Diabetes Mellitus Associated with Other Endocrine Disorders

Symposium on Endocrinology

Diabetes Mellitus Associated with Other Endocrine Disorders ]. E. Eigenmann, D.V.M., Dr. med. vet., Ph.D.* and Mark E. Peterson, D.V.M.t

Diabetes mellitus is the metabolic disorder characterized by disturbances of carbohydrate, lipid, and protein metabolism. 15• 39 Diabetes mellitus may be either overt (frank, persistent hyperglycemia) or chemical (normal or slightly elevated blood glucose concentration accompanied by abnormal glucose tolerance) in nature. The hyperglycemia of diabetes mellitus results from either an absolute or relative lack of insulin and/or a defect in insulin action at the target tissues. 15• 39 In the latter situation in which a diminished responsiveness of tissues to the action of insulin action exists, circulating insulin concentrations may be subnormal, normal, or even elevated. Therefore, the hyperglycemia associated with diabetes mellitus is not always the result of a lack of insulin. Hyperglycemia associated with high levels of insulin (characteristic of an insulin-resistant state at target tissues) may develop in association with other endocrine disorders and may be reversible if the underlying cause of the insulin resistance is detected and treated.

CLASSIFICATION OF DIABETES MELLITUS IN MAN Primary or idiopathic diabetes can be divided into two main types according to the recent designations of the National Diabetes Group (Table 1). Type I (insulin-dependent, ketosis-prone) diabetes mellitus usually occurs in young people, whereas Type II (insulin-independent, nonketosis prone) diabetes mellitus occurs primarily in mature individuals and is usually associated with obesity. 6 · 15• 39 The clinical, genetic, and immunologic features of Types I and II diabetes mellitus are summarized in Figure 1. In man, diabetes mellitus may also develop secondary to pancreatic disease or hypersecretion of hormones with actions antagonistic to those of *Assistant Professor of Medicine, Department of Clinical Studies, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania tStaff Endocrinologist, Department of Medicine, The Animal Medical Center, New York, New York Veterinary Clinics of North America: Small Animal Practice-Val. 14, No. 4, July 1984

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Table 1. Classification of Human Diabetes* l. Spontaneous diabetes mellitus

a. Type I or insulin-dependent diabetes (formerly called juvenile-onset diabetes) b. Type II or insulin-independent diabetes (formerly called maturity-onset diabetes)

2. Secondary diabetes a. Pancreatic disease (pancreoprivic diabetes, e.g., pancreatectomy, pancreatic insufficiency, hemochromatosis) b. Hormonal: Excessive secretion of contrainsulin hormones (e.g., Cushing's syndrome, pheochromocytoma, acromegaly) c. Drug induced (e.g., potassium-losing diuretics, contrainsulin hormones, psychoactive agents, diphenylhydantoin) d. Associated with complex genetic syndromes 3. Impaired glucose tolerance (formerly called chemical diabetes, asymptomatic diabetes, latent diabetes, and subclinical diabetes): Normal fasting plasma glucose, and 2-hour value on oral glucose tolerance test > 140 mg/dl but < 200 mg/dl 4. Gestational diabetes: Glucose intolerance that begins during pregnancy *From National Diabetes Data Group. Diabetes, 28:1039, 1979.

Type I (Insulin-Dependent) Diabetes Genetic Susceptibility

+ Environmental Factors (?Viral Infection)

Autoimmune___.,. Beta Cell Response Injury +

'---------~Death

Type II (Insulin-Independent) Diabetes Genetic Susceptibility -...Insulin Deficiency and/or R e s i s t a n c e - Absolute or

+ Relative Lack O b e s i t y - - - - - - - - . - Insulin Resistance--------_,~ of Insulin

Etiologic factors in diabetes mellitus in man are shown.

Figure l. Proposed etiologic factors in human, idiopathic diabetes.

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insulin (see Table 1). 13 · 15• 18 Compared to the idiopathic (Types I and II) forms of diabetes mellitus, however, secondary diabetes is a less common cause of human diabetes mellitus.

TYPES OF DIABETES MELLITUS IN DOGS Diabetes mellitus is a frequent disease of the dog, but because of a lack of comprehensive endocrinologic, pathologic, immunologic, and genetic studies, data on canine diabetes mellitus is less complete than in man. In a epizootologic study of diabetes mellitus in the dog, its prevalence was estimated to range from 1 in 100 to 1 in 500 dogs presented to veterinary hospitals. 29 The risk was fcund to be lowest in young dogs, with about 2 to 3 per cent of affected animals being 1 year of age or younger. In young animals, the risk is approximately equal for males and for females, but in older dogs, females are at greater risk. Kramer, et al. 24 has characterized an inherited Type I (hypoinsulinemic) diabetes in young Keeshound dogs. These dogs appear to suffer from the inability to develop and/or maintain a normal number of pancreatic B cells. A review of juvenile Type I diabetes mellitus has recently been published. 25 Other reported breeds affected by the Type I disease at a young age include Labrador Retrievers, German Shepherds, Standard Poodles, and mixed breeds. In these dogs, two basic lesions appear to play a role in the pathogenesis of the disease. The less common appears to be primary atrophy of the B cells, such as is observed in Keeshound dogs. The second lesion appears to be atrophy of an exocrine and endocrine pancreas observed in familial clusters of cases and in single ca~es. Additionally, in some instances, diabetes mellitus appears to be triggered by an infectious disease, reminiscent of findings in human Type I diabetes (see Fig. 1). Although Type I-like diabetes mellitus of juvenile onset does occur, the majority of cases of diabetes mellitus develop in the mature dog. 16• 29 As opposed to diabetes of mature-onset (Type II, noninsulin-dependent) of man, however, most adult diabetic dogs require insulin therapy to survive. In addition, insulin levels (knowledge of which is a prerequisite for categorizing cases into Type I or Type II diabetes) have been measured infrequently in diabetic dogs, and conflicting results have been obtained. In one study, investigators demonstrated that diabetic dogs brought to a veterinary clinic had very low circulating insulin levels, suggesting that canine diabetes mellitus is generally associated with hypoinsulinemia, similar to Type I diabetes mellitus of man. 28 Kanecko, et al., 21 however, classified canine diabetes into several groups by measuring the insulin response to a glucose load. These investigators showed that insulin levels in diabetic dogs may be low, normal, or elevated. They also attempted to compare dogs with undetectable insulin levels to human beings affected by Type I diabetes, and dogs with normal or elevated insulin levels to human beings affected by Type II diabetes. However, a classification performed according to insulin levels alone seems questionable, because it provides no clues as to the pathogenesis or etiology of the disorder. Moreover, regardless of the diabetes-inducing principle,

