Diabetes mellitus in cats (Proceedings)

Management of the uncomplicated feline diabetic can occasionally be controlled by oral hypoglycemic agents (approximately 25-35%). This is because approximately 90% of the feline diabetic patients are similar to human Type2 diabetes mellitus (non-insulin dependent diabetes mellitus-NIDDM). However, by the time the cat is diagnosed with diabetes mellitus, the blood glucose is severely elevated (often>450 mg/dl) and many cats are ketotic, thus insulin is usually required. If oral hypoglycemic therapy is to be considered by the clinician for initial therapy, several classes of drugs may be considered. Sulphonylurea drugs are the preferred drugs in diabetic cats. They exert their hypoglycemic effect by stimulating insulin release by the beta islet cells and increase sensitivity to insulin by its receptors. This author's preferred drug is glypizide (2.5 mg bid, initially increased to 5 mg bid after 2 weeks). Glypizide therapy should only be considered in diabetic cats that are in reasonably good health (good appetite and state of nutrition/hydration). It should never be the sole therapy for cachectic, ketotic cats. Glypizide's major side effects include: anorexia and vomition. If these signs occur the drug should be withdrawn for at least 24-36 hours and readministered at a lower dose. Concerns for glypizide usage include: delayed onset of action and the potentiality of amyloid deposition in the beta islet cells, thus increasing insulin exhaustion. Other oral hypoglycemic agents extensively used in humans but relatively unproven in cats include: alpha-glucosidase inhibitors, which reduce GI glucose absorption (Acarbose), transition metals, which increase insulin sensitivity (chromium, vanadium), thiazolidinediones, which increase insulin sensitivity and biguanides which block glucose production in the liver and increase insulin sensitivity (Meformin).

Although oral glypizide therapy can be considered, insulin continues to be the treatment of choice in diabetic cats. The insulin preparation preferred by this author is bovine PZI. The cat and bovine have similar amino acid sequences in their insulin molecules and PZI has the longest duration of activity. Insulin glargine is relatively new synthetic long-acting insulin derivative which has demonstrated encouraging results in preliminary studies in felines with diabetes mellitus. This author prefers to hospitalize diabetic cats initially and start with 0.25-0.50 IU/kg. beef PZI bid depending on the degree of hyperglycemia and a serial blood glucose curve constructed for 48 hours. Client education for feline owners is similar to that of canine diabetic pet owners.

The diet should be low in carbohydrates and high in protein, and thus will reduce postprandial hyperglycemia, obviously if the cat has concurrent renal disease the clinician should recommend feeding a diet lower in protein and higher in fat content. The cat is fed bid prior to the administration of insulin and care is taken to facilitate weight loss in obese cats and to guard against hypoglycemia, similar to canine diabetics.

The patient should be rechecked weekly for 4 weeks (similar to diabetic dogs) and a fructosamine level run initially at 6-8 weeks and the 2-3 times/year.

