Management of difficult diabetes cases: a case-based approach (Proceedings)

Pathophysiology of dm

Diabetes mellitus (DM) is a common endocrine disease in dogs and cats characterized by an absolute or relative deficiency of insulin. This results in a decreased ability of cells to take up and utilize not only glucose, but also amino acids, fatty acids, and electrolytes. In addition the lack of insulin results in increased gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, and protein catabolism. Factors that have been identified as predisposing factors in cats include obesity, advancing age and being male. In dogs, older females are at higher risk of developing DM. Poodles, Dachshunds, Miniature Pinschers, Beagles, Golden Retrievers, and Miniature Schnauzers are considered to be at higher risk than the general canine population. Keeshonden appear to have a genetic predisposition to the disease.

Two types of DM are recognized in man, and these classifications can be applied to the disease in dogs and cats. Type I DM (insulin dependent diabetes mellitus) is due to an absolute deficiency of insulin. This form of diabetes is characterized by minimal secretory response to β-cell secretagogues such as glucagon, and is the most common form of diabetes recognized in the dog. Type II DM (non insulin dependent diabetes) is characterized by abnormal insulin secretion and peripheral insulin resistance, and results in a stable reregulation of the blood glucose concentration at a higher concentration. This type of DM is rare in the dog but is common in the diabetic cat. The two types of diabetes are classically distinguished by characteristic responses to challenge by insulin secretagogues such as glucose, glucagon, or arginine. In type I DM, there is a decreased or negligible secretion of insulin compared to normal animals, whereas in Type II DM, total insulin secretion may be normal or increased, although the pattern of secretion may be abnormal. The insulin concentration is still insufficient however, to prevent hyperglycemia. The phenomenon of glucose toxicity complicates interpretation of glucagon tolerance tests, particularly in cats, and the glucagon tolerance test is of little practical utility in clinical practive.

Diagnosis

The diagnosis of DM is made based on characteristic clinical signs of diabetes mellitus (polyuria, polydipsia, polyphagia, and weight loss), and documentation of hyperglycemia and glycosuria. In dogs the diagnosis is usually straight forward, however in cats it may be complicated by the occurrence of marked stress hyperglycemia. When making a diagnosis of DM in cats, it is therefore important not only to document persistent hyperglycemia and glucosuria, but also to rule out other diseases that may cause similar clinical signs. Measurement of fructosamine concentrations or urine glucose of samples collected in the home environment may allow the clinician to distinguish between stress induced hyperglycemia (and resultant glycosuria) and persistent hyperglycemia due to diabetes mellitus. Glucosuria may also occur secondary to ketamine anesthesia, chronic renal failure, and post-obstructive diuresis so is not on its own diagnostic for diabetes mellitus. The presence of significant ketonuria together with hyperglycemia, is diagnostic for diabetes mellitus in both dogs and cats.

Cats are also unique in that DM in this species may be transient or intermittent. In one study, 10 diabetic cats were reported to go into spontaneous remission after 1-3 months of therapy. In other studies, up to 70% of cats with DM have been reported to go into spontaneous clinical remission, with good glycemic control. Unfortunately, the glucagon tolerance test is not useful in predicting whether or not a cat is likely to go into remission. In dogs, diabetes mellitus is usually permanent, unless DM occurs secondary to profound insulin resistance, due to hormones such as progestagens and glucocorticoids. This type of diabetes is sometimes referred to as type III DM. In these cases, if the diagnosis is made early and the cause of insulin resistance can be removed, the diabetes may also resolve.

Poor response to insulin

Clinical signs suggestive of inappropriate response to insulin therapy include recurrence or persistence of clinical signs of DM, disorientation or seizures due to hypoglycemia, an insulin dose higher than 2 U/Kg/dose in the dog or >6U/dose in the cat, or recurrent ketoacidosis. Adequate assessment of the cause of the problem requires performing a blood glucose curve. Measurement of glycosylated hemoglobin or fructosamine may also be helpful. Once this data has been evaluated, appropriate changes in treatment or further diagnostic testing can then be instituted. In dogs and cats receiving twice daily insulin, most glucose curves can be performed during working hours (8am to 6pm). Common problems that may lead to a poor response to insulin include problems with owner administration, inappropriate insulin dose or formulation, insulin induced hypoglycemia, rapid metabolism of insulin, and insulin resistance. It is important to take into consideration the level of stress of the patient while in the hospital when interpreting the results of blood glucose curves. It is also important to appreciate that blood glucose curves show significant day to day variability. Other factors such as clinical signs, results of urine blood glucose measurements at home, serum fructosamine concentrations, and changes in physical examination (especially body weight), should be taken into account when interpreting the results of a blood glucose curve.

