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& ACTH Testing Procedures Diplomate ACVIM Associate Professor, Small Animal Medicine Department of Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, CO 80523 (970) 491-1243, FAX 491-1275 dgreco@vth.colostate.edu Polyendocrine Gland Failure in Dogs A four year old male castrated Shih Tzu weighing 7 kg is presented for continued lethargy and weight gain following diagnosis and treatment of hypoadrenocorticism with Florinef (0.1 mg BID PO) and oral sodium chloride supplementation in food. A minimum data base reveals mild hyponatremia (Na- 136 meq/L), anemia (PCV-37) and hypercholesterolemia (540 mg/dl). The Florinef dose is increased to 0.2 mg BID PO and the food heavily salted. Recheck examination 2 weeks later reveals more weight gain and worsening hyponatremia and hypercholesterolemia. Mild alopecia is now evident on the tailhead. A thyroid panel shows increased serum endogenous canine TSH (1.2 ng/dl, normal < 0.4 ng/dl), decreased total serum thyroxine concentration ( 0.7 mg/dl, normal 1.2-3.8mg/dl), and a positive antithyroglobulin antibody test. A diagnosis of polyendocrine gland failure (Schmidt's syndrome) was made and the dog was placed on levothyroxine therapy (0.1mg levothyroxine BID). Recheck examination 6 weeks later shows resolution of the clinical signs of lethargy, and regrowth of hair on the tailhead. Serum chemistry profile, complete blood count and post-pill TT4 concentrations are in the normal range. Polyendocrine gland failure encompasses a variety of endocrine deficiencies caused by immune-mediated destruction of endocrine tissue. Synonyms for this syndrome include autoimmune polyglandular syndrome, polyglandular failure syndrome, organ-specific autoimmunity, immunoendocrinopathies and Schmidt's syndrome.1,2 Polyendocrine gland failure syndrome is defined as the occurrence of two or more immune-mediated endocrinopathies (hypothyroidism, hypoadrenocorticism and/or insulin-dependent diabetes mellitus (IDDM), hypoparathyroidism, etc) in the same individual.1-6 The polyendocrine autoimmune failure syndromes are divided into types I and II. Type I is characterized by hypoparathyroidism, hypoadrenocorticism, hypogonadism, and thyroid disease; it is also attended by oral candidiasis and non-endocrine disorders such as chronic active hepatitis. It occurs in young human beings (less than 10 years of age) and has never been described in animals.1 Polyendocrine gland failure type II is defined as the occurrence of two or more of the following disorders in the same individual; adrenal insufficiency, primary hypothyroidism, insulin dependent diabetes mellitus (IDDM), primary hypogonadism, myasthenia gravis, hyperthyroidism, and celiac disease.1 Schmidt's syndrome, the most common form of polyendocrine gland failure in humans and dogs, is characterized by concurrent hypoadrenocorticism and hypothyroidism.1,2 See Table 1 for a description of the components of the syndromes. In a recent retrospective of 225 cases of canine hypoadrenocorticism, 4% of the dogs also suffered from hypothyroidism, 0.5% had concurrent IDDM, and one had concurrent hypothyroidism, IDDM and hypoparathyroidism.7 Another report of 111 dogs with adrenal insufficiency reported that at least 10% had one other endocrinopathy including hypothyroidism, IDDM, hypoparathyroidism and primary gonadal hypoplasia.8 Because most dogs with hypoadrenocorticism, IDDM or hypothyroidism are neutered, it is very difficult to determine if immune destruction of the testes or ovaries also occurs as part of this syndrome in dogs. However, male infertility associated with immune-mediated orchitis has been described.9 Further studies will determine if this form of orchitis is also associated with endocrinopathies such as immune-mediated thyroiditis. A single case of Schmidt's syndrome has been described in a middle-age female dog; treatment of the hypothyroid state resulted in precipitation of the hypoadrenocorticism.10 The presence of serum autoantibodies to thyroid and adrenal tissue was observed in this dog as definitive evidence of autoimmune polyglandular syndrome Type II.10 Pathogenesis Type II polyendocrine gland failure is inherited as an autosomal dominant trait in humans associated with the presence of human leukocyte antigens (HLA).1,3 Lymphocytic and plasmacytic destruction of affected endocrine glands may be documented histologically. Circulating organ specific autoantibodies are commonly present.3 Environmental factors combined with an HLA-associated genetic predisposition are thought to trigger the process. Immunologic abnormalities in the Type II syndrome include defects and alterations of cell surface markers, but the most consistent abnormality is a functional defect leading to a decrease in suppressor T cell activity.4 Immune-mediated destruction of endocrine glands is usually a slow process and clinical signs of endocrine deficiencies may only manifest after a significant portion of the endocrine tissue has been destroyed. Therefore, while autoantibodies to endocrine tissue may initiate and contribute to the immune destruction of the gland, often there is no longer sufficient endocrine tissue remaining at the onset of the clinical endocrinopathy to demonstrate the presence of autoantibodies. Signalment Many endocrine disorders, such as lymphocytic thyroiditis, hypoparathyroidism hypoadrenocorticism, and Type I or insulin-dependent diabetes mellitus (IDDM) have an autoimmune basis in both dogs and man.11-20 Polyendocrine gland failure, type II, has been well-documented in man and occasionally in the dog.1,3,9 In human beings, females are more likely to suffer from the disease than males. 1 A sex predilection for females has also been documented in both IDDM and hypoadrenocorticism in dogs.1,7, 8 Familial tendencies may be difficult to follow in dogs because litters of puppies are usually separated early in life. However, dogs with immune-mediated endocrine disorders tend to cluster in certain breeds of dogs. Hypoadrenocorticism is inherited in standard poodles and Leonbergers.21,22 There is a distinct breed predisposition for primary hypothyroidism in beagles, golden retrievers, Doberman pinschers, Irish setters, miniature schnauzers, dachshunds, cocker spaniels, and miniature poodles.8 Diabetes mellitus (IDDM) is inherited in Keeshounds and some golden retrievers.23 In a recent retrospective of 10 dogs with multiple endocrine deficiencies, two dogs were mother and daughter and one dog had a sibling with hypoadrenocorticism.23 Hypoadrenocorticism is the most common endocrinopathy observed in type II polyendocrine gland failure and is usually followed by the development of hypothyroidism, or less frequently by the development of IDDM. 1 Studies show that 45-50% of human beings with adrenal insufficiency secondary to Type II polyendocrine gland failure develop a second endocrinopathy.1 The most common second endocrinopathy, primary