Diabetes mellitus is a chronic disorder of carbohydrate metabolism due to relative or absolute insulin deficiency. Most cases of spontaneous diabetes occur in middle-aged dogs and middle-aged to older cats. In dogs, females are affected twice as often as males, and incidence appears to be increased in certain small breeds such as Miniature Poodles, Dachshunds, Schnauzers, Cairn Terriers, and Beagles, but any breed can be affected. Obese male cats seem to be more commonly affected than female cats, and breeds such as Burmese, Russian Blue, Norwegian Forest Cat, Abyssinian, and Tonkinese appear predisposed.
Etiology and Pathogenesis of Diabetes Mellitus
The pathogenic mechanisms responsible for decreased insulin production and secretion are multiple, but usually they are related to destruction of islet cells, secondary to either immune destruction or severe pancreatitis (dogs) or amyloidosis (cats). Chronic relapsing pancreatitis with progressive loss of both exocrine and endocrine cells and their replacement by fibrous connective tissue results in diabetes mellitus. The pancreas becomes firm and multinodular and often contains scattered areas of hemorrhage and necrosis. Later in the course of disease, a thin, fibrous band of tissue near the duodenum and stomach may be all that remains of the pancreas. In other cases, the numbers of β cells are decreased, and the cells become vacuolated; in chronic cases, the islets are difficult to find.
Insulin resistance and secondary diabetes mellitus are also seen in many dogs with spontaneous hyperadrenocorticism Cushing Disease (Pituitary-dependent Hyperadrenocorticism) in Animals Cushing disease is hyperadrenocorticism caused by an ACTH-secreting tumor of the pituitary gland. Clinical signs include polyuria, polydipsia, alopecia, and muscle weakness. A low-dose dexamethasone... read more and after chronic administration of glucocorticoids or progestins. Pregnancy and diestrus also can predispose to diabetes mellitus. In dogs, but not cats, progesterone leads to release of growth hormone from mammary tissue, resulting in hyperglycemia and insulin resistance. Obesity also predisposes to insulin resistance in both dogs and cats.
Cats with diabetes mellitus usually have specific degenerative lesions localized selectively in the islets of Langerhans, whereas the remainder of the pancreas appears to be normal. The selective deposition of amyloid in islets, with degenerative changes in β cells, is the most common pancreatic lesion in many cats with diabetes. The amyloid appears to arise from islet-associated polypeptide (IAPP), which is secreted together with insulin from the β cells. Cats are unable to process IAPP normally, which leads to excessive accumulation and conversion into amyloid. As cats age, a greater percentage of their islets contain amyloid. Cats with diabetes have a greater percentage of their islets affected, with larger amounts of amyloid than age-matched cats without diabetes. The amyloid or IAPP (or both) lead to physical disruption of the β cell and insulin resistance, resulting in diabetes.
Infection with certain viruses in people may cause selective islet damage or pancreatitis and has been suggested to be responsible for certain cases of rapidly developing diabetes mellitus. This has yet to be documented in dogs or cats. The selective degeneration and necrosis of β cells is accompanied by infiltration of the islets by lymphocytes and macrophages. Stress, obesity, and administration of corticosteroids or progestogens may increase the severity of clinical signs.
Complete expression of the complex metabolic disturbances in diabetes mellitus appears to be the result of a bihormonal abnormality. Although a relative or absolute deficiency of insulin action in response to a rising extracellular glucose concentration has long been recognized as the major hormonal abnormality, the importance of an absolute or relative increase of glucagon secretion has been appreciated more recently. Hyperglucagonemia in diabetes may be the result of increased secretion of pancreatic glucagon, enteroglucagon, or both. Increased glucagon appears to contribute to development of severe hyperglycemia by mobilizing hepatic stores of glucose and to development of ketoacidosis by increasing the oxidation of fatty acids in the liver.
Clinical Findings of Diabetes Mellitus
The onset of diabetes is often insidious, and the clinical course chronic. The disturbances in water metabolism develop primarily because of an osmotic diuresis. The renal threshold for glucose is ~180 mg/dL in dogs and ~280 mg/dL in cats.
Common clinical signs include:
Some dogs and up to 50% of cats present with decreased appetite. Other clinical signs include hepatomegaly, lethargy, cataract formation (dogs), and diabetic neuropathy (mainly cats). Signs are usually slowly progressive over weeks to months.