The difficult to control diabetic

As stated previously, dogs and cats do not need to be as tightly controlled with respect to glucose levels as human diabetics. However patients that remain PU/PD, urinate in the house, continue to lose weight, remain lethargic despite receiving adequate amounts of insulin (> 1.5 IU/kg per injection on bid protocols or > 2 IU/kg on sid protocols) fall into this category. Those dogs and cats that demonstrate marked fluctuations in insulin requirements and develop periods of hypoglycemia alternating with PU/PD (suggestive of hyperglycemia or the Somogyi effect) are termed "brittle diabetics". The clinician should consider 4 major causative categories in order to alleviate the problem. 1) A review with the pet owner regarding insulin administration is the first and most "mundane" step ( making sure that the insulin is fresh and not expired, making sure that the insulin is not frozen, heated, vigorously shaken, diluted). Watching the owner administer a dose of insulin to the pet provides valuable information about technique . Examining the the subcutaneous areas on the patient where the insulin is administered (they should be rotated with each injection and there should be no areas of fibrosis or scaring which would inhibit reliable absorption of insulin) also provides valuable information. 2) A review with the owner regarding the dog or cat's diet (bid, prior to each insulin injection-avoidence of snacks unless signs of mild hypoglycemia occur) and exercise regimine. 3) A thorough review by the clinician for endogenous causes ( metestrus in unsprayed females, hypothyroidism/obesity, hyperthyroidism-especially in older cats, hyperadrenocorticism, acromegaly-especially in cats, renal and hepatic insufficiency, cardiovascular disease, hypertension and disorders in lipid metabolism, inflammatory conditions-pancreatitis, UTI, pneumonia, etc.. 4) Rarer conditions ( pheochromocytoma, glucagonoma and non-endocrine neoplasia-liver, large soft-tissue sarcomas. 5) Iatrogenic (this author has encountered many patients with IMHA, IMTP, lymphosarcoma, IBD and various forms of atopy that became difficult-to-control diabetics because of their dependency on glucocorticoids). Also, the use of progestins (megesterol) to delay estrus in dogs or treat various dermatopathies in cats are potent insulin antagonists (they stimulate STH release). 6) Anti-insulin antibodies-If the diabetic dog is not receiving porcine insulin and the diabetic cat is not receiving bovine insulin, the possibility of the development of ant-insulin antibodies may exist. The true clinical signficance of anti-insulin antibodies in dogs and cats remains unclear, however in humans the presence of increased titers of anti-insulin antibodies may result in the need for extremely high insulin doses; occasionally resulting in prolonged hypoglycemic episodes due insulin being persistently released from insulin-antibody complexes. More clinical research is needed to understand the significance of this phenomenon. In poorly controlled the use of the serum fructosamine test is an extremely valuable tool in assessing the degree of glycemic dysfunction. The clinician should be diligent reviewing the history, performing a thorough physical examination, reviewing the past laboratory tests, radiographs, ultrasounds, etc.. Serial blood glucose curves should be performed to determine if there is absolute insulin resistance, marked fluctuations in glucose levels or the Somogyi effect. From the above findings the clinician should construct a diagnostic/therapeutic plan to improve the patient's glycemic control

Diabetic ketoacidosis(DKA)

DKA can be considered in the same clinical category as end-stage renal failure or liver failure (cirrhosis). DKA occurs when all the body's cpmpensatory mechanisms to produce energy and still retain some degree of normoglcemia have failed. Often there are complicating medical conditions adding to the diabetic state of the patient (necrotizing pancreatitis, pyometra, hyperadrenocorticism, severe UTI/sepsis, prostatitis, IBD, pneumonia, etc.). Severe DKA should be considered a medical emergency and is the result of oncontrolled ketone formation within the body, with subsequent metabolic acidosis and marked dehydration/hyperosmolality. As stated previously, this deadly syndrome arises from the release of FFA in the circulation as the cells metabolize fats for an energy source in the face of hypoinsulinemia, hyperglucagonemia and elevations of cortisol, STH, and epinephrine. These FFA are concentrated in the liver and converted to ketone bodies (acetoacetic acid,beta-hydroxybutyric acid and acetone). Metabolic acidosis develops as a result of the accumulation of ketone bodies and lactic acid (produced because of faulty muscle metabolism).

A small percentage of affected dogs and cats are presented with a history of being fairly controlled diabetics that are now decompensated due to any of the complicating dieases mentioned above. Often, DKA patients are presented for the first (prior to ever being treated with insulin), as a result of having busy pet owners, owners that were out of town for a prolonged period of time or the pet owners being unaware of the early signs of diabetes mellitus (farm dogs or outside cats).

The most common clinical sign exhibited by dogs and cats with DKA include: lethargy, weakness, somnolence, dehydraton, weight loss/severe muscle wasting, hepatomegaly (often accompanied by jaundice-especially with cats due fatty liver infiltration), tachypnea (the "so-called" Kussmaul breathing in an attempt by the respiratory system to blow off large volumes of CO2 to raise the blood pH), vomition, acetone odor on the breath (smells like nail polish remover).