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insulin levels may be high, normal, or undetectable depending on the stage of the disease. For instance, if normal dogs are rendered diabetic by treatment with growth hormone (GH), diabetes mellitus will be transient or permanent, depending on the duration of treatment. Insulin levels in such dogs are initially high, later becoming normal and eventually subnormal. If the administration of GH is stopped after a few days, the disease reverses. However, if GH therapy is continued for several days and then stopped, the disease persists and insulin levels decline steadily, despite cessation of the treatment. This process occurs over a period of several months, and affected dogs survive for months, even if no insulin is given. 37 Moreover, in postnatal life, pancreatic B cells rarely undergo cell division. Thus, the number of insulin-producing pancreatic B cells is finite, and in the dog, regardless of the initiating cause and cessation of the action of the diabetogenic agent, the hyperglycemic diabetic state will further compromise the insulin secretory capacity. There are few known causes for diabetes mellitus in the mature dog. It is known, however, that several underlying disturbances can be associated with canine diabetes mellitus, and it is possible that secondary diabetes mellitus may be the most common form of the disease in the mature dog. It is possible that severe pancreatic disease can produce secondary diabetes in the dog; 30 however, the suggestion that pancreatitis is a common cause of diabetes mellitus is at variance with the finding of Gepts, who found only occasional changes in the exocrine pancreas in diabetic dogs. 17 More important secondary causes of diabetes in the dog, however, include GH and glucocorticoid excess. In this article, we will discuss the clinical, diagnostic, and therapeutic aspects of the diabetes that may develop in association with other endocrine disorders in the dog and cat.

GROWTH HORMONE EXCESS When factors precipitating diabetes mellitus in dogs are evaluated carefully, it becomes clear thet the disease occurs frequently in aged females and is manifested during the corpus luteum phase (diestrus) of the estrus cycle, when the synthesis of progesterone is maximal. 16• 23• 45 This is in keeping with the findings from epizootologic studies that indicate that intact female dogs are at higher risk than males. 29 Thus, it appears that progesterone alone cannot be responsible for the precipitation of the disease, for only a minor fraction of intact females develop diabetes mellitus. Thus, progesterone in conjunction with a genetically determined predisposition or another progesterone-controlled diabetogenic factor must be responsible for the induction of the disease. Despite the known relationship between the manifestation of diabetes mellitus and the period following estrus (progesterone phase), the pathogenesis involved in the disorder has remained obscure. Recent studies of induction of mammary tumors by progestagens revealed that progestagens, in addition to their tumor-induction potency in some dogs, induced diabetes mellitus and soft-tissue changes reminiscent of human acromegaly. 44 From

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the latter observations, the hypothesis was derived that both conditions (diabetes mellitus and acromegalic changes) could have been caused by progestagen-induced GH overproduction. This could explain why some intact female dogs develop diabetes mellitus during their progesterone phase. GH, especially in carnivores (dogs, cats), exerts a powerful diabetogenic action. 46 There is ample evidence that the diabetogenic action of GH is mainly brought about by induction of insulin resistance on insulin targets such as adipose tissue. GH restricts glucose transport by inducing a glucose transport "limiting factor" normally inhibited by insulin. This may well be the high affinity Ca2 + -ATPase found in fat-cell membranes, and this Ca2 +ATPase may be involved in other insulin-sensitive metabolic steps. 42 • 43 GH appears to induce insulin resistance at a site on the insulin receptor distal to the insulin-binding site (that is, transduction) or at one or more of the intracellular reactions important in insulin action. 20 · 41 It has been shown that GH-induced diabetes mellitus in the dog may be reversible or permanent, depending on the dose of GH administered, the duration of GH treatment, and the animal's individual response to GH. At any rate, during the early stage of treatment circulating insulin levels increase approximately twentyfold, whereas, within only a matter of a few days, pancreatic insulin content falls below 10 per cent. 2• 37 This striking shift of pancreatic insulin towards peripheral insulin is likely to be the result of the appreciable insulin resistance GH can induce. Yet, the rate of secretion of insulin is elevated over the rate of formation of insulin, thus, explaining the final exhaustion of pancreatic B cells taking place in GH diabetes. Historical and Clinical Signs In a study conducted by Eigenmann, 21 dogs that developed glucose intolerance or frank diabetes mellitus either during diestrus or during progestagen therapy were investigated. 12 Ten of these dogs developed the signs during the progesterone phase of the estrus cycle. The time elapsed between the last estrus and the time of presentation for investigation ranged from 3 to 5 weeks (average 3 to 5 weeks). Eleven dogs had been repeatedly treated with medroxyprogesterone acetate (MPA). MPA is used, particularly in Europe, as an estrus-repressing agent. In the group that developed glucose intolerance after MP A administration, the time elapsed between MPA administration and the appearance of signs ranged from 6 to 12 weeks (average 7 1/2 weeks). Thirteen out of the 21 dogs showed, at least to some degree, signs of acromegaly (see the article on acromegaly). Some of the animals exhibiting acromegalic signs had developed noticeable signs for the first time; and in others, the history revealed that signs has been present earlier. In all the latter animals, however, the reappearance or worsening of the acromegalic signs occurred in a period shortly after estrus MPA administration. It is worthwhile noting that among the 10 dogs exhibiting a fasting hyperglycemia of more than 10 mM, only 2 aminmals exhibited acromegaly, but that all ll animals exhibiting a fasting glucose of less than 10 mM showed acromegaly. Even animals having a plasma glucose of more than lO mM usually did not present with weight loss.

