What's new, what's old, and what works in diabetes mellitus (Proceedings)

Diabetes mellitus (DM) is one of the most common endocrinopathies seen in cats. DM arises from a variety of pathophysiological causes. Causes of DM in cats include islet-specific amyloid deposition, chronic pancreatitis, obesity, infection, other illness, drugs, etc. Obesity and islet-amyloidosis are potential causes for NIDDM. Both conditions cause insulin resistance. Severe amyloidosis will cause IDDM. In cats being treated with insulin, their needs may wax and wane. This may be due to "glucose toxicity". Animals that are persistently hyperglycemic will develop insulin resistance. As their hyperglycemia is corrected with insulin, their insulin resistance will dissipate, lowering their insulin needs.

Clinical Features

There are 4 classic signs of DM: Polyuria, Polydipsia, Polyphagia, and Weight loss. Due to the relative or absolute lack of insulin, the patient becomes hyperglycemic. When the renal threshold is exceeded, glucosuria with resultant polyuria develops. Without insulin, peripheral tissues are unable to utilize glucose. This leads to the break-down of muscle and fat. Basically, as far as the patient's body is concerned, it's starving & in a catabolic state. Additionally, polyphagia develops because the amount of glucose entering the satiety center in the hypothalamus is mediated by insulin. If glucose does not enter the satiety center, the patient constantly feels hungry.

Unfortunately some cats are not presented for veterinary care until the DM is progressed. Patients may be suffering from diabetic ketoacidosis or peripheral neuropathy at the initial visit.

Diagnostics

DM is diagnosed based upon clinical signs and documentation of fasting hyperglycemia and glucosuria. It can be somewhat challenging to diagnose DM in cats because of their frequent severe stress hyperglycemia. Fructosamine levels can be used to establish the diagnosis.

A minimum data base consisting of a CBC, chemistry profile, urinalysis plus culture should be obtained on all cats suspected of having diabetes. This is necessary to establish the diagnosis, rule out any concurrent disorders and evaluate the overall health of the patient.

CBC:

there are not any "classic" findings for DM on the CBC. Leukocytosis may suggest either inflammation or infection. Pancreatitis and infections are problems commonly seen with DM. Mild polycythemia suggests dehydration. Mild anemia typical of chronic disease may also be seen.

Chem panel: hyperglycemia will be present. Other changes that can be present:

     • Liver enzymes are often elevated due to either hepatic lipidosis or pancreatitis.

     • A mild prerenal azotemia may be found. It can be challenging to rule out kidney disease in diabetics because DM causes many alterations in the urine. It may be necessary to recheck bloodwork after fluid diuresis (prerenal azotemia will resolve with adequate hydration).

     • Hyperlipidemia and hypercholesterolemia will be found in diabetics. This is because 1)decreased movement of triglycerides into fat depots 2)decreased hepatic degradation of cholesterol and 3)increased hepatic production of very-low-density-lipoproteins. These lipid abnormalities cause of many of the vascular abnormalities found in people.

     • Amylase and lipase are poor indicators of pancreatitis. PLI may be measured to help diagnose pancreatitis. Abdominal ultrasound is useful for diagnosing pancreatitis.

UA: glucosuria!

The urine will be isosthenuric to minimally concentrated as a result of the osmotic diuresis caused by the glucosuria. Ketones may be found. Trace amounts of ketones may be seen in an otherwise healthy diabetic. However, any time ketonuria is noted, the patient must be carefully evaluated. Ketones often signify diabetic ketoacidosis which is an emergency! Proteinuria may be found as well.

Urine culture:

Urine should always be cultured in diabetic patients. There is a high incidence of occult infections among diabetics. It is hypothesized that diabetics are more prone to UTIs because the glucosuria serves as such a good media for bacterial growth.

Based upon this minimum data base, other diagnostics may be indicated. These can include abdominal radiographs and/or ultrasound, thyroid panels, PLI measurements, etc.

