The Missing Link in Laminitis: Healthy Horse - Laminitic Horse

Page 1 The Missing Link in Laminitis: Healthy Horse - Laminitic Horse One of the greatest impediments to understanding and developing effective treatment for laminitis is embedded in the name itself. The word laminitis literally means inflammation (itis) of the laminae. So these horses have continued to be considered as having a disease of the hoof and treatment strategies have, for the most part, remained stuck with ministering to the hoof problem and the laminae inflammation. Though there are hoof recoveries, the horse invariably continues to have repeated laminitic episodes. That is because laminitis is a metabolic disease that affects the hoof, not a disease of the hoof per se. My research has shown that laminitis and type 2 diabetes are more than similar and that the damage to the hoof is an end product of this disease process. If there is going to be any possibility of recovery for these horses the whole horse needs to considered and not just the hoof. This is a long and involved article, but it gets to the heart of the story of laminitis. Although this material is difficult to follow, it explains for the first time, how laminitis begins, progresses and continues. All horses need the sugar glucose to survive - it is the essential energy source of all cell life. Horses have glucose circulating in the blood, available for the cells as needed, including the cells of the laminae. Horses are also able to produce more glucose in the liver from non-carbohydrate sources when the demand is extended. In healthy horses this production of excess glucose stops once the demand is met. In laminitic horses it continues past the immediate needs and contributes to the already excess of glucose in the liver and the circulating blood. To begin to understand how to reverse laminitis it is essential to know where and how this production of excess glucose in the liver starts and stops in the healthy horse and in the laminitic horse. What has become evident through my research is that laminitis is rooted in the dynamic relationship between the enzyme 11beta-Hydroxysteroid Dehydrogenase-1 (11beta-HSD1) and the sustained activation of glucocorticoids in tissue-specific cells at particular target sites. This enzyme is the pivotal switch in the activation process that not only leads to elevated glucose in the blood but also all the parameters of equine metabolic syndrome. Glucocorticoids Glucocorticoids are steroids (hormones) found naturally in the body and produced by the adrenal cortex, the outer layer of the adrenal glands which sit on top of the kidneys. Glucocorticoids regulate carbohydrate, fat and protein By Joseph Thomas, PhD Printed in: Natural Horse Volume 8, Issue 5 Glossary of terms and definitions: Cortisol: the major natural glucocorticoid, secreted from the adrenal cortex, that affects the metabolism of glucose, protein and fats, as well as regulates the immune system. Due to its direct impact on these very important systems cortisol is referred to as an active glucocorticoid. Cortisone: a natural glucocorticoid secreted from the adrenal cortex that is metabolically convertible to cortisol. Given this function of waiting to be converted to cortisol, cortisone is considered inactive until this process occurs. Beta cells: the only cells in the pancreas that secrete insulin. Hypothalamus, corticotropin releasing hormone (CRH), and Hippocampus: the hypothalamus and hippocampus are brain centers that are both dramatically affected by glucocorticoid activity. The hypothalamus produces corticotropin releasing hormone (CRH) which is the predominant stimulator of ACTH from the pituitary gland (refer to Figures 2 &3). Both these brain centers are seriously influenced by stress leading to glucocorticoid activation and increased blood glucose levels and inhibition of cellular glucose absorption, even within the hippocampus nerve cells. Triglycerides: a natural fat synthesized from carbohydrates for storage in fat cells. metabolism. Glucocorticoids also inhibit the release of adrenocorticotropic hormone (ACTH, a hormone secreted from