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Laboratory Findings Of the 21 dogs studied, 10 had frank hyperglycemia (plasma glucose concentration more than 10 mM or more than 180 mg per dl), whereas the remaining 11 had fasting glucose levels that ranged from 5.4 to 7. 7 mM. In addition, despite extreme elevation of basal insulin levels, these dogs exhibited glucose intolerance and drastic elevation of GH levels when compared with results obtained in normal dogs (Fig. 2A). Thus, as expected from the initial hypothesis, GH levels are high, and diabetes in such animals is characterized by hyperinsulinemia rather than hypoinsulinemia; this is consistent with insulin resistance. The mean glucose disappearance coefficient K (K = 69.3 per TV2 glucose = per cent elimination rate per minute), a parameter for the animal's ability to tolerate glucose, was found to be 0. 9 ± 0.1 in affected animals, whereas normal animals exhibited a K value of 3. 9 ± 0.2 (mean ± SEM; p less than 0.05). If such animals are subjected to progestagen withdrawal and/or ovariohysterectomy, GH levels drop, and despite appreciably lowered insulin levels, glucose tolerance improves (see Fig. 2). Diabetes mellitus, however, may not disappear in some animals (see treatment). In 14 dogs studied, the K value was 0. 9 ± 0.1 before and 2.9 ± 0.2 after progestagen withdrawal and ovariohysterectomy (mean ± SEM; P less than 0.05).

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Figure 2. A, Plasma levels of glucose, insulin, and GH before (= 0 minutes) and during an IVGTI in 21 dogs with signs of diabetes mellitus or acromegaly . _ (10 dogs during a natural progesterone phase and 11 during treatment with low doses of MPA). o-o = IVGTI in 20 normal dogs. B, Plasma levels of glucose, insulin, and GH levels before ( = 0 minutes) and during IVGTI in 14 dogs during a stage ofGH elevation (._) and again when GH levels had lowered after ovariohysterectomy (o-o); seven cases presented during a natural progesterone phase and seven during treatment with MPA. Note: Improvement in glucose tolerance and GH levels in face of a weaker insulin secretion after ovariohysterectomy. (From Eigenmann, J. E.: Diabetes mellitus in dogs and cats. In Proceedings of the Kal Kan Symposium for the Treatment of Small Animal Diseases, 1982, pp. 51-58; with permission.)

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As described previously, signs of acromegaly occurred in all dogs that had a plasma glucose concentration of less than 10 mM, whereas only two of the ten dogs with glucose levels greater than 10 mM exhibited acromegalic signs. Thus, the trend for acromegaly appears to be much higher in animals with only moderate disturbance of glucose tolerance. Dogs with appreciable disturbances of glucose tolerance appear to have acromegaly much less commonly. In this respect, it is worthwhile mentioning that the insulin/glucose ration (insulin in microunits and glucose in millimoles) was 18.7 ± 2. 9 in the group exhibiting a lower plasma glucose (all dogs affected by acromegaly), whereas the group exhibiting frank diabetes (acromegaly being present only occasionally) had an insulin/glucose ratio of only 8.35 ± 4.27 (mean ± SEM; p less then 0.01), despite the fact that both groups exhibited similar plasma GH levels. Dogs exhibiting signs of acromegaly and hyperglycemia during a natural progesterone phase (diestrus) have progesterone levels within the normal range but elevated GH levels. In animals developing signs during diestrus, ovariohysterectomy or a spontaneous reduction in progesterone is followed by a slight, but inevitable, drop in GH levels (see Fig. 2). In animals that develop signs after MP A administration, plasma levels of the compound at the time of presentation are usually low. GH levels in pregnant dogs who are invariably under the influence of progesterone are only occasionally elevated. 7- 11 Lesions in the Pancreas Lesions in the pancreas include hypoplasia and vacuolization of the islets. Islets still exhibiting normal size also show typical vacuolization (Fig. 3). Pathogenesis The finding of hyperinsulinemia in these dogs with GH excess points to insulin resistance as the factor responsible for their hyperglycemia and/ or glucose intolerance. This is further supported by the fact that the insulin requirement of diabetic dogs having GH elevation, despite elevated endogenous insulin levels, is appreciably higher than the insulin requirement of diabetic dogs not having GH elevation (see section on treatment). These findings are compatible with GH-induced diabetes. GH causes glucose intolerance mainly by inducing insulin resistance. 1 In contrast to other species, such as the rat, carnivores are particularly sensitive to the diabetogenic action of G H. 1· 37• 46 Administration of G H to the dog can lead within a matter of days to a diabetic state that is initially characterized by hyperinsulinemia. If exposure to high GH levels persists, exhaustion of pancreatic B cells and hypoinsulinemia may ensue. 37 It is important to note that, in affected dogs, there is generally no correlation between the degree of GH elevation and the degree of hyperglycemia. When dogs are given comparable amounts of GH, even under the most controlled situations, there is wide variation in response. Some dogs do develop overt diabetes and some do not. 3 Similarly, the time course and the extent of response in experimentally induced GH diabetes can vary from experiment to experiment. 2 In the dogs studied, it is of interest to

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Figure 3. Photomicrograph of pancreatic tissue (tail) from a diabetic dog (natural progesterone phase); the dog recovered from diabetes after ovariohysterectomy. (HE stain, 2.90 x .) Note: Hydropic degeneration of B cells, hydropic changes in intercalated ducts (arrows), unaffected acinar tissue. (From Eigenmann, J. E.: Diabetes mellitus in dogs and cats. In Proceedings of the Kal Kan Symposium for the Treatment of Small Animal Diseases, 1982, pp. 51- 58; with permission. )

note that animals having a plasma glucose of less than 10 mM have a higher insulin/glucose ratio than do animals exhibiting a plasma glucose of greater than lO mM. Less pronounced hyperglycemia, therefore, appears to be at least partly the result of a relatively higher plasma insulin concentration, preventing plasma glucose concentrations from appreciable escape. Further, the degree of hyperglycemia also depends upon the duration of exposure to GH. 37 The fact that GH is elevated in animals exhibiting diabetes during progestagen exposure but not in dogs developing diabetes independently of such exposure precludes the possibility that GH elevation may be caused by hyperglyce mia or the diabetic state as such. Additional evidence for GH as a major factor in inducing insulin resistance, glucose intolerance, and acromegaly in some dogs exposed to progestagen or progesterone is derived from the following: (l) all the observed endocrine, metabolic, and physical changes in such dogs reflect the result of a persistent elevation of biologically active GH, and (2) following GH correction, there is a correction of the GH excess associated changes. It is interesting to find that only two out of ten dogs exhibiting frank diabetes (plasma glucose greater than lO mM) showed acromegalic signs and that, among dogs exhibiting mild hyperglycemia, all were consistently acromegalic. These findings suggest that the opportunity to develop acromegaly is inversely correlated with the catabolic state (hyperglycemia) and/ or availability of insulin in these animals. It is possible that in the