Treatment

The goal of therapy is to minimize the clinical signs of DM and prevent the complications associated with DM. Reducing the hyperglycemia and minimizing the fluctuations in blood glucose concentrations will greatly improve the patient's quality of life. The goal is NOT to make the animal normal. Overzealous therapy can lead to hypoglycemia which is a far more deadly state. Treatment of diabetes centers on dietary therapy, appropriate body weight, exercise, insulin therapy, and oral hypoglycemic agents.

Diet:

Dietary therapy is crucial in the treatment of DM. Diet should be aimed at correcting obesity and providing a consistent caloric content and schedule. Semi-moist foods should be avoided because they cause hyperglycemia. High protein diets are recommended for managing feline DM. In cats, insulin release is signaled by amino acids, not glucose. Normal cats use amino acids as precursors for gluconeogenesis rather than dietary carbohydrates. Both high protein and high fiber diets tend to have lower carbohydrate levels. This may be the most important aspect.

The feeding schedule is important in attempting to minimize fluctuations in blood glucose. Animals who nibble throughout the day should be allowed to do so. Patients who eat meals should have their meals timed so as to maximize the effectiveness of the insulin.

Exercise:

Exercise promotes weight loss and has a glucose lowering effect. It will increase blood flow to muscles and therefore lead to an increased mobilization of insulin. While it can be somewhat challenging to get cats to exercise, laser pointers, cat trees and other toys will often get cats to play.

Insulin:

Insulin therapy remains the cornerstone in management of diabetes. Tailoring insulin therapy to the needs of the individual patient can be both challenging and frustrating. Factors such as the type of insulin, the dose, and the frequency of administration can all be adjusted to provide the most optimal treatment for each patient. Appropriate monitoring of insulin therapy is one of the most crucial aspects of successful management of diabetes mellitus.

One common area of confusion for practitioners is how classification schemes for diabetes relate to insulin therapy. A classification scheme is sometimes borrowed from human medicine in which DM is divided into two categories, type I and type II. Type I DM arises from destruction of the insulin-secreting pancreatic beta cells and is characterized by hypoinsulinemia. Type II DM is due to insulin resistance and dysfunctional beta cells. Both types encompass a spectrum of pathology wherein the patient can be either a non-insulin dependent diabetic (NIDDM) if there is only mild disease present or be an insulin dependent diabetic (IDDM) when there has been progression of the disease. Further clouding the issue is the concept of glucose toxicity. Prolonged hyperglycemia results in impaired pancreatic insulin secretion and peripheral insulin resistance. Thus, the hyperglycemic state itself causes the patient to require exogenous insulin. With correction of hyperglycemia, the glucose toxicity will resolve. The patient may become NIDDM and insulin requirements can change dramatically. These patients will still benefit from insulin therapy, particularly when first receiving treatment for diabetes. Veterinary patients most often are IDDM, at least at the time of initial presentation.

Insulin Preparations

Many different insulin formulations are commercially available with different preparations being appropriate for varying situations. In recent years, most manufacturers have discontinued beef and pork preparations in favor of human recombinant insulin. Insulin formulations vary in duration of effect, time to onset and potency. There are short-, intermediate- and long-lasting preparations. The short-acting insulins have a rapid onset and are quite potent. In veterinary patients, these preparations are most useful in emergency situations such as diabetic ketoacidosis and hyperosmolar nonketotic diabetes. Regular insulin is the most common short-acting insulin in veterinary medicine. Lispro insulin has also been used recently. For healthy diabetic cats, long-acting insulins such as glargine and PZI are used. Insulin glargine, trade-name Lantus, is frequently used to manage DM in cats. Glargine is a synthetic human insulin analog produced by recombinant DNA technology. Glargine is acidic (pH=4) and forms micro-precipitates when injected into the relatively neutral subcutaneous space. The formation of these microprecipitates allows for a slow, uniform absorption of the insulin, making it suitable for once to twice daily insulin administration in the cat. Studies have suggested that cats treated with twice daily glargine are more likely to go into diabetic remission than are cats treated with once daily glargine or twice daily PZI. Glargine is typically instituted at a dose of 1-2 U/cat bid. Protamine Zinc Recombinant Insulin and PZI Vet have also been used in the successful management of DM in cats. Detemir is a newer synthetic insulin analog that is produced using recombinant DNA technology in yeast. Detemir is long-acting and very potent. Lower doses of Detemir compared to other insulins are usually used.