hypothyroidism, develops 10-20 years after the first endocrinopathy. As in human beings, most dogs are diagnosed with hypoadrenocorticism in young adulthood as the first endocrinopathy of polyendocrine gland failure.23 In dogs, the second endocrinopathy usually develops 12 to 18 months after the first endocrinopathy.23 Clinical Signs Clinical signs of hypoadrenocorticism can be highly variable, particularly in the initial stages of the disease when the dog is only glucocorticoid deficient. Typical signs include gastrointestinal symptoms such as vomiting, diarrhea and anorexia. Lethargy and weakness are also common complaints. As adrenal insufficiency progresses, dogs with hypoadrenocorticism will present in an "Addisonian crisis" characterized by extreme weakness, cardiovascular collapse, shock and bradycardia. When hypothyroidism and hypoadrenocorticism occur concurrently, the rate of clearance of cortisol is reduced. As soon as thyroid supplementation is initiated, cortisol clearance increases suddenly without a compensatory increase in cortisol synthesis resulting in an adrenal crisis. Signs such as vomiting, diarrhea, anorexia, weakness, collapse, and hypovolemic shock in a patient beginning levothyroxine replacement therapy should prompt an investigation for hypoadrenocorticism. Clinical signs suggestive of hypothyroidism in dogs with previously diagnosed hypoadrenocorticism include weight gain (obesity), continued lethargy and/or bradycardia despite adequate mineralocorticoid and glucocorticoid supplementation, heat-seeking behavior, regurgitation and dermatologic signs such as alopecia.23 Clinical signs in diabetic dogs with concurrent hypothyroidism include insulin resistance, poor diabetic regulation, obesity, lethargy, dermatologic disease, and regurgitation.23, 24 Dogs with concurrent hypothyroidism and IDDM often have increasing insulin requirements as hypothyroidism may cause insulin resistance.14 The findings of regurgitation secondary to megaesophagus in a diabetic, Addisonian or hypothyroid dog should also prompt a search for multiple endocrinopathies because myasthenia gravis (a common cause of megaesophagus) has been reported to be associated with polyendocrine gland failure in dogs and man.1,13, 23 Laboratory Abnormalities Dogs with Type II polyendocrine gland failure will often exhibit hypercholesterolemia and hyponatremia as characteristic clinicopathologic features.23 Hyponatremia is a commonly observed electrolyte disturbance in humans and dogs with hypothyroidism.25,26 Dogs suffering from concurrent hypoadrenocorticism and hypothyroidism will often exhibit hyponatremia despite adequate mineralocorticoid supplementation (as evidenced by normalization of serum potassium, see Table 2.).23 The hyponatremia will be unresponsive to an increase in dietary sodium chloride. The findings of both hypercholesterolemia and hyponatremia in an otherwise well-regulated dog with hypoadrenocorticism are highly suggestive of concurrent hypothyroidism.23 Hyponatremia, severe hypercholesterolemia (>500 mg/dl) and insulin resistance in an obese diabetic dog should prompt the clinician to test for hypothyroidism.24 More unusually, the findings of decreased insulin requirements, hyponatremia and hyperkalemia should alert the clinician to the possibility of Addison's disease in a diabetic dog (see Table 3). Dynamic Endocrine Testing Documentation of hypoadrenocorticism can be achieved with an adrenocorticotropin response test. To perform the test, a serum sample is obtained before, and 1 hour after intravenous administration of synthetic ACTH (Cosyntropin; 0.5 mg/kg). 7,8 Endogenous plasma ACTH may be measured to determine if the hypoadrenocorticism is primary or secondary. This specimen must be collected in an EDTA tube, spun within an hour of sampling and stored in plastic prior to the administration of any corticosteroids.7 Dogs with primary hypoadrenocorticism will exhibit a subnormal response to ACTH administration. The baseline cortisol concentration is usually low or undetectable and the post-ACTH cortisol concentration is also low or undetectable. Endogenous plasma ACTH concentrations are dramatically increased in animals with primary hypoadrenocorticism as a result of loss of negative feedback to the pituitary caused by decreased serum cortisol concentrations.7 Because diabetes mellitus and glucocorticoid replacement therapy can be associated with decreased serum total thyroxine (TT4) concentrations as a result of euthyroid-sick syndrome, diagnosis of thyroid deficiency in patients with concurrent IDDM or Addison's disease may be difficult. Increased endogenous canine thyroid stimulating hormone (cTSH) concentrations in association with a decreased total thyroxine (TT4) and/or free T4 by dialysis may be diagnostic for primary hypothyroidism.27 If the patient is on glucocorticoid supplementation and the serum eTSH and TT4 are decreased, a free T4 by dialysis should be submitted. Alternatively, the glucocorticoid can be discontinued for 48 hrs and the thyroid panel resubmitted. Although specific tests for polyendocrine gland failure are not commercially available, indirect evidence of immune-mediated thyroiditis may be obtained by documenting the presence of antithyroglobulin antibodies. Treatment Treatment of multiple endocrinopathies consists of specific hormone replacement; for example, 22-44 mg/kg/day levothyroxine divided BID for hypothyroidism, 0.5 units insulin BID for IDDM, and mineralocorticoid (DOCP, 2.2 mg/kg, IM q 25-30 days) and glucocorticoid (0.22 mg/kg q 24 hr PO) supplementation for hypoadrenocorticism.7,8 However, when the hypothyroid and hypoadrenal states occur concurrently, the rate of clearance of cortisol is reduced. When thyroid supplementation is initiated first, cortisol clearance increases suddenly without a compensatory increase in cortisol synthesis resulting in an adrenal crisis. Hence one should assess adrenal function prior to initiation of levothyroxine therapy in animals with suspected multiple endocrinopathies.10 Hypothyroid dogs that experience vomiting or weakness following institution of thyroid supplementation should be screened for hypoadrenocorticism with an adrenocorticotropin test. On the other hand, thyroid hormone supplementation (22-44 mg/kg BID-q 24 hrs, PO) can be instituted immediately following diagnosis of hypothyroidism in dogs with existing hypoadrenocorticism. Improvement in clinical signs and hyponatremia should occur within 4 weeks of adequate supplementation of thyroid hormone. Dogs with concurrent IDDM and hypothyroidism should show improvement in glycemic control when thyroid hormone supplementation is instituted within 4 weeks. Summary In summary, the diagnosis of polyendocrine gland failure is based on the presence of compatible clinical signs, classic clinicopathologic features, a high index of clinical suspicion for the disease and dynamic endocrine testing. Hopefully, the practitioner will have a heightened awareness of the clinical signs of concurrent endocrinopathies, such as hypothyroidism, in dogs with existing hypoadrenocorticism or diabetes mellitus. References