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hyperinsulinemic dog with GH-induced diabetes, the catabolic situation invariably associated with pronounced and prolonged diabetes eventually outstrips the anabolic effects normally exerted by GH. In the dog with experimentally-induced GH diabetes, body weight initially increases. Later, when the signs of diabetes become more severe despite continued GH administration, the body weight decreases. This is in keeping with the fact that some of the dogs presented with diabetes do not have, at least initially, one of the classical signs of the disease-that is, weight loss. The fact that GH levels drop after ovariohysterectomy and progestagen withdrawal is evidence for an ovarian and progestagen-GH interrelationship. Moreover, the observations that a spontaneous drop of progesterone levels is followed by a spontaneous drop in GH levels and that pregnant animals generally have normal GH levels suggest that GH levels in some dogs are paradoxically controlled by natural levels of progesterone. The mechanism whereby the GH axis becomes responsive to progesterone remains unknown. The disorder may be present at birth or develop later in life. The fact that GH levels in some cases were elevated to an extent certainly sufficient to induce diabetes mellitus earlier in life but that the animals did not develop diabetes sooner would suggest that the condition, for some unknown reason, develops in older age. In this context, it is important to realize that dogs, in contrast to other species, exhibit almost identically high post-estrus progesterone-concentration increases whether thay are pregnant or not. 5 Additionally, dogs' reproductive cycles do not cease in old age. Whether such lifelong exposure to "pregnancy progesterone levels" contributes to or provides the necessary environment for the development of the disorder is unknown, but it remains an interesting possibility. Management In dogs with glucose intolerance resulting from GH excess, the following diagnostic and therapeutic points are emphasized: (1) prompt recognition of hyperglycemia or impaired glucose intolerance; (2) prompt correction of hyperglycemia and performance of ovariohysterectomy in order to lower GH and insulin output and preserve most of the remaining B-cell activity. Recognition of Hyperglycemia or Glucose Intolerance. In any intact female dog presenting with signs of acromegaly and/or diabetes (respiratory stridor, increased number of skin folds, increased abdominal size, fatigue, polyuria/polydipsia) either during progestagen treatment or during a progesterone phase, the plasma glucose should be evaluated immediately. Testing only the urine for glucose is insufficient for the diagnosis, because a number of animals affected by the disorder(s) may have only mild elevations of fasting plasma glucose. These animals, however, because of their glucose intolerance, may readily spill some glucose in the urine after food ingestion. If the fasting plasma glucose is only moderately elevated (less than 150 mg per dl), the most appropriate means of diagnosing glucose intolerance is by means of an intravenous glucose tolerance test. Although normal animals generally have glucose assimilation coefficients (K) of more than 3, affected animals have K values of less than 2. In normal dogs, as a

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rule, plasma glucose levels should return to a preload concentration within 60 minutes of the load. Ovariohysterectomy. It has proved practical to ovariohysterectomize affected intact females as soon as possible regardless of whether the animal has developed the disease when treated with progestagens or during a luteal phase. Even in dogs in which the chance for recovery from diabetes is minimal, ovariohysterectomy is recommended. Intact female dogs who have developed diabetes because of progesterone-induced G H excess, even when full recovery would not occur following ovariohysterectomy, will invariably increase their insulin demand during the following progesterone phase. Progesterone at that time will again lead to high GH levels, and the resistance to insulin may develop abruptly and be extreme. It is impossible to predict the degree of the resistance, and the owners of such dogs are often unable to cope with the changes in insulin requirement. It is also possible that such dogs, because of insufficient insulin administration, may develop ketoacidosis. Treatment at that time may be frustrating, especially if the animal is also affected by pyometra and/or renal failure. The recommendation to ovariohysterectomize dogs as soon as possible, provided the animal is not ketotic, appears to have only advantages. The advantages are that early ovariohysterectomy in dogs who still suffer from appreciable GH elevation leads to a rapid decrease in GH levels and, thus, to an amelioration of the insulin resistance. Thereby, one enhances the chance of recovery because one ameliorates the diabetic condition that is known to be B-cell toxic. Moreover, if ovariohysterectomy is performed early, the time course of a decrease in insulin requirement becomes more predictable. Finally, it has to be emphasized that suppression of estrus (chemical ovariohysterectomy) in such animals is contraindicated. Some veterinarians who have the notion that estrus and diestrus are somehow involved in the pathogenesis of diabetes in intact females attempt to eliminate cycles by administering estrus-suppressing agents such as MPA. By doing this, they obviously directly provoke the hormonal situation-for example, progestagen-induced GH excess, which is responsible for the development and dysregulation of diabetes in such animals. Because of the lack of knowledge, the safety of testosterone derivatives such as mibolerone (Cheque-drops*) remains unknown. Although testosterone derivatives are C 19 steroids, it is conceivable that by cross-reacting on progesterone receptors they have progestagen-like activities. Insulin Treatment. It is crucial to determine at which blood glucose level to start insulin replacement. This question is complex and in a clinical setting there is generally no straightforward answer to this. The reasons for this are that, in general, the clinician does not have information on the animal's actual plasma insulin, GH, and progesterone levels and that even these parameters do not allow direct conclusions as to the actual pancreatic insulin reserve or the degree of insulin resistance. Plasma insulin levels should, however, be obtained whenever possible. The findings of a high plasma insulin level mean that the animal has a fair chance for recovery when adequately treated, and the findings of subnormal or absent insulin levels mean that the chance for recovery is minimal. In the dog who has a *The Upjohn Company, Kalamazoo, Michigan.