Problems with owner administration

Diagnosis of problems of owner administration of insulin may be detected either by a thorough history or by administration of insulin from a new bottle in the clinic by a clinician or veterinary technician, followed by a repeated blood glucose curve. Care should be taken to monitor the patient carefully in this setting however, because severe hypoglycemia can result if the insulin dose has been escalated due to problems with administration. If hypoglycemia does occur, the dose of administered insulin should be decreased by at least 25-75 % and a blood glucose curve repeated after 7 days of the new dose.

Inappropriate insulin dose or formulation

In most cases this diagnosis can be made easily by evaluation of the blood glucose curve. Most dogs and cats require insulin administration twice daily for good glycemic control, so this is the first change to consider if once a day therapy is being used. Appropriate insulin products for use in dogs include

Insulin Induced Hypoglycemia

Insulin induced hypoglycemia) occurs when excessive amounts of insulin are administered. When the blood glucose concentration drops below 65 mg/dl in response to insulin, compensatory mechanisms drive the blood glucose back into the normal range. These mechanisms include increased glycogenolysis, and gluconeogenesis by the liver, and release of catecholamines, glucagon, cortisol, and growth hormone which oppose the action of insulin. As the blood glucose returns toward normal however, there is not enough insulin present to oppose and dampen these the effect of these hormone increases, and hyperglycemia may result. Since a spot-check blood glucose or urine measurement performed in the afternoon in such a case may reveal hyperglycemia and glycosuria, increases in insulin dosage based on these measurements may worsen the situation. The diagnosis of insulin induced hypoglycemia is made by performing a serial blood glucose curve (samples q 2 hours). The condition is treated by decreasing the insulin dose by 25 – 75 % followed by reevaluation of a serial glucose curve 3 - 5 days later.

Rapid metabolism of insulin

Rapid metabolism of insulin refers to a situation when the effect of insulin does not last as long as is necessary to control hyperglycemia for the majority of the treatment period. In most diabetic dogs and cats, twice daily insulin administration is necessary for ideal glycemic control. In some cases however the duration of effect may be only 5 - 8 hours. This may mean that hyperglycemia is present for a significant proportion of the day, even when twice daily administration is instituted. In most cases clinical signs of hyperglycemia are not present and no change to therapy is necessary. In some cases an insulin preparation with a longer duration may be necessary. Alternatively three times a day insulin treatment can be considered.

Insulin Resistance

There are many varied causes of true insulin resistance, however most commonly it occurs due to the effect of excessive concentrations of hormones that oppose insulin. In many cases this is due to the presence of concurrent disease (see table).

Insulin resistance in dogs and cats (*most common)

Insulin Resistance is defined as peripheral resistance to the effects of insulin such that persistent hyperglycemia occurs despite the administration of >2.2 U/kg of insulin in the dog or >6-8 U per cat. Insulin resistance may be caused by a large number of factors.

Progesterone may be a cause of profound insulin resistance in bitches which are in estrus or diestrus. Exogenous administration of progesterone may also result in insulin resistance. The insulin resistance that occurs is thought to be due to stimulation of growth hormone secretion. Excessive growth hormone secretion and insulin resistance may also occur due to the presence of a growth hormone secreting pituitary neoplasm. Excessive growth hormone secretion either due to exogenous progestagens (usually dogs) or due to a growth hormone secreting pituitary tumor (occurs primarily in cats) is called acromegaly. In bitches with insulin resistance due to estrus or diestrus, ovariohysterectomy will result in a rapid resolution of insulin resistance. Treatment for acromegaly relies on removal of the source of exogenous progestagens or treatment of the pituitary neoplasm. The importance of other sex hormones such as androgens in causing insulin resistance are not well understood in the dog or cat.

Both endogenous and exogenous glucocorticoids are an important cause of insulin resistance in the dog and cat. Glucocorticoids cause insulin resistance by a number of mechanisms including increased hepatic gluconeogenesis, decreased tissue utilization of glucose, and decreased cellular receptor affinity for insulin. Insulin resistant diabetes mellitus is a complication in 10% of dogs with hyperadrenocorticism. The clinical signs of these two endocrine diseases are very similar so it is important to maintain a high index of suspicion for hyperadrenocorticism (Cushings disease) in any case of insulin resistant diabetes mellitus. Care should be taken when treating these animals for their Cushings disease since their insulin requirement will decrease dramatically as endogenous glucocorticoid secretion decreases.

Insulin resistance may also occur due to hyperglucagonemia in cases of bacterial infection, trauma, congestive heart failure, azotemia, and glucagon secreting tumors. The resistance resolves once the underlying problem is corrected. Severe renal failure results in insulin resistance due to increased glucagon concentrations, defective transport of insulin into cells, and acidosis. Acidosis decreases receptor affinity for insulin and results in derangements of intracellular glycolysis. Other possible causes of insulin resistance which have not yet been well defined in the dog and cat include obesity, phaeochromocytoma, subcutaneous breakdown of insulin, insulin antibody formation, and post-receptor defects (abnormality of signal transduction with-in the cell).

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