Diabetic animals have decreased resistance to bacterial and fungal infections and often develop chronic or recurrent infections such as cystitis Bacterial Cystitis in Small Animals Bacterial cystitis is infection and inflammation of the urinary bladder. Clinical signs are pollakiuria, hematuria, dysuria, and urinating in inappropriate places. Hematuria may be more noticeable... read more , prostatitis Prostatitis in Dogs and Cats Inflammation of the canine prostate gland usually is suppurative, and acute prostatitis may result in abscesses. Chronic prostatitis occurs secondary to benign prostatic hyperplasia. Various... read more , bronchopneumonia Pneumonia in Dogs and Cats Pneumonia is an inflammation of the pulmonary parenchyma that results in respiratory disturbance. It can be caused by a variety of organisms, including viruses, bacteria, fungi, parasites, and... read more , and dermatitis. This increased susceptibility to infection may be related in part to impaired chemotactic, phagocytic, and antimicrobial activity associated with decreased neutrophil function. Radiographic evidence of emphysematous cystitis (rare) due to infections with glucose-fermenting organisms such as Proteus sp, Aerobacter aerogenes, and Escherichia coli, which results in gas formation in the wall and lumen of the bladder, is suggestive of diabetes mellitus. Emphysema also may develop in the wall of the gallbladder in diabetic dogs.
Hepatomegaly due to lipid accumulation is common in diabetic dogs and cats. The fatty liver results from increased fat mobilization from adipose tissue. Individual liver cells are greatly enlarged by the accumulation of multiple droplets of neutral lipid. In cats, hepatic lipidosis may occur in conjunction with diabetes mellitus.
Cataracts develop frequently in dogs (not cats) with poorly controlled diabetes mellitus. The lenticular opacities appear initially along the suture lines of lens fibers and are stellate (“asteroid”) in shape. Cataract formation in dogs is related to the unique sorbitol pathway by which glucose is metabolized in the lens, which leads to edema of the lens and disruption of normal light transmission. Although the same sorbitol pathway seems to be present in cats, the development of cataracts is rare. Other extrapancreatic lesions associated with diabetes mellitus in people, such as nephropathy, retinopathy, and micro- and macrovascular angiopathy, are rare in dogs and cats.
Diabetic ketoacidosis is a form of decompensated diabetes mellitus in which cells use free fatty acids as an energy source, because they cannot access glucose due to absolute or relative insulin deficiency. In the presence of elevated glucagon and other counter-regulatory hormones, free fatty acids are broken down into ketoacids. As ketoacids and glucose accumulate in the blood, metabolic disturbances occur, which can be profound and life threatening. These include dehydration, hypovolemia, elevated anion gap, metabolic acidosis, electrolyte disturbances, azotemia, elevated liver enzymes, hyperlactatemia, and clinical signs of vomiting and anorexia. Treatment involves rehydration and the use of short- and long-acting insulins to reduce ketone production and establish euglycemia.
Hyperosmolar hyperglycemic state is another syndrome of decompensated diabetes mellitus. It is characterized by profound hyperglycemia (serum glucose > 600 mg/dL) and hyperosmolality (> 320 mOsm/kg), with a normal pH and no or mild ketonemia or ketonuria. It is less common than diabetic ketoacidosis. In the classical form animals are not ketotic or acidotic, however, mixed forms occur with severe hyperosmolality compounded by ketoacidosis.
Diagnosis of Diabetes Mellitus
Elevated serum fructosamine
A diagnosis of diabetes mellitus is based on persistent fasting hyperglycemia and glycosuria. The normal fasting value for blood glucose in dogs and cats is 75–120 mg/dL. In cats, stress-induced hyperglycemia is a frequent problem, and multiple blood and urine samples may be required to confirm the diagnosis. Measurement of serum fructosamine can assist in differentiating between stress-induced hyperglycemia and diabetes mellitus. In cases of stress-induced hyperglycemia, the fructosamine concentrations are normal. In all cases, a search should be made for drugs or diseases that predispose to diabetes.
Treatment of Diabetes Mellitus
Successful treatment depends on:
Excellent client communication: Up to 25% of diabetic patients are euthanized on day 1 of diagnosis for reasons that can often be mitigated with education about diabetes and goals of therapy.
The use of basal insulins in cats to improve remission rates.
Appropriate dietary management.
Frequent monitoring, often best performed at home.