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Figure 4. Time course of plasma GH levels following ovariohysterectomy or spontaneous decrease of progesterone levels (P) in nine dogs exhibiting GH overproduction and glucose intolerance during diestrus (left panel). Time course of plasma GH levels during a spontaneous diecrease in plasma progesterone levels in five out of the nine dogs shown on the left. The corresponding progesterone concentrations ( = P) in ng per ml are indicated in the figure on the right of each corresponding GH concentration; tf = ovariohysterectomy (right panel). (From Eigenmann, J. E.: Diabetes mellitus in dogs and cats. In Proceedings of the Kal Kan Symposium for the Treatment of Small Animal Diseases, 1982, pp. 51-58; with permission.)

fair chance for recovery, strict control of the blood glucose levels is warranted because of its positive influence on the recovery, 19· 27· 38 whereas in dogs with undetectable insulin levels, because of the minimal chance for recovery, strict control is unwarranted. In general, one can assume that the longer the signs have persisted, the less the chance for recovery. By questioning owners carefully, one can often learn that the animal in question had similar symptoms during earlier progesterone phases. The frequency of episodes is likely to be of additional influence on the chance of recovery. It is important to know whether the dog has developed diabetes following estrus or during progestagen medication. In dogs treated with progestagens, GH levels can remain elevated for prolonged periods of time, thus decreasing the chance for recovery (Fig. 5). Progestagens, probably because of their depot effect, appear to influence GH secretion more profoundly. As a rule, it is recommended to substitute insulin if the plasma glucose is above 150 mg per cent in dogs with progestagen treatment and if plasma glucose is above 200 mg per cent in dogs who develop diabetes during the progesterone phase. Later, in the treatment of GH-induced diabetes, the question arises as to which factors at what time will influence the dog's insulin requirement.

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Figure 5. A 4-year-old Scottish Terrier. The dog had received the last MPA administration three months before being referred because ofPU/PD. Fasting glucose was found to be 14.6 mmol per L (246.6 mg per cent). An IVGTT revealed glucose intolerance, highly elevated insulin levels, no response to glucose load, and high GH levels (Fig. 4). This dog did not recover from diabetes mellitus, and GH levels remained elevated for several months. (From Eigenmann, J. E., and Eigenmann, R. Y.: Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. II. Studies in the ovariohysterectomized, oestradiol-primed bitch. Acta Endocrinol. (Copenhagen) 98:603-608, 1981; with permission.)

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Two factors play a significant role: (1) the GH-induced insulin resistance, and (2) the functional recovery of the residual pancreatic B cells. GH usually decreases within a matter of days after ovariohysterectomy. This is particularly true for dogs who develop the disease during a natural progesterone phase. Recovery of residual B cells takes days to weeks. After ovariohysterectomy, it is recommended to keep such dogs for a few days in the hospital and to adjust their insulin requirement by monitoring the afternoon blood glucose. As soon as the glucose starts to drop, the daily insulin dose is decreased accordingly. In some dogs, even during hospitalization, the insulin requirement may drop to zero. In other dogs, the daily insulin requirement may initially decrease, then apparently plateau, and, finally, decrease slowly over a certain period of time. Figure 6 shows a typical case of insulin adjustment before and after ovariohysterectomy in a dog that developed diabetes mellitus during the progesterone phase. If a dog does not recover during its hospital stay, it is discharged and its insulin requirement, if indicated, is generally decreased at home. Once the dog is at home, monitoring the patient becomes slightly more complicated, because blood glucose measurements are not as easily performed as in the hospital. At this time, afternoon blood glucose should be evaluated at least once a week and, if indicated, the insulin dose should be lowered. In quite a number of dogs, however, weekly monitoring of blood glucose becomes insufficient and the insulin dose has to be lowered according to the clinical signs of mild hypoglycemia. Although hypoglycemia represents nightmares to some clinicians, hypoglycemic signs are still the best biologic indicator for improving B-cell function. One obviously advises the owner to observe the dog closely and to take action as soon as mild signs of

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hypoglycemia, such as weakness in the rear legs, occur. At that time, the dog must be given carbohydrates orally and, subsequently, several smaller meals are offered throughout the day. The insulin dose is promptly lowered the following morning. This procedure is continued until the dog's insulin requirement reaches zero or another plateau. · At this time, it should be emphasized that insulin therapy should not be withdrawn simply on the basis of the finding of a negative morning urine glucose. Although this procedure may be appropriate in some cases, there is no means by which the clinician can predict this possibility. Urine glucose measurements are an insensitive way of assessing the animal's glucose tolerance. The following example shows that even basal plasma glucose measurements may be insensitive. The dog shown (Fig. 7A) at the time of diagnosis already had relatively low insulin levels. After appropriate insulin treatment and ovariohysterectomy, the insulin dose was lowered according to afternoon blood glucose readings and eventually reached zero. Over a period of 2 days, when the dog was given no insulin, the afternoon glucose started to rise again. An intravenous glucose tolerance test performed at that time revealed that the dog, according to the glucose tolerance test, was still diabetic. Then, over the next 2 weeks, the dog was treated with decreasing amounts of insulin. Another glucose tolerance test performed 7 days later showed that at that time the glucose tolerance had greatly improved (Fig. 7A and B). This is compatible with the known fact that recovery of the B cells may take time and that strict control of blood glucose levels is important if total recovery is to occur. 19• 27 · 38 Finally, it should be emphasized that intact female dogs that have suffered from GH-induced diabetes, even after recovery, are likely to have at least some degree of permanent functional damage to the insulin-secreting B cells. These dogs should not be further exposed to any diabetogenic agents such as glucocorticoids.

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Figure 7. A, Plasma glucose levels, insulin dose, and plasma GH levels in a dog with spontaneous GH diabetes. Note: Initial increase in insulin requirement and drop after ovariohysterectomy; drop of elevated GH levels; resting plasma glucose levels increased again after insulin withdrawal and the dog is glucose intolerant (K = 1.2); glucose tolerance improved after the animal had been given insulin again for 2 weeks. B, Plasma glucose disappearance curves and glucose assimilation coefficient (K) in the dog shown in part A. X - x before treatment; o-o after ovariohysterectomy and insulin withdrawal when afternoon blood glucose levels had normalized; ......... 7 days after the dog had been given insulin again for 2 weeks. Note: Diabetic glucose tolerance (K = 1.2) despite only slightly elevated resting blood glucose levels and negative urine glucose readings and improvement of the glucose tolerance after the dog had been given insulin again for 2 weeks.