Page 2 the pituitary gland. ACTH regulates blood cortisol, and cortisol opposes the action of insulin.) The wide-ranging actions of these steroids are directed at intensifying the production of high-energy fuel, i.e. glucose, and reducing all other metabolic activity (such as immune response) that is not directly supportive of this demand. In the evolution of the horse, this action has been essential for survival as it provides the energy needed for quick response, rapid flight, and endurance. Among these glucocorticoids that provide this burst of energy are two that are also involved in the origin, development and progression of laminitis and diabetes mellitus (DM). These two are cortisol (which opposes the secretion and the action of insulin) and cortisone (which waits to be converted to cortisol when more cortisol is needed). 1 Diabetes mellitus is defined as "belonging to a group of diseases exhibiting elevated blood glucose due to deficient insulin concentration and/or aberrant insulin activity". 2 Laminitis shares these aspects of the DM disease process, as well as many others. It is well established that excess glucose in the blood goes along with decreased glucose consumption by the hoof s laminae and that this glucose deprivation is a significant contributor to laminae separation. 3 Insulin, secreted from the beta cells of the pancreas, is responsible for pushing glucose into cells, and of course that means laminae cells as well. In a healthy horse, cortisone and cortisol convert from one to the other (cortisone being the inactive form and cortisol being active) according to the body s needs. The self-regulatory nature of this conversion process in healthy horses works on over-drive in laminitic horses resulting in a sustained activation of cortisol thereby producing excess blood glucose. Through this sustained activation, the same metabolic process essential for the horse's survival becomes the source of laminitis. The Missing Link 11beta-Hydroxysteroid Dehydrogenase-1 The progression of laminitis and diabetes described in the previous article of this series (NHM Volume 8, Issue 4, The Easy Keeper: Myth and Dangers) showed that there is an elevation of circulating blood insulin in the early stage of laminitis and DM followed by a decreasing insulin level and a concomitant rise in serum glucose. Furthermore, it was shown that as laminitis progresses insulin levels in the blood decrease and blood glucose elevates which is indicative of beta cell damage. Recent research shows, in addition, that: 1) there is a striking increase in the activity of the enzyme known as 11beta- Hydroxysteroid Dehydrogenase-1 (11beta-HSD1) in the beta cells when there is sustained activation of cortisol and 2) that the activity of this enzyme has damaging effects on the pancreatic beta cells after the onset of diabetes but not before. 4 As beta cell function is identical across species, the clear implication of this research is that this is the same way that beta cells are damaged in laminitis. What is 11beta-HSD1's activity and purpose? 11beta-HSD1 regulates glucocorticoid activity. It is through this enzyme s expression at specific target sites throughout the body that cortisone is converted to cortisol. The term expression is used rather than concentration because it is the effects of 11beta-HSD1 rather than its quantity that influence the glucocorticoid activity at these particular places. 11beta-HSD1 s expression in the liver, fat, muscle and brain tissue is pivotal in the development of laminitis. 5 It is through this expression in the fat and muscle cells that the fat deposits develop that are so familiar in laminitic horses. Even more fundamental to the development of these fat deposits is the liver. 11beta-HSD1 s expression in the liver promotes the excess triglycerides that form the fat deposits. The Easy Keeper: Myth and Dangers article in the previous issue of NHM explains exactly how the liver creates these fat deposits in laminitic horses. The effect of the conversion of cortisone to cortisol through the expression of 11beta-HSD1 occurs through the glucocorticoid receptor (GR). This is a molecular structure within the target cells of the liver, fat, muscle and brain that allows for selective binding of cortisol. This means that the glucocorticoid conversion process is actually a very tissue

Page 3 The Missing Link in Laminitis specific activity, e.g. cortisol binds to a liver cell or a fat cell. 11beta-HSD1 expression in the liver cell, for example, converts inactive cortisone into active cortisol amplifying its effect through the glucocorticoid receptor. 6 This has the effect of quickly accumulating an excess of cortisol in the liver cells while rarely effecting a surplus of circulating blood cortisol. In the liver the intensified expression of 11beta-HSD1 stimulates an increase in phosphoenol-pyruvate carboxykinase (PEPCK), the crucial enzyme that elevates glucose production. This happens through a process known as gluconeogenesis in which glucose is made from non-carbohydrate sources in the body, e.g. amino acids. Remember in healthy horses, this is useful when extra glucose is needed for situations such as stress related activities that might induce a fight or flight response, yet in laminitic horses, this is just more glucose on top of already too much. It doesn t end there - higher levels of blood glucose are also produced through this enzymatic activity as well as all the other parameters of insulin resistance, including obesity. This strongly suggests that increased local glucocorticoid action in the liver contributes to the development of type 2 diabetes in people6 and laminitis in horses. Figure 1 graphically presents this process. Both the hypothalamus and the hippocampus, centers in the brain, have high levels of glucocorticoid receptors allowing for the rapid conversion of cortisone to cortisol through 11beta- HSD1 expression. As both of these centers are highly sensitive to stress, the high number of glucocorticoid receptors in these areas indicates that stress is also a trigger for sustained activation of cortisol, and indeed the research indicates that glucocorticoid activation occurs within minutes of a stressful situation. 7 This means that stress is a very real factor in laminitis. The conversion of cortisone to cortisol through the expression of 11beta-HSD1 within the liver. This conversion process results in enhanced activation of glucocorticoid receptors (GR) influencing the enzyme PEPCK, thereby producing excess levels of glucose both in the liver and the circulating blood. Negative Feedback Loop of the Pituitary-Adrenal Glands The negative feedback loop of the pituitary-adrenal glands is a current explanation of the metabolic breakdown in horses with Cushing s syndrome and laminitis. This explanation describes these horses as having excess blood levels of ACTH and variable levels of cortisol, occasionally stated in excess, indicating a defective feedback loop of this system. 8 Given this understanding, the laboratory blood tests that are frequently chosen to determine the presence or absence of these metabolic issues assess the concentrations of cortisol and ACTH circulating in the blood. The evolution of this understanding of the Equine Metabolic Syndrome has been heavily influenced by the research into the human condition of Cushing s disease. In humans, Cushing s disease involves a pituitary gland tumor or, more rarely, an adrenal gland tumor. The tumors indeed disrupt the normal regulation of the feedback loop and certainly do produce excess blood levels of ACTH and variable levels of cortisol. However, although pituitary tumors have been reported in some elderly horses through post mortem examination, these horses had no previous history or recorded reports of any symptoms or signs of Cushing s. 9 In 1999, Johnson and Gamjam of the University of Missouri, both veterinarians and researchers, presented another model for explaining Cushing s without a tumor based on the enzymatic activity of 11beta-HSD1 in peripheral tissue, the skin of horses. It was labeled as Peripheral Cushing s where inactive cortisone converts to active cortisol creating

Page 4 cortisol excess in peripheral skin tissue though not in the blood stream. 10 This 1999 veterinarians research might have just found the important piece, though not the site. The Hypothalamic-Pituitary-Adrenal Axis Circulating free cortisol, secreted from the adrenal cortex into the bloodstream, has the ability to cross cell membranes for interaction with target receptors. It is this free cortisol that is needed at the specific target sites previously mentioned so that the horse has the correct amount of glucose to sustain the life of the body s cells. Healthy glucocorticoid activity is occurring at these receptors ceaselessly throughout the horse s daily life. The conversion process between cortisone and cortisol by 11beta-HSD1 dictates glucocorticoid access to receptors at the target sites. The Hypothalamic-Pituitary-Adrenal (HPA) axis is the supplier of the circulating free cortisol through an intricate feedback loop described as simply as possible in the following section. (Figure 2 is offered as visual assistance to the HPA axis description.) The secretion rate and concentration of this free cortisol is regulated through the release of ACTH, a derivative of a peptide known as POMC (proopiomelanocortin) located in the pituitary gland. The hypothalamus also has a primary influence through the corticotropin-releasing hormone (CRH) that enhances the secretion of ACTH through the stimulation of POMC. There are two other primary factors influencing the concentration of free cortisol in the bloodstream at any given time. The first of these is the circadian regulation. This refers to the daily rhythm through high and low concentration times of ACTH release and circulating cortisol. In a healthy horse these concentrations remain relatively constant. In laminitic horses the low cortisol levels are higher than in healthy horses, stimulating a continual over-drive of the HPA axis. The second primary factor is stress. 