Monitoring

Clinical Observations

Some of the most valuable information regarding diabetic patients is also among the easiest and least expensive to obtain. Monitoring the cardinal clinical signs of diabetes- appetite, water intake, urination, and weight- provides the greatest insight as to control of the patient's diabetes. The owner should note trends in water and food intake and urination. In addition to providing information as to how the patient is doing in the home environment, this gives the owner a role in the treatment of their pet. In many cases, the owner is the first to recognize that their pet's needs for insulin have changed. However, the owner should not alter therapy without first discussing changes with their veterinarian. Another important reason to involve the owners in the patient monitoring is to ensure that the pet has a good quality of life and is receiving appropriate treatment. Properly educated owners will be more observant of warning signs that their pet's diabetes is poorly controlled. This will allow them to seek veterinary care sooner. Additionally, if the owners are dissatisfied because with the continued clinical signs of diabetes (particularly polyuria), they may decide to euthanize the pet without pursuing further treatment. If they feel involved in their pet's care, they will hopefully alert their veterinarian that better control of the diabetes is needed prior to deciding to euthanize.

Accurately recording the patient's weight on every visit to the hospital is essential for monitoring diabetic control. Uncontrolled diabetics frequently lose weight despite a good appetite, indicating a need for further evaluation. Conversely, a patient who gains weight may require changing their insulin dosage.

Veterinarians need to be prepared to invest the necessary time to properly educate clients, particularly those clients whose pets are newly diagnosed diabetics. Time, at least half an hour, should be set aside to discuss the appropriate care and monitoring of diabetic pets. In addition to observing for signs of hypoglycemia and hyperglycemia, owners will need instructions in the appropriate care and administration of insulin. Manufacturers recommend refrigerating insulin; because injection of cold fluids can increase discomfort, it is advisable to allow the insulin dose to warm to room temperature prior to administration. Owners should be taught to roll the insulin vial to ensure adequate mixing of the contents. Finally, owners need to be shown how to administer subcutaneous injections. Using sterile water instead of insulin, watch the owners go through all the steps of administration of insulin, including drawing up the appropriate dose and subcutaneous injection. Technicians can also instruct owners in proper injection techniques.

Glucose Curves

Glucose curves are somewhat controversial in the monitoring of diabetic cats. Glucose curves allow determination of the duration of insulin as well as evaluation of the dose and type of insulin. However, there is very little reproducibility in glucose readings within individual cats. When performing a glucose curve, blood glucose values need to be evaluated every 2 hours for a minimum of 8-12 hours. Due to differences in activity and food intake, some animals will require different insulin doses at morning and night. To properly evaluate each dose will then require a 24-hour glucose curve.

The first question that needs to be answered when interpreting a glucose curve is whether the insulin is effective in lowering the blood glucose. Both the nadir and the glucose differential will help answer that question. The nadir, the lowest blood glucose, represents the time at which insulin activity peaks. The glucose differential, the difference between the highest and lowest blood glucose readings, should also be determined when evaluating whether the insulin is effective. It usually signifies poor control if the glucose differential is greater than 250. For diabetic cats, blood glucoses should be between 100-300 mg/dl throughout the day. If the insulin appears ineffective, the dose must be considered and whether there is any possibility for incorrect administration.

If the insulin effectively lowers the blood glucose concentration, the nadir needs to be next examined. The nadir ideally should fall between 100-150 mg/dl. If the nadir is < 80 mg/dl, the insulin dose should be decreased by 10-25%. If the nadir is > 150 mg/dl, either the insulin dose should be increased by 10-25% or the patient needs to be evaluated for possible insulin resistance. If the nadir is between 100-150 mg/dl, the duration of insulin is the final parameter to be addressed.