Table 1. Associated endocrine and non-endocrine disorders (in order of frequency) of polyglandular autoimmune syndromes. Polyglandular autoimmune syndrome I (PGA I)
(* reported in dogs) Table 2: Indications for thyroid testing in dogs with hypoadrenocorticism (Addison's disease) or diabetes mellitus
Table 3: Signs of hypoadrenocorticism in dogs with hypothyroidism or IDDM
Etiology of Feline/Canine Diabetes Mellitus Diabetes mellitus is a commonly occurring feline endocrinopathy. Historically, feline diabetics were suspected to be insulinopenic; however, recent research indicates that most cats (50-60%) develop diabetes similar to non-insulin dependent diabetes mellitus (NIDDM) in humans. The etiology of NIDDM diabetes is undoubtedly multifactorial. Obesity, genetics, and amyloidosis of the islets are involved in the development of NIDDM in human beings. Obesity and amyloidosis are also involved in the pathogenesis of NIDDM in cats. It is now recognized that the classic metabolic abnormalities found in NIDDM include decreased insulin secretion and peripheral insulin resistance, both of which may be consequences of abnormal amyloid production by pancreatic beta cells. In 1986, a previously unidentified protein called islet-amyloid polypeptide (IAPP or amylin) was identified as the main component of amyloid deposits in a human insulinoma. This novel protein was also found to be the main component of islet amyloid (IA) isolated from pancreatic islets in humans with NIDDM and in feline diabetics. The development of this form of amyloid may play a pivotal role in the pathogenesis of NIDDM in cats and in human beings. Impaired secretory ability In cats and humans with NIDDM, the first phase insulin secretory response is markedly reduced or absent. The second phase is delayed and exaggerated. The insulin response twenty minutes after a glucose injection is reduced approximately 80% compared to normal cats, and the maximal capacity to release insulin is reduced 80 - 90 %. In humans, normal pulsatile insulin secretion is affected, with a reduction in the normal pulse pattern, as well as the amount of insulin secreted per pulse. For glucose-stimulated insulin secretion to occur, extracellular glucose binds glucose receptors on the beta cell surface. The receptors function both as sensors and transporters. In vitro experiments suggest that the main defect in beta cell function is impaired glucorecognition. There is a decreased ability of extracellular glucose to induce insulin release. This may be due to reduced synthesis of the glucose transporter in the beta cell membrane. Intracellular concentrations of glucose become insufficient to trigger insulin release. Another factor influencing impairment of insulin secretion in NIDDM is glucose toxicity. Glucose toxicity is the seemingly paradoxical inhibition of insulin secretion by persistently marked hyperglycemia. The chronic hyperglycemia causes down-regulation of the glucose transporters on beta cell membranes, resulting in decreased insulin secretion. This may help explain the phenomenon of transient diabetes in the cat; as oral hypoglycemic drugs or dietary modifications induce a period of normoglycemia, glucose toxicity subsides and beta cell function and insulin secretion improves, "resolving" the diabetic state. Finally, IAPP itself is capable of inhibiting insulin secretion. Insulin Resistance Another major distinguishing feature of NIDDM is peripheral insulin resistance. Obesity plays a significant role in the insulin resistance seen in feline diabetics, and is a well-documented risk factor for development of NIDDM in humans. The resistance is due to internalization of the insulin receptors in membranes of muscle and fat cells. Obesity also decreases receptor affinity for the insulin molecule. To summarize the current hypothesis of the pathogenesis of NIDDM, peripheral insulin resistance (due to obesity, elevated plasma IAPP, or both) causes chronic stimulation of insulin production in the pancreatic beta cells. IAPP is co-synthesized with the insulin. Impaired insulin secretion causes insulin and IAPP to accumulate in the beta cells. The high local concentrations of IAPP causes polymerization of IAPP to form insular amyloid in these cells. The deposition of insular amyloid further impairs glucorecognition and diffusion of nutritive substances into the beta cells. Eventually, IA leads to necrosis of the beta cells and release of amyloid into the extracellular space. Clinical Presentation of the Diabetic Cat Neutered males cats are 1.5 times as likely as female cats to develop diabetes mellitus. Other risk factors for the development of diabetes mellitus in cats include increased body weight (>6.8 kg), older age (>10 yrs) and neutering.3 Most diabetic cats present with the classic clinical signs of polyuria and polydipsia. Based on the pathogenesis of diabetes mellitus, one would predict that polyphagia would be a common historical finding in diabetic cats; however, only about 12% of diabetic cats exhibit polyphagia. Cats often will present with chronic complications of diabetes, such as gait abnormalities resulting from diabetic neuropathy or with chronic gastrointestinal signs such as vomiting and diarrhea. Physical examination findings of non-ketotic diabetes mellitus in cats are typically non-specific. The most common physical examination findings in cats include lethargy and depression, dehydration, unkempt haircoat, and muscle wasting. About 35% of diabetic cats are obese upon initial examination; obese diabetic animals are more likely to suffer from NIDDM. Hepatomegaly and nephromegaly are often observed diabetic cats. Characteristic signs of diabetes mellitus, such as plantigrade rear limbstance resulting from diabetic neuropathy are uncommonly observed. A diagnosis of diabetes mellitus should be based on the presence of clinical signs compatible with diabetes mellitus and evidence of fasting hyperglycemia and glycosuria. The presence of clinical signs only may be misleading as hyperthyroidism and renal disease may present with similar clinical signs in cats. To complicate matters further, many cats are susceptible to ěstress-inducedî hyperglycemia in which the serum glucose concentrations may approach 300-400 mg/dl. In addition, renal glycosuria may be found in animals with renal tubular disease and occasionally with stress-induced hyperglycemia. Therefore, the presence of all three criteria (clinical signs of DM, fasting hyperglycemia and glycosuria) are necessary to confirm a diagnosis of diabetes mellitus in cats. Recent studies have investigated the use of serum fructosamine and glycosylated hemoglobin concentrations in distinguishing stress-induced hyperglycemia from overt diabetes mellitus at the time of