Longterm success depends on the understanding and cooperation of the owner. Treatment involves a combination of weight reduction, diet, insulin, and possibly oral hypoglycemics. Intact females should be neutered. In cats, recent evidence has supported the use of high-protein, low-carbohydrate diets. In dogs, diets high in fiber and complex carbohydrates are preferred.
Diet and weight reduction alone will not control the disease, so initial therapy with insulin is required. Most dogs require two doses of insulin a day. In general, NPH or lente is the initial insulin of choice at a dose of 0.5 U/kg, twice a day. With twice daily injections, two meals of equal calories are given at the time of insulin administration. Diets high in simple sugars (semi-moist foods) should be avoided.
Clinical signs and serial blood glucose determinations are used to monitor therapy after initial stabilization at home for 5–7 days. Blood glucose testing is best performed at home to avoid changes in the pet's routine and to minimize the stress of in-hospital testing. Studies both in dogs and cats have shown that at-home monitoring improves glycemic control and increases the likelihood of obtaining remission in diabetic cats.
In dogs with poor glycemic control being given NPH or lente insulin, use of the basal insulin detemir should be considered. Because of its potency, the starting dosage of detemir is 0.1 U/kg, twice daily, with reassessment of clinical signs and glycemic control in 1 week.
In cats, high-protein diets along with insulin therapy are initiated, with reevaluation in 5–7 days. In newly diagnosed cats, insulin glargine is the insulin of choice. Glargine is a long-acting basal insulin. Used in conjunction with high-protein, low-carbohydrate diets, it is associated with remission of diabetes and discontinuation of insulin therapy in 80%–90% of cases within the first 3–4 mo of treatment. NPH, lente, or PZI insulins may also be used in cats, with starting dosages ranging from 1 to 3 units, twice daily. However, these insulins are not associated with high rates of diabetic remission.
The use of oral hypoglycemic agents (glipizide) has been evaluated in diabetic cats. Glipizide is a sulfonylurea that stimulates the release of insulin from functional β cells. Glipizide should not be used in thin or ketonuric cats when absolute insulin deficiency is likely and exogenous insulin administration is required. Glipizide is administered at an initial dose of 2.5 mg, twice daily, PO, in conjunction with dietary management. Clinical response is seen at 3–4 wk. Short-term success is seen in 50% of treated cats, with longterm success rates (>1 yr) of ~15%. Alternatively, glimepiride and glyburide (other sulfonylureas) may be administered to cats at 2 mg/day (glimepiride) or 0.625 mg/day (glyburide). Acarbose, an oral α-glucosidase inhibitor, has also been used in cats at a dose of 12.5–25 mg, 2 to 3 times a day, in conjunction with diet and/or insulin to control hyperglycemia.
Ketoacidosis is a serious complication of diabetes mellitus and should be regarded as a medical emergency. Therapy includes correcting dehydration by administration of IV fluids, such as 0.9% NaCl or lactated Ringer’s solution; reducing hyperglycemia and ketosis by administration of crystalline zinc (regular) insulin; maintaining serum electrolyte levels, especially potassium, through supplemental administration of appropriate electrolyte solutions; and identifying and treating underlying and complicating diseases, such as acute pancreatitis or infections.
Numerous insulin regimens have been used in treatment of ketoacidotic diabetes mellitus. In the intermittent insulin regimen, regular insulin at 0.2 U/kg, IM, is the initial dosage, followed by hourly administration of 0.1 U/kg. Once the serum glucose is <250 mg/dL, the insulin is administered SC at 0.25–0.5 U/kg, every 4–6 hr, with careful monitoring of the serum glucose at 1- to 2-hr intervals. During aggressive treatment with insulin, blood glucose levels may fall rapidly, and the addition of 2.5%–5% dextrose to the IV fluids may be required. Recent studies advocate the use of glargine rather than regular insulin in the management of ketoacidotic diabetes mellitus, with encouraging results.
When insulin therapy has been instituted, the blood glucose should be checked frequently until an adequate maintenance dose has been determined. Once the animal is on maintenance therapy and its condition is stable, therapy should be reassessed every 4–6 months.
Diabetes is a common endocrine disorder seen in clinical practice.
Client education is extremely important.
Basal insulins are the preferred treatment in cats, with lente the insulin of choice in dogs.
At-home monitoring improves outcome and is well accepted by pet owners.
For More Information
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