The duration of insulin's activity is the time that it takes the blood glucose concentration to return to baseline. For insulin given once daily, blood glucoses will preferably be in an acceptable range for 20-24 hours following insulin injection; twice daily insulin will ideally have a duration of 10-14 hours. Following changes in insulin therapy, it will be necessary to wait one to two weeks to evaluate the new protocol to give the patient time to adjust.

Measuring "spot-checks" of blood glucose concentrations does not replace the need for glucose curves. Spot-checks do not provide any information regarding the true nadir, time to peak activity, or the duration of effect of insulin and they often reflect the stress of having blood drawn. Without knowing the effectiveness or duration of insulin's activity, rational decisions regarding insulin type, dose or frequency of administration cannot be made. One of the most important reasons to perform glucose curves as opposed to measuring glucose "spot-checks" is to avoid the Somogyi phenomenon. The Somogyi phenomenon results from excessive insulin administration. When diabetics receive excessive insulin and their blood glucose drops either too low or too rapidly, several physiologic mechanisms such as the release of insulin-antagonistic hormones are activated. These mechanisms counteract the effects of insulin to protect the animal from hypoglycemia. A rebound hyperglycemia rapidly follows and may be all that is witnessed if glucose spot-checks or urine testing are the sole means of monitoring. Given the wide range of insulin peak activity, it is impossible to guess when the glucose nadir might occur. Evaluation of diabetic control upon a single blood glucose at the presumed nadir will allow for insulin overdose and resultant hypoglycemia.

Monitoring may differ in patients that have been on insulin therapy for a period of time and appear to be well-regulated in the home environment (based upon water intake, appetite and weight). A recent study found fasting blood glucoses that were obtained immediately prior to morning insulin administration were typically between 100-300 mg/dl. Morning hypoglycemia suggested insulin overdose and the need for a dose reduction whereas values > 300 mg/dl indicated the need for a serial glucose curve. The owner's observations and the clinician's physical examination findings were often successful at delineating between good and inadequate glycemic control.

Cats are much more likely to suffer from a stress-induced hyperglycemia than are dogs. Hospital visits and repeated venipuncture can create a great deal of stress for many cats. Minimizing potential stress to the cat will provide a more accurate glucose curve. Having a "cats only" boarding area where they will not be exposed to dogs may calm some cats. A very useful management technique is admitting the cats to the hospital the day before their glucose curve will be done. This gives the cat a chance to acclimate to his/her surroundings and recover from the car ride and physical exam. Glucose readings taken at the same time of day with the same dose of insulin can differ by over 100 mg/dl purely due to the cat having adjusted to being in the hospital. Many cats also object less to having blood obtained via an "ear prick". Owners can be taught how to obtain blood this way and obtain glucose readings at home.

Urine testing

Many practitioners advise owners to monitor their diabetic pets' urine for glucose. While this may be helpful for noting trends, it is dangerous to allow owners to change insulin dosage based upon their findings. Well-controlled diabetics usually have small amounts of glucosuria (100 mg/dL-500 mg/dL). Repeatedly finding negative glucosuria often means that excessive insulin is being administered. When moderate to large amounts of glucose are found in the urine, this indicates either too much or too little insulin is being administered. The Somogyi phenomenon can result in large amounts of glucosuria due to rebound hyperglycemia. If the owners mistakenly increase the insulin dose based upon the premise that glucosuria indicates insufficient insulin administration, that error could prove fatal for the patient. If owners wish to monitor the urine, instruct them to keep a notebook of their findings. That information can be used to supplement their observations of the pet's appetite, water intake and frequency of urination. The owners can also screen for ketonuria. While glucose may be present in the urine of a well-controlled diabetic, ketones are not. If owners detect ketonuria, they should immediately contact their veterinarian.