diagnosis and during monitoring of insulin therapy. Glycosylated proteins are formed by an irreversible, non-enzymatic binding of glucose to hemoglobin or protein. As plasma glucose concentrations increase, glycosylation increases proportionately. Serum fructosamine is formed by glycosylation of serum protein such as albumin. The concentration of fructosamine in serum is directly related to blood glucose concentration. However, due to the shorter lifespan of albumin compared with hemoglobin, fructosamine concentrations reflect more recent (1-3 weeks) changes in serum glucose concentrations than do glycosylated hemoglobin measurements. Normal fructosamine concentrations in cats are 283 ± 32 mmol/L (< 350 mg/dl). Diabetes Mellitus in Dogs ETIOLOGY Insulin dependent diabetes mellitus (IDDM) is a diabetic state in which endogenous insulin secretion is never sufficient to prevent ketone production. Type I diabetes mellitus is a diabetic state in which insulin secretion may be reduced or absent and which is readily corrected by exogenous insulin. KEY POINT: Most dogs suffer from Type I diabetes or IDDM. Type III or secondary diabetes mellitus is the result of another primary disease or drug therapy producing insulin resistance (hyperadrenocorticism, hyperthyroidism, acromegaly, progestational drugs) or destroying pancreatic tissue (pancreatitis). Secondary diabetes is common in both dogs (pancreatitis, endocrinopathies) and cats (drugs, endocrinopathies, pancreatitis). In animals with uncomplicated diabetes mellitus, hyperglycemia results from impaired glucose utilization, increased gluconeogenesis and increased hepatic glycogenolysis. Decreased peripheral utilization of glucose leads to accumulation of glucose in the serum followed by osmotic diuresis. Progressive dehydration causes the classic clinical signs of polyuria with compensatory polydipsia. Impaired glucose utilization by the hypothalamic satiety center combined with loss of calories in the form of glycosuria results in the clinical signs of polyphagia and weight loss, respectively. Insulin is anabolic; therefore, insulin deficiency leads to protein catabolism and contributes to the clinical signs of weight loss and muscle atrophy. As a consequence of protein catabolism, amino acids such as alanine are utilized by the liver to promote gluconeogenesis and contribute to hyperglycemia. With insulin deficiency, the hormone-sensitive lipase system which is normally suppressed by insulin, becomes activated. The unrestrained lipolytic activity of hormone sensitive lipase results in the clinical signs of weight loss in a previously obese or overweight animal. CLINICAL SIGNS OF NON-KETOTIC DIABETES MELLITUS Dogs suffering from diabetes mellitus range in age from 4-14 years with a peak incidence at 7-9 years. A genetic basis for diabetes mellitus is suspected in the keeshonden. Other commonly affected breeds include miniature and toy poodles, dachshunds, miniature schnauzers , beagles, puliks, Cairn terriers and miniature pinschers. In dogs, females are twice as likely to develop diabetes than are males. Most diabetic animals present with the classic clinical signs of polyuria and polydipsia. Weight loss is commonly observed in dogs. In some cases, polyphagia is also observed. In dogs, progressive polyuria, polydipsia and weight loss develops relatively rapidly usually over a period of several weeks. Another common presenting complaint of diabetes mellitus in dogs is acute onset of blindness caused by bilateral cataract formation. Physical Examination Findings Physical examination findings of non-ketotic diabetes mellitus in dogs are typically non-specific. In dogs, the most common physical examination findings are dehydration and muscle wasting or thin body condition. About 25-30% of diabetic animals are obese upon initial examination. Hepatomegaly isusually observed in diabetic dogs. Cataracts are observed in approximately 40% of diabetic dogs. Clinical Pathology A diagnosis of diabetes mellitus should be based on the presence of clinical signs compatible with diabetes mellitus and evidence of fasting hyperglycemia and glycosuria. Common clinicopathologic features of diabetes mellitus in dogs include: fasting hyperglycemia hypercholesterolemia, increased liver enzymes (ALP, ALT), neutrophilic leukocytosis, proteinuria, increased urine specific gravity and glycosuria. Hypoadrenocorticism in Small Animals A 3 year old black male standard poodle weighing 20 kg presents for intermittent anorexia, vomiting and diarrhea of seven months duration. Past history includes repeated episodes of lethargy and anorexia that respond to fluid therapy. Physical examination reveals a thin dog with no obvious abnormalities. A complete blood count, serum chemistry profile, and urinarlysis shows a mild, normocytic, normochromic anemia, and eosinophilia. Fecal examination is negative for parasites. The dog is sent home with a tentative diagnosis of inflammatory bowel disease, dietary allergy or occult parasitism. Treatment consists of limited antigen dietary therapy and a course of fenbendazole. Six months later the dog is presented to the emergency clinic in hypovolemic shock after an acute onset of vomiting and diarrhea; the dog had been at a boarding facility for five days . Heart rate on admission is 50 beats per minute. Results of an emergency chemistry profile include azotemia (BUN 187 mg/dl, normal 17-32mg/dl, Cr 4.3 mg/dl, normal 0.6-2.0 mg/dl), hyponatremia (Na-125 meq/L, normal 145-160 meq/L), hyperkalemia (K-7.8 meq/L, normal 3.7-5.4 meq/L), hypochloremia (98 meq/L, normal 112-129 meq/L), and mild hypercalcemia (12.3 mg/d, normal 9-11.5 mg/dl). Urine specific gravity is 1.012. The dog is treated with shock doses (90 ml/kg/hr) of fluids (0.9% NaCl) and glucocorticoids (dexamethasone sodium phosphate,1 mg/kg IV). An adrenocorticotropin response test (0.5 U/kg Cosyntropin, IV) performed at admission reveals a low baseline cortisol (<0.1 mg/dl, normal 1-4 mg/dl) with no response to ACTH (post cortisol-(<0.1 mg/dl, normal > 6 mg/dl) one hour later. The dog recovers uneventfully, gains weight (25 kg) and is maintained on deoxycorticosterone pivalate (DOCP 2 mg/kg IM q 30 days) and daily prednisolone (0.2 mg/kg PO q 24 hrs) for the rest of his life. Routine blood work (CBC, chemistry profile, U/A) is monitored every 6 months. (Introduction) The diagnosis and treatment of hypoadrenocorticism (Addison's disease) can be one of the greatest challenges faced by veterinary practitioners. The purpose of this review is to describe the clinical diagnosis and treatment of hypoadrenocorticism in dogs and cats. Hypoadrenocorticism is a result of deficient secretion of both mineralocorticoids (aldosterone) and glucocorticoids.1 Naturally-occurring primary hypoadrenocorticism is usually caused by immune-mediated destruction of the adrenal cortex in both cats and dogs;1-4 however, lymphomatous infiltration of the adrenals has been reported as a cause of hypoadrenocorticism in cats.5 Secondary hypoadrenocorticism, in which the pituitary gland produces inadequate amounts of adrenocorticotrophic hormone (ACTH), can be caused by chronic steroid therapy or less commonly by tumors, trauma, or congenital defects of the pituitary gland.1 Secondary hypoadrenocorticism is rare in both dogs and cats. Hypoadrenocorticism, which is glucocorticoid deficient only (hypocortisolemia), has been termed "atypical" Addison's disease.6-9 Secondary hypoadrenocorticism is always atypical and primary hypoadrenocorticism can be atypical in the early stages of the disease prior to destruction of the zona glomerulosa. (Signalment, Clinical Signs and Laboratory Abnormalities) Canine hypoadrenocorticism is most often diagnosed in young female dogs (70%) of any breed. 