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HYPERADRENOCORTICISM Hyperadrenocorticism (Cushing's syndrome) is a common disorder in the dog that results from either excessive cortisol production by the adrenal cortex (bilateral adrenocortical hyperplasia or functional adrenal tumor) or from the prolonged administration of pharmacologic doses of glucocorticoids.14 Alterations of glucose metabolism occur frequently in dogs with hyperadrenocorticism. Approximately 40 to 60 percent of dogs have elevated fasting glucose concentrations, whereas the prevalence of overt diabetes mellitus in canine hyperadrenocorticism is about 15 per cent. 26 • 36 • 40 As in states of GH excess, insulin resistance, characterized by the presence of endogenous hyperinsulinemia in the face of normal or elevated plasma glucose concentrations, is also a common feature of hyperadrenocorticism in the dog. 36 Pathogenesis of Alterations in Glucose Metabolism Both increased hepatic gluconeogenesis and decreased glucose uptake by peripheral tissues appear to contribute to the impaired carbohydrate metabolism associated with glucocorticoid excess. 18 · 34 The underlying mechanisms for these changes in glucose production and utilization, however, are incompletely understood. For insulin to exert its biologic effects, it must be synthesized by the pancreatic beta cells, secreted in the bloodstream, and transported to tissues where the hormone interacts with specific cell membrane receptors to initiate a series of postreceptor (intracellular) events. Recent in vitro and in vivo evidence suggests that glucocorticoid excess produces an insulin-resistant state by either altering the binding of insulin to its receptor (receptor defect) or impairing the intracellular response to insulin. 4· 20 • 32 Since insulin normally acts to suppress hepatic production of glucose and to increase its utilization by peripheral tissues, such a receptor or postreceptor defect would result in increased hepatic glucose production and decreased glucose utilization by tissues. The hyperinsulinemia commonly associated with states of glucocorticoid excess appears to represent a secondary compensatory response to this insulin resistance. With such target-tissue defects in insulin action, such hyperinsulinemia is usually sufficient to maintain plasma glucose concentrations near normal; however, under conditions of limited insulin reserve and/or pronounced insulin resistance, progressive hyperglycemia and ketoacidosis will develop. 22 • 33 • 36 Laboratory Findings In dogs with hyperadrenocorticism, a spectrum of baseline plasma glucose and insulin concentrations occurs (Fig. 8), including: (1) normal concentrations of both glucose and insulin (Group I); (2) normal glucose concentrations with mild to moderate hyperinsulinemia (Group II); (3) hyperglycemia with moderate to severe hyperinsulinemia (Group III); and (4) severe hyperglycemia (overt diabetes mellitus) with relative insulin deficiency (Group IV). This spectrum of abnormalities in basal fasting concentrations of glucose and insulin appears to represent progressive stages of deterioration in insulin sensitivity and glucose tolerance produced

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by chronic cortisol excess.34 • 36 Most dogs with hyperadrenocorticism compensate for the glucocorticoid-induced insulin resistance by increasing pancreatic insulin secretion; resultant hyperinsulinemia maintains circulating glucose at normal or near-normal levels. In susceptible dogs with limited insulin reserve, however, chronic glucocorticoid excess may produce overt diabe tes mellitus (see Group IV; Fig. 8). In most dogs with hyperadrenocorticism that have adequate insulin reserve (Groups I to III; see Fig. 8), only mild to moderate glucose intolerance can be detected using glucose tole rance testing (Fig. 9A). To overcome the insulin resistance associated with hyperadrenocorticism, however, both basal and glucose-stimulated insulin secretion is markedly enhanced, in order to maintain normal or near-normal glucose tolerance (see Fig. 9A). Consistent with this endogeneous insulin resistance, dogs with hyperadrenocorticism are also resistant to the glucose-lowering effects of exogenous insulin administration (see Fig. 9B). Diagnosis of Hyperadrenocorticism in Dogs with Glucose Intolerance or Overt Diabetes Mellitus. It can be difficult to diagnose hyperadrenocorticism in dogs with glucose intolerance or overt diabetes mellitus on clinical grounds alone,

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because many clinical signs (polyuria, polydipsia, polyphagia, and hepatomegaly) are common to both diabetes and hyperadrenocorticism. Underlying hyperadrenocorticism should be suspected in any diabetic dog that has or develops hair loss, abdominal distension, calcinosis cutis, or other clinical signs suggestive of glucocorticoid excess. In many diabetic dogs with untreated hyperadrenocorticism, resistance to the glucose-lowering effects of exogenous insulin therapy also develops; concurrent hyperadrenocorticism should be excluded in any diabetic dog that has sustained hyperglycemia and glycosuria despite high daily insulin doses (more than 2.2 units per kg). 22· 33 Specific laboratory tests (ACTH stimulation, dexamethasone suppression) must be used to definitively confirm hyperadrenocorticism and to differentiate pituitary-dependent adrenal hyperplasia from adrenal tumors (see the article on hyperadrenocorticism). Caution must be used when interpreting test results, however, because the "stress" associated with poorly controlled diabetes mellitus alone could alter the test results. Dogs with diabetes should not be evaluated for hyperadrenocorticism with these testing procedures until azotemia and ketoacidosis have resolved and diabetic control with insulin has stabilized. If only slightly abnormal test results suggestive of hyperadrenocorticism are obtained, it is usually wise to withhold treatment for hyperadrenocorticism and reconfirm the abnormal test results l to 3 months later, in order to prevent unnecessary and potentially dangerous treatments. Treatment of Concurrent Diabetes Mellitus and Hyperadrenocorticism In dogs with glucose intolerance or overt diabetes mellitus associated wtih hyperadrenocorticism, the cause of the underlying hyperadrenocorticism determines treatment. Functional adrenocortical tumors should be surgically removed, whereas pituitary-dependent hyperadrenocorticism is usually most easily managed with the adrenocorticolytic drug o, p'-D D D (see the article on hyperadrenocorticism). In dogs with only mild to moderate hyperglycemia and glucose intolerance, exogenous insulin therapy is not required. Correction of hypercortisolism alone will reverse the associated glucose intolerance and endogenous insulin resistance (evidenced by hyperinsulinemia) in these dogs (Fig. 10). In dogs with hyperadrenocorticism that develop hypoinsulinemic overt diabetes (plasma glucose more than 250 mg per dl) with or without concurrent ketoacidosis, therapy should be initiated and the diabetes stabilized prior to treatment of hyperadrenocorticism. Because of cortisolinduced insulin resistance, many diabetic dogs with untreated hyperadrenocorticism will require high daily doses (more than 2.2 units per kg) of insulin to control severe hyperglycemia and prevent ketoacidosis. 22 • 33 Correction of hyperadrenocorticism with surgical adrenalectomy or o,p'-DDD removes the cause of insulin resistance (that is, cortisol excess) and reduces the daily insulin requirements in these dogs. A serious complication associated with the standard o,p'-DDD protocol during the initial treatment period (see the article on hyperadrenocorticism) in diabetic dogs with insulin resistance, however, may be a rapid decrease in daily insulin