Laboratory abnormalities include: marked hyperglycemia (often>500mg/dl), azotemia (pre or primary), elevations in LFTS (SAP, ALT gamma GT, fasting bile acids, total bilirubin) and occasionally pancreatic enzymes (a 3-fold increase in serum amylase, lipase and markedly increased serum TLI are highly suggestive, but not always consistent with pancreatic parenchymal destruction). Electrolytes may be variable and always don't reveal total body measurements. Patients with DKA may have an elevated potassium (K) level because in metabolic acidosis there is a shift of K from the intracellular compartment to the extracellular compartment in an attempt to buffer the blood. This may mask a significant depletion of total body K due to anorexia, vomition and urinary osmotic diuresis due to glycosuria and ketonuria. The astute clinician keeps this in mind when formulating a therapeutic plan. The same may be said regarding total body sodium (Na). Excessive Na losses due to osmotic diuresis and vomition and diarrhea may initially occur. In order to attempt to correct this Na deficit, the distal tubules of the nephron will vigorously attempt to reabsorb Na (stimulated by increased aldosterone secretion). Inorganic phosphorus is also unpredictable (severe osmotic diuresis may result in a decrease in phosphorus, however, renal failure and a drop in GFR can produce hyperphosphatemia). Metabolic acidosis is obviously present with blood ph levels being <7.1 and serum bicarbonate <12 meq/L. In this author's experience, the use of the anion gap does little to contribute in the management of DKA dogs and cats. A urinalysis is an inexpensive, rapid means of collecting information about the extent of DKA and look for complicating factors. Patients that are spilling heavy glucose and ketones in the urine are often quite ill, require intensive nursing care and will take longer to become regulated than non-DKA patients. This is because beside the lack insulin there are several insulin antagonists circulating in the DKA patient's bloodstream (glucagon, cortisol, epinephrine and STH). The presence of pyuria may be the result of pyelonephritis, prostatitis or pyometra. Bilirubinuria may be present in secondary liver disease. A low urine specific gravity coupled with an elevated serum creatinine may indicate primary renal failure.

Therapy for DKA

The clinician faced with managing a DKA patient must adhere to being thorough, diligent in his/her continued assessment of the patient and to follow a rational, consistent plan. Fluid therapy is a necessity-the choices can be initially starting 0.9% saline with potassium, magnesium and phosphate supplementation, or a balanced electrolyte solution that contains the above additive electrolytes and adding more of them to the fluids if indicated (Normosol is a good choice for this) Lactated Ringer's solution should be avoided in DKA patients, especially with concurrent liver disease because the impaired liver may be unable to convert the lactate into bicarbonate and thus add to the already present lactic acidosis. Regular crystalline insulin should be administered either q1h IV or IM (1 unit for a cat; 2-3 units for dogs). Regular insulin has a rapid onset of action a short duration (10-30 min./peak effect 1-4 hrs. and 3-8 hrs. duration of effect) is the insulin of choice in DKA. An alternative method is to insert 2 IV catheters (1- jugular for fluid therapy, measurement of central venous pressure and to draw blood for followup testing, 2- cephalic catheter for insulin administration-mix 1.1 IU/kg {cat} and 2.2 IU/kg. dog in 250 ml of 0.9% saline given q 2-4 h). After a few hours of the above therapy and blood glucose is rapidly being reduced; 2 1/2 % dextrose is often added to the fluids as these patients will be anorectic for > 12-18 hours. Sodium bicarbonate is administered to correct the acidosis if serum HCO3 is < 12 meq/L (ml HCO3= 0.1x kg.x 24-{HCO3} usually given over a period of 2-4 hours). The most common point that is missed by clinicians in the management of DKA is neglecting to supplement potassium, It is important to remember that these patients are depleted of total body potassium and that not only does insulin drive glucose into the cells but also potassium (that is why insulin may be life saving in severe adrenal insufficiency/shock or urinary obstruction-both conditions may cause serum K to be > 12 meq/L). Blood glucose should be checked q2h-minimally and electrolytes qid. An ECG monitor should be attached to the patient to document any dysrhythmia that may occur (APCs, PVCs, sinus bradycardia, AV block, V. tach., V. fib., etc.).

There is a rare syndrome that can occur termed Non-Ketotic Hyperosmolar Syndrome. In this syndrome (this author has seen it mainly in cats), the blood glucose is severely elevated (>650 mg/dl), the Na is often > 165 meq/L and the serum osmolality > 350 mOsm/kg. The patient displays all the CNS signs associated with DKA because the brain is dehydrated. However, there is no ketonemia or ketonuria and the serum HCO3 is not severly decreased. The patients are treated similar to DKA patients except for the use of HCO3 and that they are a lot more sensitive to insulin therapy. Prognosis is usually fair to poor.

Prognosis of DKA

The prognosis for these patients is fair to good as long as the complicating conditions can improved and managed.

Insulinoma

These uncommon tumors arise from the pancreatic beta islet cells and are functional, secreting supraphysiological concentrations of insulin, resulting in profound hypoglycemia. Insulinomas are extremely rare in cats and not much statistical information can be gleaned from the handful of reported cases.

Canine insulinomas are usually seen in middle-aged to older dogs, (3-15 years). Irish Setters, Standard Poodles, German Shepherds, Boxers, Fox terriers and collies appear to be the breeds with the highest incidence. There appears to be no sex predilection.

