGNOSIS TO DEVELOPMENT OF COMPLICATIONS NECESSATATING EUTHANASIA RANGED FROM DAYS IN FOUR UNTREATED HORSES.

52 THERE ARE SEVERAL ANECDOTAL REPORTS OF HORSES BEING MAINTAINED FOR SEVERAL YEARS WITH CLOSE MONITORING AND MEDLICAL TREATMENT. NOTE: HYPERINSULINEMIA IS A NEGATIVE PROGNOSTIC INDICATOR. INSULIN CONCENTRATIONS ARE THEREFORE RECOMMENDED IN THE INITIAL EVALUATION AS WELL AS ON- GOING FOR MANAGEMENT.

53 AAEP CASE -CONTROL STUDY: PASTURE AND ENDOCRINOPATHY- ASSOCIATED LAMINITIS IN HORSES Lupine Valley Equine is participating to further research on this disease. QUESTIONS? THANK YOU

Johnson, Philip J. BVSc, MS, Diplomate ACVIM, Diplomate ECEIM,MRCVS et al. Obesity Paradigm: An introduction to the Emerging Discipline of Adipobiology. AAEP Proceedings 2006; 52:41-49.

54 Johnson, Philip J. BVSc, MS, Diplomate ACVIM, Diplomate ECEIM,MRCVS et al. Obesity Paradigm: An introduction to the Emerging Discipline of Adipobiology. AAEP Proceedings 2006; 52: Frank, Nicholas DVM, PhD,Diplomate ACVIM. Insulin Resistance in Horses. AAEP Proceedings 2006; 52: Schott,Harold C. II DVM,PhD,Diplomate ACVIM. Pituitary Pars Intermedia Dysfunction: Challenges of Diagnosis and Treatment.. AAEP Proceedings 2006; 52: White, Nathaniel II, DVM, MS, Diplomate ACVS. Equine Colic.. AAEP Proceedings 2006; 52:

Nutrition for the Metabolic/Cushingoid Horse. Ocean State Equine Associates 2205 Providence Pike North Smithfield, RI 02896

Nutrition for the Metabolic/Cushingoid Horse Ocean State Equine Associates 2205 Providence Pike North Smithfield, RI 02896 Goals What are PPID and EMS? What is their link to IR? How is IR linked to laminitis?