1,2,8 However, hypoadrenocorticism has been reported in families of Leonbergers and standard poodles suggesting a genetic basis in some breeds.10,11 Young cats of any breed or sex can also develop hypoadrenocorticism.4,5 Historical findings compatible with hypoadrenocorticism include intermittent vomiting, diarrhea, weight loss, lethargy, depression, anorexia, and weakness.1-9 There may be a history of vomiting or diarrhea responsive to non-specific treatment, such as intravenous fluids, only to have signs reoccur several days to weeks later. Often the clinical signs come and go (waxing and waning) periodically. As the disease progresses, the animal may present with collapse, hypothermia, shaking, polyuria, and polydipsia,. Hair loss and melena are unusual historical findings. Signs of megaesophagus, such as regurgitation and weight loss, have been reported uncommonly in dogs with both typical and atypical hypoadrenocorticism.1, 12 Differential diagnoses for the common clinical signs consistent with hypoadrenocorticism include inflammatory bowel disease, intestinal parasitism (trichuriasis), bilious vomiting syndrome, and renal disease.1,2,13 A comparison of clinical signs hypoadrenocorticism in cats and dogs is shown in Table 1 and a comparison of typical and atypical hypoadrenocorticism in dogs is listed in Table 2. Physical examination of animals in an acute Addisonian crisis reveals weak pulses, bradycardia, prolonged capillary refill time, severe mental depression, and profound muscle weakness.1,2 Clinical features which should heighten the index of suspicion of hypoadrenocorticism include a normal or slow heart rate in the face of circulatory shock, previous response to corticosteroid or fluid therapy, and a"waxing and waning" course of disease prior to collapse. Classic electrolyte abnormalities, such as hyponatremia, hyperkalemia, hypochloremia, and sodium to potassium ratios of less than 20 to 1, are highly suggestive of primary hypoadrenocorticism.1,2 However, gastrointestinal disease (trichuriasis), acute renal failure, post-renal azotemia and abdominal/thoracic effusions (third space) are additional differential diagnoses. 1,2,13,14 Azotemia and hyperphosphatemia also attend primary hypoadrenocorticism making it difficult to differentiate from acute renal failure. Azotemia associated with hypoadrenocorticism may be prerenal as a result of dehydration , hypovolemia or gastrointestinal hemorrhage.1,15 Hypercalcemia may be observed in up to 30% of dogs with hypoadrenocorticism as a result of hemoconcentration.16 Metabolic acidosis results from decreased hydrogen ion secretion in the renal distal tubule, increased generation of acids secondary to reduced tissue perfusion, and renal retention of organic acids.1,2 Hypoalbuminemia has been described in associated with hypoadrenocorticism; however, a cause and effect relationship has not been defined. 2,17 Animals with glucocorticoid deficiency only, will not show classic electrolyte imbalances, but may present with hypoglycemia as a result of impaired gluconeogenesis and glycogenolysis.1,5,6 Hematological findings include mild normocytic normochromic (non-regenerative) anemia; however, if the animal is dehydrated the underlying anemia may be masked. The absence of a stress leukogram is a subtle but important feature of atypical hypoadrenocorticism.6,7,9 The presence of a normal or elevated eosinophil or lymphocyte count in a stressed animal should be viewed with suspicion for hypoadrenocorticism, particularly atypical Addison's disease. Eosinophilia and lymphocytosis are seen in 20% and 10% of dogs with primary hypoadrenocorticism, respectively. 1,2 Urine specific gravity is frequently low and is attributed to medullary washout (inadequate medullary gradient due to sodium depletion) and decreased medullary blood flow.1 Dilute urine in the face of azotemia and hyperkalemia may easily be mistaken for acute renal failure. Hormonal assays are required to confirm the presence or absence of adrenal disease and to differentiate between hypoadrenocorticism and renal failure. (Electrocardiography, ultrasound and radiographic findings) If bradycardia is present, an electrocardiogram may be helpful in the diagnosis of hypoadrenocorticism, especially when serum electrolytes are not immediately available. Classic electrocardiographic findings reported with hyperkalemia include prolonged QRS complexes, decreased R wave amplitude, increased T wave amplitude ("spiked" T waves), and prolonged or absent p waves.1 Sinoatrial standstill is the most common arrhythmia noted. Electrocardiagraphic changes should not be used to determine the exact serum potassium concentrations because serum potassium concentrations do not directly correlate with specific EKG changes; however, the EKG is useful in an emergency setting. Radiographs may demonstrate signs associated with volume depletion or decreased tissue perfusion, such as microcardia, narrowed vena cava, and hypoperfused lungs. Megaesophagus has been reported uncommonly in dogs with both typical and atypical hypoadrenocorticism.1,2,12 Ultrasound cannot be routinely used to identify "small" adrenals, particularly since the right adrenal may be difficult to image in normal animals. (Diagnostic testing) Diagnosis of primary hypoadrenocorticism is based on clinical signs, classic electrolyte imbalances, and confirmation with an ACTH response test. To perform the test, a serum sample is obtained before, 30 minutes (cats) and 1 hour (cats and dogs) after intravenous administration of synthetic ACTH (cosyntropin; 0.5 mg/kg).1,2 Administration of a single dose of dexamethasone sodium phosphate prior to obtaining baseline or one hour post ACTH cortisol samples will not interfere with the test. However, administration of prednisolone will interfere with the ACTH response test because prednisolone will cross react with the cortisol assay.2 If corticosteroids have already been administered, one can wait 24 hours and perform the ACTH response test after the short-acting corticosteroids have dissipated.2 Endogenous plasma ACTH may be measured to determine if the hypoadrenocorticism is