Clinical Signs

Due to the paradoxical secretion of excessive insulin and subsequent hypoglycemia, the CNS is the organ system that displays the most vivid clinical signs. Affected patients may display episodic rear-leg weakness, tremors, irritability, mental dullness, exercise intolerance, compensatory polyphagia, ataxia, seizures and coma. The degree of severity of clinical signs displayed by the patient depends upon: a) the level of hypoglycemia, b) the rate of drop in the blood glucose and c) the chronicity of the condition.

Differential causes of profound weakness with or without hypoglycemia include: extra-pancreatic neoplasia (often large liver tumors or large soft-tissue sarcomas), toy breed or hunting dog hypoglycemia, various non-neoplastic hepatopathies ( porto-systemic shunts, severe hepatitis, cirrhosis, glycogen-storage diseases, etc.), adrenal insufficiency (primary or secondary), panhypopituitarism, uremia (severe anorexia), myasthenia gravis and profound hypothyroidism (myxedematous crisis).

Diagnosis

Insulinoma can be confirmed by the simultaneous occurrence of hypoglycemia and hyperinsulinemia. In classic human endocrinology the patient is said to satisfy all 3 facets of Whipple's Triad ( 1} The presence of CNS signs,2} The CNS signs being present in conjunction with profound hypoglycemia and 3} The amelioration of the CNS signs by the administration of 2.5-5% dextrose). For many years this author has utilized the amended insulin:glucose ratio (AIGR) as an ancillary test in the diagnosis of insulinoma. (Ratio=(Insulin x 100/(Glucose) -30). Values that significantly exceed 30 are considered to be highly suspicious for insulinoma. In "gray-zone" situations, serial simultaneous measurements of glucose and insulin may be necessary to confirm the diagnosis. Additionally, a persistently subnormal serum fructosamine level documents chronic hypoglycemia. The CBC and biochemical panel are usually normal (save for the hypoglycemia, occasional hypokalemia {insulin causes the intracellular transport of K) and elevated SAP, ALT, etc.-if the insulinoma has already metastasized to the liver {>50% of canine insulinomas are malignant}. Thoracic and abdominal radiographs are valuable in detecting metastatic foci or large masses; improved imaging techniques (ultrasonography/CT/MRI) can often localize these usually small functional tumors.

Treatment (emergency measures)

The most important principle is to try to restore normal brain function. This is initially accomplished (hopefully) by inserting an indwelling IV catheter and slow, consistent administration of 50% dextrose (1 ml/kg over 5-10 min.) The clinician should avoid overzealous dextrose administration of dextrose to produce hyperglycemia. This will only "feed" the tumor by supplying with excess glucose which results in excess release of excess insulin causing a rebound hypoglycemia. In severe cases with violent seizures, diazepam, phenobarbital, soluble glucorticoids and 20% mannitol may be necessary to combat the seizures and cerebral edema. Once the patient is conscious and able to eat, small amounts of a high protein, low carbohydrate should be fed q 4-6h. In those patients in which the seizures have been chronic or severe/violent, there may persistent laminar necrosis occurring in the cerebrum, necessitating long-term use of anti-convulsants

Once the patient has been stabilized, a two week regime of frequent feedings, oral diazoxide ( a benzothiazide antihypertensive drug which blocks insulin release from the beta islet cells) beginning at 10 mg./kg/divided tid and occasionally propanolol (a beta adrenergic blocker) can be instituted to get the patient ready for surgery.

Surgery is the treatment modality of choice. In order to prevent intra and postoperative hypoglycemia the patient is prepared with an intravenous drip of Normosol R with 2.5% dextrose, soluble prednisolone succinate and prophylactic, broad-spectrum antibiotics. This regimine is continued for at least 36 hours post-surgically in order to maintain splanchnic perfusion and reduce the likelihood of post-operative pancreatitis. An exploratory laparotomy is performed in the hope of finding this tiny neoplasm(s) in the pancreatic parenchyma and to visualize any metastatic nodules (omentum, liver, lymph nodes etc.). Insulinomas occur in about equal frequency between the duodenal and omental wings. Approximately 15-20% of insulinomas can be seen as multiple nodules in canine patients. The controversy arises when no definitive tumor can be located. Some surgeons advocate a partial pancreatectomy (50-60% of the pancreas), in the hope of excising occult tumor tissue. If a tumor nodule is identified, it should be removed by gentle, blunt dissection or "finger fracturing", so as to minimize the development of traumatic pancreatitis. Debulking/complete excision of any metastatic lesions will increase survival times and minimize any additional hypoglycemic episodes. It is obvious that close post-operative monitoring of the patient is mandatory ( serial CBC's, blood glucose, electrolytes, renal/hepatic function, amylase/lipase) to guard against potential complications (persistent hypoglycemia, transient hyperglycemia, hyperkalemia and pancreatitis.