11 Both the hypothalamus and the hippocampus are acutely responsive to stressful situations as they trigger the release of CRH thereby enhancing the secretion of ACTH. This can happen within minutes of the stressful situation. These areas are activated by emotional and physical stress, including exercise that goes beyond the physical limits of the individual horse, as well as acute and chronic illness. Illness is a trigger in laminitic horses as they have compromised immune systems due to an aspect of the HPA axis known as the immuneadrenal axis. Further discussion of this issue is beyond the scope of this article, yet it is important to know that the immune involvement within the metabolic syndrome is also a consequence of the relationship of 11beta-HSD1 and glucocorticoid conversion. Practical Significance As a horse owner, knowing that the root of laminitis involves sustained activation of glucocorticoids through enzymatic regulation at very specific target receptors may seem too abstract to help you help your horse. But in reality this information reinforces the absolute need to follow careful care and management practices. Because laminitic horses already have this sustained activation of glucocorticoids and the nature of the receptors is to amplify their effects, anything that increases this activity can initiate an acute episode. There are three factors in particular that are clear from this information: The HPA axis. The main sites for feedback control by circulating blood cortisol are the pituitary gland (1) and the hypothalamic-corticotropin releasing center (2) which secretes CRH. Feedback control also involves higher nerve centers (3), i.e. the hypothalamus and hippocampus of the brain, and is triggered by stress. There is also a short feedback loop dealing with inhibition of CRH by ACTH (4). The hypothalamic neurotransmitters influence the secretion of CRH and ACTH as well as the inhibition of CRH. 'Adrenal' refers to the adrenal cortex.

Page 5 The Missing Link in Laminitis 1 The introduction of any amount of glucose to a laminitic or insulin resistant or Cushing's horse through sources such as grain or sweets or sugar-rich grass sets the enzymatic process into over-drive. 2 An oral administration of cortisone, one of the many corticosteroids given for a wide range of health problems, is rapidly activated to cortisol and so increases the blood glucose load. The effect of this drug is not new information but the mechanism of the effects can now be explained through the enzymatic activity presented in this article. One of the side effects of corticosteroid use is laminitis which can occur following even a single dose of corticosteroid. Horses on corticosteroids commonly have an abnormally high level of blood glucose, as in diabetes. 12 Likewise, the intake of grains and sugars by non-diabetic, non-ir, non-laminitic horses on corticosteroids should be limited. 3 Extreme emotional and physical stress activates the glucocorticoid receptors in the hypothalamus and hippocampus to trigger a release of CRH, which in turn enhances the secretion of ACTH. The results of this activity can push the system into a rapid surge of excess glucose in the blood. Summary The conversion of cortisone to cortisol occurs through the expression of 11beta-HSD1 at specific target sites in a horse s body. It is through this local activity that all cells in the horse s body receive life sustaining energy in the form of glucose. When the horse needs additional energy this enzyme switches on to supply the increased demand for glucose. In a laminitic horse, due to the existing overload of blood glucose, this very tissue-specific action of 11beta-HSD1 sets in motion a cascading chain of events that causes laminae separation. Please note: This laminitic model applies only to horses with a metabolic syndrome and does not involve horses that have laminae separation falling under the category of "mechanical founder". My Treatment Strategy Schematic displaying the HPA axis regulating the secretion of both inactive cortisone and unbound cortisol in the circulating blood. These steroids are shown crossing a target cell membrane in an area such as the hippocampus activating the glucocorticoid conversion and stimulating the receptors that then supplies the HPA axis maintaining the metabolic process. Adrenal refers to the adrenal cortex. So the production of excess glucose in the liver starts from the horse s need for extra glucose by exactly this process where the expression of 11beta-HSD1 at individual liver cells activates cortisol production through the conversion process thereby stimulating the crucial enzyme PEPCK that makes glucose from available non-carbohydrate sources.