primary or secondary. This specimen must be collected in an EDTA tube, spun within an hour of sampling and stored in plastic prior to the administration of any corticosteroids.2 Dogs and cats with primary hypoadrenocorticism will exhibit a subnormal response to ACTH administration. The baseline cortisol concentration is usually low or undetectable and the post-ACTH cortisol concentration is also low or undetectable. Endogenous plasma ACTH concentrations are dramatically increased in animals with primary hypoadrenocorticism (> 100 pg/ml) as a result of loss of negative feedback to the pituitary caused by decreased serum cortisol concentrations.1,2 In the case of secondary hypoadrenocorticism, which is caused by a pituitary deficiency of ACTH, the endogenous ACTH concentrations are typically decreased (<20 pg/ml).1 The response to exogenous ACTH is diminished, but not as dramatically as for primary hypoadrenocorticism. Baseline cortisol and post-ACTH cortisol concentrations may be in the normal range. (Therapy: Acute adrenal crisis ) Acute adrenocortical insufficiency is a life-threatening emergency; therefore, therapy must be initiated immediately. Treatment of the Addisonian crisis consists of four parts: 1) fluid therapy and electrolyte stabilization, 2) glucocorticoid replacement therapy 3) treatment of gastrointestinal hemorrhage, and 4) mineralocorticoid replacement therapy.1,2,15,18 Of primary importance is rapid administration of large volumes of intravenous fluids; 0.9% NaCl is the fluid of choice. Fluid delivery is best accomplished using a jugular catheter. Blood samples for a complete blood count (CBC), chemistry profile, and resting cortisol level can be obtained through a central jugular catheter prior to initiating therapy. Rapid administration of intravenous fluids restores blood volume and improves renal perfusion which decreases serum potassium concentration via dilution and promotion of renal potassium excretion.1,2,18 However, if hyperkalemia persists, serum potassium can be rapidly decreased by intravenous administration of regular (crystalline) insulin and glucose (0.03 to 0.06 units/lb; for every unit of insulin given, 4 ml 50% dextrose) or intravenous administration of 10% calcium gluconate (0.4 to 1 mg/kg over a 10 - 20 minute period) to counteract the effects of elevated potassium on the heart.1,18 Glucocorticoid therapy, using ultra-short acting corticosteroids such as dexamethasone sodium phosphate (2-4 mg/kg) or prednisolone sodium succinate (15-20 mg/kg), should be instituted immediately.18 Dexamethasone may be preferred in animals that require immediate glucocorticoid administration as it will not interfere with the cortisol assay; in addition, a single dose of short-acting corticosteroid will not suppress the hypothalamic pituitary adrenal axis.2 Some Addisonian dogs may hemorrhage into the gastrointestinal tract because because of poor intestinal perfusion caused by shock..2,15 Treatment of anemia secondary to severe gastrointestinal hemorrhage should include blood transfusion coupled with gastrointestinal protectants. Rapid correction of hyovolemia with 0.9% NaCl is usually sufficient to correct most electrolyte abnormalities, however, oral mineralocorticoid supplementation with fludrocortisone acetate (Florinef) can be instituted as soon as vomiting ceases. Metabolic acidosis often resolves after fluid therapy; however, severe acidosis (pH < 7.1) may be treated with sodium bicarbonate.18 Hypoglycemia, if present and symptomatic, should be treated with a slow intravenous bolus of 50% dextrose (0.5 - 1.0 ml/kg).1,18 (Maintenance therapy and Prognosis) Mineralocorticoid supplementation, using oral fludrocortisone (Florinef Ň, 15-20 mg/kg/day PO q 24 hr) or deoxycorticosterone pivalate (DOCP, 2.2 mg/kg q 25 days) should be initiated after the results of dynamic adrenal testing confirm a diagnosis of hypoadrenocorticism. Glucocorticoid supplementation (0.22 mg/kg) must be given with DOCP as this drug has no glucocorticoid activity.19 Fludrocortisone, on the other hand, does provide some glucocorticoid activity; therefore, additional prednisolone supplementation is only required in about 50% of dogs.1, 19 All dogs should receive additional corticosteroids during periods of stress (i.e. elective surgery). Cats with hypoadrenocorticism are managed with injectable corticosteroids such as Depo-Medrol (10 mg/cat q 3-4 weeks) and DOCP (12.5 mg/cat q 3-4 weeks).4 Most dogs require DOCP every 25-35 days and most cats require DOCP every 30 days.19 Monitoring of serum electrolytes should be used to determine the optimal dosing interval. Addisonian animals receiving DOCP should be monitored every 3 weeks until the dosage and interval of administration is determined and dogs receiving fludrocortisone should be monitored weekly until electrolytes become normal. In patients with normal potassium, but low sodium concentrations, sodium chloride tablets supplementation has been recommended in the past; however, the cause of the hyponatremia should be investigated and a thorough thyroid evaluation (TT4, cTSH) should be undertaken (see polyendocrine gland failure in small animals). Signs of DOCP toxicity include hypokalemia, hypernatremia, polydipsia and polyuria; however, DOCP toxicity is very difficult to induce.20 The practitioner may want to consider cost and size issues with regard to choosing between Florinef and DOCP. 19 In large breed dogs (> 25 kg), DOCP may be a more economical choice. In a recent study looking at the response of Addisonian dogs to treatment, it was found that fewer than 20% of the dogs required the manufacturer's recommended dose (2.2 mg/kg q 25 days) of DOCP. Therefore, if cost is a consideration, an initial dose of 1.5 mg/kg q 25 days can be administered and the response to therapy monitored. In the same study, adverse effects (iatrogenic Cushing's) occurred in almost one third of the dogs receiving fludrocortisone and necessitated a change to DOCP.19 (Prognosis) The long-term prognosis for animals treated for hypoadrenocorticism, once an adrenal crisis is controlled, is excellent with 80% of the dogs having a good to excellent response to therapy.19 Furthermore, the median survival time in one study was 5 years and very few of the dogs died of complications associated with hypoadrenocorticism.19 With appropriate glucocorticoid and/or mineralocorticoid replacement therapy, dogs and cats with hypoadrenocorticism should be expected to live a normal life. The importance of life-long therapy must be emphasized to the owners, as well as the potential for increasing glucocorticoid requirements during stressful situations. References
Table 1. Clinical Signs and Abnormal Laboratory Findings in Dogs and Cats with Primary Hypoadrenocorticism (Addison's disease).1,9
Table 2. Comparison of the clinical features of typical and atypical hypoadrenocorticism
Table 3. Protocols for dynamic adrenal function testing in dogs and cats.