In patients with unidentified tumors or whose owners elect not have surgery performed, medical management can often yield long-term survival (in this author's experience 1-4 years). As discussed before diazoxide is the mainstay of therapy. Its disadvantages include considerable expense and availability (it is an "orphan drug"). Frequent feedings should always be a part of the therapeutic regimine. Glucorticoids (prednisone or dexamethasone) can be administered judiciously in order not to induce iatrogenic hyperadrenocorticism. If the patient remains refactory to the above medical therapy, this author has used octreotide ( a long-acting derivative of somatostatin-which blocks insulin release from the beta cells ) in a few dogs with mixed results.

Disadvantages include expense and poor response if the neoplastic cells are devoid of somatostatin receptors.

Patients with metastatic disease may benefit from the chemotherapy agent streptozotocin ( a nitrosurea alkyllating agent that is cytotoxic beta islet cells). This author has used streptozotocin in a similar manner as cisplatin (both are nephrotoxic in the dog). 1) saline diuresis/mannitol prior to chemotherapy 2) streptozotocin at 500mg/square meter body surface area in 0.9% saline over a period of 3-4 hours and 3) saline/mannitol diuresis for 1-3 hours. This protocol is repeated q3 weeks for 5 treatments, like cis or carboplatin. The CBC's and renal function as well as the blood glucose should be closely monitored at least 3 weeks , Butorphanol is this author's choice as an anti-nausient during chemotherapy.

Glucagonoma

This extremely rare pancreatic endocrinopathy (only 9 canine cases published thus far) is associated with skin lesions (termed in dogs as superficial necrolytic dermatitis) that are crusty and scaly, erythemic and located on the footpads, perineum, abdomen, hocks, nose and mucocutaneous junctions. Hyperglycemia is usually a prominent feature. Clinically (this author has only managed one poodle with this syndrome) one might find lethargy, depression, anorexia and occasionally lymphadenopathy, PU/PD due to secondary diabetes mellitus and secondary pyoderma. The diagnosis is difficult to confirm because no veterinary reference laboratory in the USA performs glucagon assays. In the above above patient, this author drew a plasma sample and a second sample from a "normal" dog and glucagons levels run and compared between both dogs at a local human teaching hospital. Treatment for canine glucagonoma patients is similar to that of insulinomas (exploratory surgery, medical therapy-except for glucagonomas one uses insulin for the persistent hyperglycemia, amino acids/high protein diets {remember glucagon causes gluconeogenesis}, fatty acids/zinc supplementation and octreotide).

Pancreatic gastrinoma

This author reported a case similar to its human counterpart (Zollinger-Ellison syndrome) in a German Shepherd dog in the 1980's. The patient had relentless diarrhea, steatorrhea, melena, abdominal pain, anorexia and weight loss. Serum gastrin levels of this patient when compared to a "normal" control dog were markedly elevated (>185 ng/l-normal canine range-10-40 ng/l). Hypergastrinemia can produce severe gastric and duodenal ulceration and the massive concentration of acid causes intestinal malabsorption. The above patient underwent an exploratory laparotomy. A small pancreatic nodule (gastrinomas can be found in the pancreas, duodenum and stomach) was found in the duodenal wing (immunohistologically found to be a D or delta islet cell tumor). Unfortunately the dog's liver was infiltrated with metastatic nodules (also delta pancreatic islet cell origin ) and it was euthanitized on the OR table. In the 21st century patients with inoperable, metastatic disease can be managed with proton pump inhibitors (Prilosec, Nexium, Prevacid etc.) and octrotide and interferon alpha b.

References

Drazner, FH: Small Animal Endocrinology Churchill Livingstone. 1984.

Drazner, FH: A Case Report of a Dog with Gastrinoma, Resembling the Zollinger-Ellison Syndrome. California Veterinarian. 1978.

Mooney, CT. and Peterson ME (eds) BSAVA Manual of Canine and Feline Endocrinology. BSAVA. 2004.

Monroe, WE: Disease of the Endocrine Pancreas and Pituitary Gland in: Leib MS.and Monroe WE.:(eds.) Practical Small Animal Internal Medicine, WB Saunders. 1997.