Fructosamine and Glycosylated Hemoglobin

Fructosamine and glycosylated hemoglobin are glycated proteins used to monitor glycemic control. Glucose is bound to hemoglobin, albumin, and other proteins in a nonenzymatic, irreversible, insulin-independent reaction that is proportional to the concentration of glucose in the blood. Thus, both the measurement of fructosamine and glycosylated hemoglobin will serve as indices of blood glucose concentrations over some preceding time interval, determined by the lifespan of the involved protein. Fructosamine measurements are commonly used in veterinary medicine because the chief plasma protein involved is albumin. Fructosamine measurements therefore furnish information regarding the previous 1-3 weeks. In addition to information regarding control of the diabetes, this index may also be useful when initially diagnosing diabetes mellitus. Given that it reflects the blood glucose concentration over a period of time, stress will not falsely elevate its value. Caution must be exercised when interpreting fructosamine levels. Many laboratories provide a normal range for nondiabetics. Even well controlled diabetics will routinely have higher blood glucose concentrations than nondiabetics. The concentration of fructosamine in a well-controlled diabetic should be either high normal or slightly above the normal range. A lower than expected or extremely high fructosamine concentration points to the need to re-evaluate therapy. Because alterations in fructosamine may be due to changes in insulin effectiveness or duration of effect, a glucose curve is often necessary prior to adjusting insulin. Fructosamine reflect the average blood glucose concentration over a period of time; therefore extreme lows and highs in blood glucose may be disguised. If the owner feels the pet is not well controlled, re-evaluation of insulin therapy is necessary regardless of the fructosamine reading.

Oral hypoglycemics

Oral medications can also be used, either in combination with insulin or in some cases, as sole agents. Sulfonylureas such as glipizide and glyburide are insulin secretagogues. For these agents to be effective, the pancreas must be capable of producing insulin. There is some concern that these drugs may cause the diabetes to progress if the underlying pathophysiology is pancreatic amyloidosis. Islet amyloid polypeptide (an amyloid precursor) is co-secreted with insulin so encouraging insulin secretion will lead to increased pre-amyloid secretion. Sulfonylureas may cause anorexia, vomiting, icterus and an increase in liver enzymes. Glipizide is initially administered at a dose of 2.5 mg/cat twice daily; this dose can be increased to 5 mg/cat twice daily if the cat tolerates the medication and improved glycemic control is necessary. Glyburide is administered at a dose of 0.625 mg/cat once daily.

Other oral agents inhibit glucose absorption from the gastrointestinal tract. Acarbose, an a-glucosidase inhibitor, is an example of a drug in this class. This agent inhibits carbohydrate digestive enzymes in the gastrointestinal tract which delays carbohydrate absorption. Acarbose can be used in conjunction with insulin therapy in both dogs and cats. Use of acarbose may result in diarrhea. The recommended dose of Acarbose is 12.5-25 mg bid in cats. Acarbose should be given with food.

Agents that improve the sensitivity of peripheral tissues to insulin have also been examined. Two trace elements, vanadium and chromium, may have insulin-mimetic effects. While these agents do not raise serum levels of insulin, they may act at a post-receptor level to activate glucose metabolism within the cell. Vanadium mimics almost every action of insulin in skeletal muscle, adipose tissue and the liver. Studies examining the use of these agents in veterinary patients have had mixed results. Vanadium administration can result in anorexia and vomiting. Long-term administration of vanadium may result in toxicity due to accumulation in various tissues. One cat was observed to suffer from reversible acute renal failure after administration of vanadium for 1 year. The dose for vanadium in cats is 0.2 mg/kg once daily, mixed with food or water. Chromium is administered to cats at a dose of 200 mg/cat once daily. This trace element should also be given mixed with food or water.

Another group of drugs that augment insulin's actions are the biguanides. Metformin is the most commonly used member of this group. In addition to its effects on peripheral tissues, metformin also inhibits hepatic gluconeogenesis and glycogenolysis. Metformin can lead to gastrointestinal disturbances such as anorexia, vomiting and diarrhea. Patients with renal, hepatic or cardiac dysfunction should not receive metformin. More studies are needed to determine a potential role for metformin in treatment for veterinary diabetic patients. The dose in cats for metformin is 2 mg/kg twice daily.