Oral Hypoglycemic Therapy in Cats with Type II Diabetes Mellitus Assessment of cats with diabetes mellitus Diabetes mellitus is one of the most common feline endocrinopathies affecting 1 in 300 cats. 1 The pathogenesis of Type 2 diabetes mellitus in cats has been previously reviewed.2-4 Diagnosis of diabetes mellitus can be challenging, particularly in the early stages when the cats are non-insulin dependent. However, once clinical signs of diabetes are observed (PU/PD, neuropathy), many cats may still benefit from alternatives to insulin therapy. In general, the primary abnormalities associated with Type 2 DM, such as obesity and insulin resistance are reversible. Insulin secretory ability, however, may be reversible (glucose toxicity) or irreversible (pancreatic amyloid deposition).2-4 In cats, the differentiation of IDDM and NIDDM is virtually impossible prior to treatment; therefore, the clinician may have to rely on the response to oral hypoglycemic agents as a guide to whether the cat has sufficient beta-cell function to be managed with oral hypoglycemic agents. Goals of therapy for diabetes mellitus include restoration of normal fasting serum glucose concentrations, normalization of serum fructosamine and reversal or attenuation of chronic complications such as diabetic neuropathy and nephropathy. As in human beings with Type 2 diabetes mellitus, the best approach to cats is a stepwise progression from dietary management to oral hypoglycemics and finally to insulin therapy when islet burn-out occurs. Diet and Exercise Exercise and diet is the cornerstone of therapy in human beings with Type 2 DM. In most diabetic cats, exercise is not a reasonable option. One mechanism by which cats may be encouraged to exercise is by feeding the cat multiple small meals hidden in various places within the house. For example, an obese diabetic cat might be encouraged to jump up on the refrigerator or counter to find small amounts of food and then have to hunt for the rest of the food at the opposite end of the house. In human diabetics, fiber supplementation is beneficial in the management of the disease. In humans and dogs, increased amounts of fiber slow the rate of glucose absorption from the intestine and minimize the postprandial fluctuations in blood glucose. This allows better glycemic control, and correction of obesity; however, the data in cats is less compelling. In the only study of high fiber diets in cats, 9 of 13 diabetic cats showed significant improvement in glycemic control with consumption of a high fiber diet. 5 Examples of high fiber diets include prescription diet w/d and r/d, Science Diet Maintenance Light, Purina OM and Iams Less Active. Because many cats find high fiber diets unpalatable, soluble fiber such as psyllium, can be mixed into the cat's regular food and glycemic control may still be enhanced. If the cat's weight is normal at the start of therapy, the diet should be fed at a maintenance level of 60-70 kcal/kg/day. If the patient is obese, caloric intake should be limited to 70 - 75% of the energy needs for the cat's optimal weight. The cat is an obligate carnivore and as such is unique among mammals in its insulin response to dietary carbohydrates, protein and fat. The feline liver exhibits normal hexokinase activity but glucokinase activity is virtually absent.6 Glucokinase converts glucose to glycogen for storage in the liver and is important in "mopping" up excess post-prandial glucose. Normal cats are in fact similar to diabetic humans because glucokinase levels drop precipitously with persistent hyperglycemia in human beings suffering from type 2 diabetes mellitus. Amino acids, rather than glucose, are the signal for insulin release in cats.7 In fact, a recent publication demonstrated more effective assessment of insulin reserve in cats using the arginine response test rather than a glucose tolerance test.8 Another unusual aspect of feline metabolism is the increase in hepatic gluconeogenesis seen after a normal meal. Normal cats maintain essential glucose requirements from gluconeogenic precursors (i.e.amino acids) rather than from dietary carbohydrates. As a result, cats can maintain normal blood glucose concentrations even when deprived of food for over 72 hrs;7 furthermore, feeding has very little effect on blood glucose concentrations in normal cats.2,9 In summary, the cat is uniquely adapted to a carnivorous diet (mice) and is not metabolically adapted to ingestion of excess carbohydrate. When type 2 diabetes occurs in cats, the metabolic adaptations to a carnivorous diet become even more deleterious leading to severe protein catabolism; feeding a diet rich in carbohydrates may exacerbate hyperglycemia and protein wasting in these diabetic cats. In fact, in human beings with type 2 diabetes, the first recommendation is to restrict excess dietary carbohydrates such as potatoes and bread and to control obesity by caloric restriction.10 Furthermore, human beings with type 2 diabetes mellitus have been shown to have improved glycemic control and improvement in nitrogen turnover during weight loss when a low-energy diet (high protein) was combined with oral hypoglycemic therapy.11 We have found high protein diets to be beneficial in increasing lean body mass and reducing post-prandial hyperglycemia. Caution should be used when high protein, restricted carbohydrate diets are used in cats also treated with insulin because the insulin requirement may decrease. Usually the insulin dose is decreased by 25%-50% in cats changing to a high protein diet while on high doses of insulin. Oral hypoglycemics Treatment of NIDDM is aimed at attenuating the physiologic abnormalities of DM by decreasing hepatic glucose output and glucose absorption from the intestine, increasing peripheral insulin sensitivity, and increasing insulin secretion from the pancreas.(Fig 1) Oral hypoglycemic agents include the sulfonylureas (glipizide, glyburide, glimiperide), biguanides (metformin), thiazolidinediones (troglitazone), alpha-glucosidase inhibitors (acarbose) and transition metals (chromium, vanadium).12,13 Indications for oral hypoglycemic therapy in cats include normal or increased body weight, lack of ketones, probable type II diabetics with no underlying disease (pancreatitis, pancreatic tumor), history of diabetogenic medications and owners willingness to administer oral medication rather than an injection. Reversal of glucose toxicity using a short course of insulin therapy prior to or in combination with oral hypoglycemic agents may improve the response to oral hypoglycemic agents.2 Dietary compliance by the owner is essential in improving the response to oral hypoglycemic agents. Agents That Inhibit Intestinal Glucose Absorption The alpha-glucosidase inhibitors impair glucose absorption from the intestine by decreasing fiber digestion and hence glucose production from food sources. 12-14 Acarbose is used as initial therapy in obese pre-diabetic human beings suffering from insulin resistance or as adjunct therapy with sulfonylureas or biguanides to enhance the hypoglycemic effect in patients with Type II diabetes mellitus. Side effects include flatulence, loose stool and diarrhea at high dosages. Acarbose and related compounds are not indicated in patients of low or normal body weight because of their effects on nutrition. Acarbose may be administered at a dosage of 12.5-25 mg/cat with meals. Side effects are more common at the high end of the dose and include semi-formed stool or in some cases overt diarrhea. The glucose lowering effect of acarbose alone is mild with blood glucose concentrations decreasing only into the 250-300 mg/dl range. However, acarbose is an excellent agent when combined with insulin or with diet and insulin to improve glycemic control. The author has had good success using acarbose and a low carbohydrate, high protein diet in cats at a dosage of 12.5 mg BID PO. Agents That Promote Insulin Release From the Pancreas The mechanism of action of the sulfonyureas is to increase insulin secretion and improve insulin resistance; however, some of these agents also cause an increase in hepatic glucose output. 