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requirements, predisposing to insulin overdosage and hypoglycemia.33 Use of a lower initial dose of o,p'-DDD (25 to 35 mg per kg per day) and a high maintenance dose of either prednisone (0.4 mg per kg) or cortisone (2 mg per kg) prevents the rapid reductions in circulating glucocorticoid levels and daily insulin requireme nts and allows for easier regulation of the diabetic state. Once normal plasma cortisol concentrations are documented by ACTH stimulation testing, o,p'-DDD should be continued at the standard maintenance dose of 50 mg per kg per week, with dose adjustments made as necessary (see the article on hyperadrenocorticism). Despite adequate control of hyperadrenocorticism, dogs with concurrent overt diabetes mellitus usually require lifelong insulin therapy to prevent severe hyperglycemia and ketoacidosis. PHEOCHROMOCYTOMA

Pheochromocytomas are functional tumors of the adrenal cortex that secrete excessive amounts of catecholamines (see the article on pheochrom-

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ocytoma). Excess catecholamines may impair carbohydrate tolerance by (1) inhibiting glucose utilization, (2) stimulating hepatic and muscle glycogenolysis, hepatic glucose production, and lipolysis, and (3) inhibiting pancreatic insulin secretion. 13• 18 In most dogs and human patients with pheochromocytoma, only mild degrees of hyperglycemia or impaired glucose tolerance can be demonstrated; insulin therapy is almost never required. Surgical removal of the adrenal tumor restores normal plasma glucose concentrations and glucose tolerance in patients with pheochromocytoma. HYPERTHYROIDISM Hyperthyroidism is the disorder resulting from excessive circulating concentrations of the thyroid hormones, thyroxine, and triiodothyronine. Although rare in the dog, hyperthyroidism has been a common disorder in the cat (see the articles on feline hyperthyroidism). 35 In human patients with untreated hyperthyroidism, the incidence of abnormal glucose tolerance has been reported to be as high as 57 per cent. 13• 31 Mild to moderate hyperglycemia and overt diabetes mellitus also develops in some cats with hyperthyroidism. 35 Thyroid hormone may affect carbohydrate metabolism in many ways. Experimentally, thyroid hormone excess increases the rate of glucose absorption, utilization, and production, and increases the rate of insulin degradation. Although some studies show that insulin secretion is also impaired in hyperthyroidism, others have revealed hyperinsulinemia, consistent with peripheral insulin resistance. 13 • 18• 31 Finally, marked elevation in circulating glucogan concentrations, which could also contribute to glucose intolerance, have been reported in 30 per cent of human patients with hyperthyroidism. 31 In most cats and human patients with hyperthyroidism, alterations in glucose metabolism are mild and do not require treatment. Occasionally, patients will develop marked hyperglycemia, glycosuria, and ketonuria, with variable insulin requirements. In most patients with overt diabetes mellitus, insulin therapy is required despite treatment of the hyperthyroid state. As with the other endocrine diseases associated with glucose intolerance, however, correction of hyperthyroidism allows for easier control of the diabetic state. REFERENCES l. Altszuler, N.: Actions of growth hormone on carbohydrate metabolism. In Creep, R. 0., and Astwood, E. N. (eds.): Handbook of Physiology. Washington, D.C., American Physiology Society, 1974, pp. 233--252.

2. Campbell, J., Pierluissi, J., and Green, G. R.: Somatotrophic diabetes: Insulin release responses to arginine and glucagon in dogs. Diabetologia, 15:205--212, 1978. 3. Campbell, J., and Rastogi, K. S.: Augumented insulin secretion due to growth hormonestimulating effects of glucose and food in dogs. Diabetes, 15:749--758, 1966. 4. Caro, J. F., and Amatruda, J. M.: Glucocorticoid-induced insulin resistance: The importance of postbinding events in the regulation of insulin binding, action, and degration in freshly isolated and primary cultures of rat hepatocytes. J. Clin. Invest., 69:866-875, 1982.