Page 6 The excess glucose produced at this moment travels to the blood and increases the level of glucose that is already circulating in the blood. All of the endocrinology research related to 11beta-HSD1 expression where excess blood glucose levels are present along with the full range of parameters involved in metabolic syndromes point to the reduction of this expression in the liver as the most promising target for reversing these diseases. The whole horse must be considered to address metabolic disorders such as laminitis. My clinical work is rooted in Chinese medical theory that views the horse as a whole rather than a group of anatomical pieces working in isolation. In the same sense, herbal formulations, to be effective, must be created as a whole, not a combination of single herbs that perform different functions. Therefore, to arrive at an effective herbal solution to laminitis, every individual herb of the twenty-five in our Laminitis Solution is formulated to work together in concert. This formulation includes a grouping of herbs that enable the body to reduce the expression of 11beta-HSD1 and glucocorticoid sustained activation. As is clear from the work presented in this article, this treatment strategy has a great influence on the recovery process of horses with laminitis. For a more thorough explanation of the therapeutic properties of our Laminitis Solution read the final section of The Easy Keeper: Myth and Dangers, in the previous issue of NHM. The foundation formula is one of six proprietary Chinese herbal formulas in the Laminitis Intervention Program. This program is designed to address all aspects and stages of this relentless disease and is consistently improving the lives of laminitic horses along the entire continuum of the disease process, naturally. Is the reversal of laminitis possible? By tracking the blood work of the horses using our herbs, over an extended period of time, we are observing changes that are highly indicative of recovery. The elevated glucose is lowering and returning to a healthy range and there is a concomitant elevation in serum insulin (prior levels were low normal) indicating a recovery of pancreatic beta cells. This result alone, recorded in many horses, not only implies beta cell function recovery but also demonstrates empirically the important theoretical findings described within this article. Copyright Joseph Thomas, PhD For more information, please visit www.forloveofthehorse.com. Acknowledgement: I would like the reader to be aware that this article would not have been possible if not for the editorial skill and countless discussions with my wife Crystal Leaman, general manager of For Love for the Horse. About the author: Joseph Thomas, PhD, has been a practitioner, teacher and consultant in Chinese medicine for more than twenty years. Prior to his commitment to Chinese medicine Dr. Thomas was a researcher at the Massachusetts Institute of Technology engaged in medical research. He joined these skills together with his love of horses and developed For Love of the Horse, LLC along with his wife and daughter.

Page 7 The Missing Link in Laminitis Footnotes/References 1. Crystal structures of 11beta-hydroxysteroid dehydrogenase 1, an important therapeutic target for diabetes. Jianjong Zhang, Obesity and Diabetes Week, July 25, 2005. 2. Clinical diagnosis and management by laboratory methods. J.B. Henry MD, W. B. Saunders Company. 3. The relationship between natural hoof wall growth and laminitis. Joseph Thomas, PhD, Natural Horse (2005) Vol 7 Issue 5 4. Increased expression and activity of 11beta-HSD-1 in diabetic islets and prevention with troglitazone. Dyplomb, L. et.al. Biochemical and biophysical research communications; 313 (2004) 5. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. Seckl, J.P. et.al. (2004) Rec Prog Horm Res 59. 6. Minireview: 11beta-hydroxysteroid dehydrogenase type 1 a tissue-specific amplifier of glucocorticoid action. Seckl, J.R. & Walker, B.R. Endocrinology (142)4, 2001. 7. Glucocorticoids, ageing and nerve cell damage. Seckl, J.P. British Society for neuroendocrinology, 2006 8. Equine metabolic syndrome: explanations and possibilities. Joseph Thomas, PhD. Holistic Horse, 2004, Vol 10, Issue 37 9. Equine internal medicine, S.M. Reed, et.al. (2004) Saunders Company. 10. Laminitis, hypothyroidism and obesity: a peripheral cushingoid syndrome in horses. Johnson, P.J., Gamjam, V.K. Proceedings of the seventeenth annual forum of the American College of Veterinary Internal Medicine, Chicago, 1999 11. Principles of Internal Medicine, Vol 11, 16th edition, Kasper, D>L> MD, et.al. 2005, McGraw-Hill. 12. Equine Drugs and Vaccines, Eleanor M. Kellon, V.M.D., Breakthrough Publications, 1995.