12 Sulfonylureas, because of provocation of insulin release, may promote progression of pancreatic amyloidosis. In cats, glipizide has been used to successfully treat diabetes mellitus at a dosage of 2.5-5 mg BID when combined with dietary therapy.15,16 The patient is evaluated weekly or every 2 weeks for a period of 2-3 months. If the fasting blood glucose decreases to less than 200 mg/dl, the glipizide should be continued at the same dosage and the cat reevaluated in 3-6 months. If the fasting blood glucose remains greater than 200 mg/dl after 2-3 months of therapy and the cat is still symptomatic (PU/PD, wt. loss), glipizide should be discontinued and insulin therapy should be instituted. If the blood glucose remains greater than 200 mg/dl and the cat becomes asymptomatic, the glipizide should be continued indefinitely and the cats should be rechecked in 3-6 months.16 Initial experience with glipizide as an oral hypoglycemic agent in cats has been disappointing. However, this may be related to patient selection and less than ideal diet rather than to overt failure of the drug. Cats with early type II diabetes are most likely to respond to any oral hypoglycemic agent. Side effects of oral hypoglycemics include severe hypoglycemia (rare in cats), cholestatic hepatitis, and vomiting. Gastrointestinal side effects, which occur in about 15% of cats treated with glipizide, resolve when the drug is administered with food.15,16 A new sulfonylurea agent, glimiperide (AmarylŇ), has fewer side effects than glipizide and can be dosed once daily. Initial studies in cats suggest that this may be a viable alternative to glipizide at a dosage of 1-2 mg per cat once daily. Again, combination of sulfonylureas and a low carbohydrate, high-protein diet has been more successful than dietary fiber therapy in this author's hands. Agents that Inhibit Hepatic Glucose Output Metformin belongs to the biguanide group of oral hypoglycemic agents.12 These agents work by inhibiting hepatic glucose release and by improving peripheral insulin sensitivity.17, 18 They have been used alone and in conjunction with other oral hypoglycemic agents to treat Type II diabetes mellitus in human beings.17 One advantage of the biguanides is that they do not promote insulin release; therefore, there is no potential for hypoglycemia when used as a sole agent. Furthermore, the concern about progression of pancreatic amyloid deposition is avoided. Side effects of the biguanides include lactic acidosis and gastrointestinal signs. Contraindications for metformin therapy in humans and presumbly in cats include concurrent renal disease (serum creatinine > 2.1), liver dysfunction, hypoxia and alcoholism. Initial studies using metformin to treat feline NIDDM have been disappointing in that the drug has been associated with severe side effects. Current research indicates that lower dosages of metformin may be safe and possibly effective oral hypoglycemics in the cat.18 In humans combining this drug with a sulfonylurea and diet (carbohydrate restriction) has been the most effective approach.17 Agents That Improve Peripheral Insulin Sensitivity A new class of oral hypoglycemics receiving attention in human medicine are the thiazolidinedione compounds.19,20 Thiazolidinediones facilitate insulin-dependent glucose disposal and inhibit hepatic glucose output by attenuation of gluconeogenesis and glycogenolysis.19 Troglitazone (Rezulin) increases transcription and translation of proteins necessary for glucose metabolism. Some authors have suggested that use of this drug early in the course of NIDDM may slow the progression of NIDDM. Side effects of troglitazone were minimal and no hypoglycemic reactions have been described. In human beings, improvement in fasting BG, glycosylated Hb, and diabetic complications were noted in all patients and were significant when compared with placebo.19 The author has used 200 mg of troglitazone once daily in cats without observing significant changes in blood glucose regulation or side effects. However, in humans, hepatic toxicity (idiosyncratic) has been observed infrequently and the drug is being pulled from the market. Recent publications report a dosage of 25 mg/kg in cats;21 however, no data is available on it's efficacy in diabetic cats. Compounds containing the transition metals, vanadium and chromium, have been shown to have insulinomimetic properties when administered in the drinking water to mice and rats suffering from experimentally-induced DM (Type I and Type II).22-25 Current research indicates that transition metals bypass the insulin-receptor and activate glucose metabolism within the cell. By acting at a post-receptor site, vanadium/chromium compounds are an ideal treatment for Type II DM which results from a lack of insulin receptor responsiveness. Unlike insulin, vanadium and chromium do not lower blood glucose concentrations in normal animals.22-25 Studies in our laboratory indicate that low doses of oral vanadium will decrease blood glucose and serum fructosamine concentrations and alleviate the signs of diabetes (polydypsia, polyuria) in cats with early type II diabetes mellitus.24 Side effects include anorexia and vomiting initially; however, most cats showed no ill effects when vanadium therapy was reinstituted. A recent USDA study of 180 patients with NIDDM found that administration of 1,000 mg of chromium picolinate once daily resulted in amelioration of the classic signs of diabetes and normalization of blood levels of hemoglobin A1c.25 Chromium may be administered at a dosage of 200 microgr/cat once daily as a tablet or capsule and vanadium is available commercially as Vanadyl Fuel (1/2 capsule once daily on food). Combining Oral Hypoglycemics with Insulin: Changes to and from Insulin Agents that impair glucose absorption from the intestine (acarbose) or increase insulin sensitivity (vanadium, metformin, troglitazone) may be combined with insulin to improve glucose control. In the case of "brittle diabetics" where small incremental changes in insulin dose may precipitate hypoglycemia, addition of a drug that enhances the action of insulin may lead to a reduction in the insulin dosage required to attain euglycemia. In humans, acarbose and metformin are commonly used in conjunction with insulin and other oral hypoglycemics (sulfonylureas) that cause insulin release. Caution should be used in combining any oral hypoglycemic agent with insulin because of the potential for severe or fatal hypoglycemia. Changes from insulin to oral hypoglycemic agents or vice versa may be necessary in some diabetic cats. If a cat is particularly sensitive to insulin or exhibits transient diabetes because of reversal of "glucose toxicity", a change to an oral hypoglycemic should be considered. On the other hand, if a cat is being managed with oral hypoglycemic agents and ketosis develops, the oral hypoglycemic agents should be discontinued and the cat should be treated with insulin. Table 1: Oral hypoglycemic drugs used in the treatment of NIDDM in humans and cats.
REFERENCES Berkowitz K, Peters R, Kjos SL, et al: Effect of troglitazone on insulin sensitivity and pancreatic b-cell function in women at high risk for NIDDM. Diabetes 45(11):1572, 1996. Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125:2510, 1989. Cam MC, Pederson RA, Brownsey RW, McNeill JH: Long-term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats. Diabetologia 36:218, 1993. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333(9):541, 1995. Ford S. NIDDM in the cat: treatment with the oral hypoglycemic medication, glipizide. Vet Clin N Amer Sm Anim Pract 25(3):599, 1995. Kahn CR, Shechter Y: Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas. In Goodman Gilman A, Rall TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics, 8th ed, Pergamon Press, New York NY 1990, pp. 1463-1495. O'Brien TD, Butler PC, Westermark P, Johnson KH. Islet amyloid polypeptide: A review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 1993;30:317-332. Rand JS. Management of Feline Diabetes. Aust Vet Practit, 27:68-76, 1997. Saltiel AR, Olefsky JM, Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45(12):1661, 1996. Shechter Y: Insulin-mimetic effects of vanadate: Possible implications for future treatment of diabetes. Diabetes 39:1, 1990. Unger RH, Foster DW: Diabetes Mellitus. In Wilson JD, Foster DW (eds): Textbook of Endocrinology, 7th ed. Philadelphia PA, WB Saunders, 1985, pp. 1062-1064. Table 1: Oral hypoglycemic drugs used in the treatment of NIDDM in humans and cats.
REFERENCES
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