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5. Concannon, P. W., Power, M. E., Holder, W., et al.: Pregnancy and parturition in the bitch. Biol. Reprod., 16:517-526, 1977. 6. Craighead, J. E.: Current views on the etiology of insulin-dependent diabetes mellitus. N. Engl. J. Med., 299:1439-1445, 1978. 7. Eigenmann, J. E., and Eigenmann, R. Y.: Radioimmunoassay of canine growth hormone. Acta Endocrinol. (Copenhagen), 98:514-520, 1981. 8. Eigenmann, J. E., and Rijnberk, A.: Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. I. Studies in the ovariohysterectomized bitch. Acta Endocrinol. (Copenhagen), 98:599-602, 1981. 9. Eigenmann, J. E., and Eigenmann, R. Y.: Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. II. Studies in the ovariohysterectomized, oestradiolprimed bitch. Acta Endocrinol. (Copenhagen), 98:603-608, 1981. 10. Eigenmann, J. E.: Diabetes mellitus in elderly female dogs: Recent findings on pathogenesis and clinical implications. J. Am. Anim. Hosp. Assoc., 17:805-822, 1981. ll. Eigenmann, J. E.: Diabetes mellitus in dogs and cats. 1n Proceedings of The Kal Kan Symposium for the Treatment of Small Animal Diseases, 1982, pp. 51--58. 12. Eigenmann, J. E., Eigenmann, R. Y., Rijnberk, A., etal.: Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinol. (Copenhagen), 104:167-176, 1983. 13. Emmer, M., Gordon, P., and Roth, J.: Diabetes in association with other endocrine disorders. Med. Clin. North Am., 55:1057-1064, 1971. 14. Feldman, E. C.: The adrenal cortex. In Ettinger, S. J. (ed.): Textbook of Veterinary Internal Medicine. Edition 2. Philadelphia, W. B. Saunders Co., 1983, pp. 1650--1696. 15. Felig, P.: The endocrine pancreas: Diabetes mellitus. In Felig, P., Baxter, J. D., and Broadus, A. E., et al. (eds.): Endocrinology and Metabolism. New York, McGraw-Hill Book Company, 1981, pp. 761-868. 16. Foster, I.: Diabetes mellitus: A study of the disease in the dog and cat in Kent. J. Small Anim. Pract., 16:29fh315, 1975. 17. Gepts, W., and Toussaint, D.: Spontaneous diabetes in dogs and cats. Diabetologia, 3:249-265, 1967. 18. Harrison, L. C., and Flier, J. S.: Diabetes associated with other endocrine diseases. In Podolsky, S., and Viswanathan, M. (eds.): Secondary Diabetes: The Spectrum of the Diabetic Syndromes. New York, Raven Press, 1980, pp. 269-286. 19. Hidaka, H., Nagulesparan, M., Kumes, I., et al.: Improvement of insulin resistance after short-term control of plasma glucose in obese Type II diabetes. J. Clin. Endocrinol. Metab., 54:217-222, 1982. 20. Kahn, C. R., Goldfine, I. D., Neville, D. M., et al.: Alterations in insulin-binding induced by changes in vivo in the levels of glucocorticoids and growth hormone. Endocrinology, 103:1054--1066, 1978. 21. Kaneko, J. J., Mattheeuws, D., Rottiers, R. P., et al.: Glucose tolerance and insulin response in diabetes mellitus of dogs. J. Small Anim. Pract., 18:85-94, 1977. 22. Katherman, A. E., O'Leary, T. P., Richardson, R. C., et al.: Hyperadrenalcorticism and diabetes mellitus in the dog. J. Am. Anim. Hosp. Assoc., 16:705-717, 1980. 23. Krook, L., Larsson, S., and Roodney, J. R.: The interrelationship of diabetes mellitus, obesity and pyometra in the dog. Am. J. Vet. Res., 21:120--124, 1960. 24. Kramer, J. W., Nottingham, S., Robinette, J., et al.: Inherited early onset, insulinrequiring diabetes mellitus of Keeshond dogs. Diabetes, 29:558-565, 1980. 25. Kramer, J. W., and Evermann, J. F.: Early-onset genetic and familial diabetes mellitus in dogs. In Proceedings of The Kal Kan Symposium for the Treatment of Small Animal Diseases, 1982, pp. 59-62. 26. Ling, G. V., Stabenfeldt, G. H., Comer, K. M., et al.: Canine hyperadrenocorticism: Pretreatment clinical and laboratory evaluation of ll7 cases. J. Am. Vet. Med. Assoc., 174:12ll-l215, 1979. 27. Madsbad, S., Krarup, T., Regeur, L., et al.: Effect of sti:ict blood glucose control on residual B-cell function in insulin-dependent diabetics. Diabetologia, 20:530--534, 1981. 28. Mann, J. G., and Martin, G. L.: Plasma insulin, glucagon am!. nonesterified fatty acids in dogs with diabetes mellitus. Am. J. Vet. Res., 33:981-985, 1972. 29. Marmor, M., Willeberg, P., Glickman, L. T., et al.: Epizootiologic patterns of diabetes mellitus in dogs. Am. J. Vet. Res., 43:465-470, 1982.

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30. Meier, H.: Diabetes mellitus iu animals. Diabetes, 9:485-489, 1960. 31. Mouradian, M., and Abourizk, N.: Diabetes mellitus and thyroid disease. Diabetes Care, 6:512--520, 1983. 32. Nosadini, R., Del Prato, S., Tiengo, A., eta!.: Insulin resistance in Cushing's syndrome. J. Clin. Endocrinol. Metab., 57:529-536, 1983. 33. Peterson, M. E., Nesbitt, G. H., and Schaer, M.: Diagnosis and management of concurrent diabetes mellitus and hyperadrenocorticism in 30 dogs. J. Am. Vet. Med. Assoc., 178:66--69, 1981. 34. Peterson, M. E., and Altszuler, N.: Spontaneous canine Cushing's syndrome: Decreased insulin sensitivity and glucose tolerance. Diabetes, 30:73A, 1981. 35. Peterson, M. E., Kintzer, P. P., Cavanagh, P. G., et a!.: Feline hyperthyroidism: Pretreatment clinical and laboratory evaluation of 131 cases. J. Am. Vet. Me d. Assoc., 183:103--110, 1983. 36. Peterson, M. E., Altszuler, N., and Nichols, C. E.: Decreased insulin sensitivity and glucose tolerance in spontaneous canine hyperadrenocorticism. Res. Vet. Sci. (in press). 37. Pierluissi, J., and Campbell, J.: Metasomatotrophic diabetes and its induction: Basal insulin secretion and insulin release responses to glucose, glucagon, arginine and meals. Diabetologia, 18:223--228, 1980. 38. Portha, B., and Picon, L.: Insulin treatment improves the spontaneous remission of neonatal streptozotocin diabetes in the rat. Diabetes, 31:165-169, 1982. 39. Renold, A. E., Mintz, D. H., Muller, W. A., eta!.: Diabetes mellitus. In Stanbury, J. B., Wijngaarden, J. B., and Frederickson, D. S. (eds.): The Metabolic Basis oflnherited Disease. New York, McGraw-Hill Book Company, 1978, pp. 80-109. 40. Rijnberk, A., der Kinderen, P. J., and Thijssen, J. H. H.: Spontaneous hyperadrenocorticism in the dog. J. Endocrinol., 41:397-406, 1968. 41. Rosenfeld, R. G., Wilson, D. W., Dollar, L. A., et a!.: Both human pituitary growth hormone and recombinant DNA-derived human growth hormone cause insulin resistance at a postreceptor site. J. Clin. Endocrinol. Metab., 54:1033--1038, 1982. 42. Schoenle, E., Zapf, J., and Froesch, E. R.: Glucose transport in adipocytes and its control by growth hormone in vivo. Am. J. Physiol., 242:E368-372, 1982. 43. Schenle, E., Zapf, J. , and Froesch, E. R. : Regulation of rat adipocyte glucose transport by growth hormone. No mediation by insulin-like growth factors. Endocrinology, 112:384-386, 1983. 44. Sloan, J. M., and Oliver, E. M.: Progestagen-induced diabetes in the dog. Diabetes, 24:337-344, 1975. 45. Wilkinson, J. C.: Spontaneous diabetes mellitus. Vet. Rec., 72:548-555, 1960. 46. Young, F. G.: Growthhormoneanddiabetes. RecentProg. Horm. Res., 8:471-510,1953. Department of Clinical Studies The School of Veterinary Medicine University of Pennsylvania 3850 Spruce Street Philadelphia, Pennsylvania 19104