Diabetes mellitus in dogs and cats (Proceedings)

Diabetes mellitus is a common endocrine disorder in dogs and cats. Recent data has shed light on the pathogenesis of the disorder in cats and has highlighted the role of diet and oral hypoglycemic therapy. In the majority of cases, the most appropriate therapy in both dog and cats includes the administration of insulin. We will discuss the role of the various insulin preparations currently available and develop a logic approach to the initial and long term management of diabetes.

The key to successful management of the diabetic patient lies in close communication with the pet owner and prompt recognition and treatment of concurrent disorders.

Key Facts

1. Insulin is still the mainstay of therapy in the majority of dogs and cats with diabetes mellitus.

2. Diet is an important part of diabetic management especially in obese patients.

3. Oral hypoglycemics may be helpful in lieu of or in combination with insulin to improve glycemic control.

4. Auto-immune disease, pancreatitis and amyloidosis are the most common causes of diabetes in dogs and cats.

Successful management of the diabetic patient involves many factors. An understanding of dietary therapy, insulin preparations, oral hypoglycemic agents and management of concurrent illness, are all required to optimize glycemic control. The goals of therapy are to control clinical signs, prevent or slow the progression of cataracts, avoid hypoglycemia and maintain ideal body weight. The challenge is to address these concerns while attempting to help the owners deal with a time consuming, expensive and chronic medical condition.

Diabetes Mellitus in dogs and cats results from a decrease in insulin secretion from the beta cells of the pancreas and/or a decrease in insulin action. There are three classifications of diabetes:

Type I diabetes is comparable to insulin dependent diabetes mellitus (IDDM) in humans. It results in low basal insulin concentrations with impaired insulin secretion following a glucose load. Treatment requires insulin injections. It is the most common form of diabetes in dogs.

Type II diabetes is similar to non-insulin dependent diabetes (NIDDM) in humans and is managed with dietary therapy and oral hypoglycemic. It causes normal to increased basal insulin concentrations with decreased secretion following a glucose load. Insulin may or may not be required for animals with Type II diabetes.

Type III diabetes is seen most commonly in hormonally-induced diabetes in dogs and cats and is similar to impaired glucose tolerance (IGT) in humans. Diabetogenic hormones (epinephrine, cortisol, glucagon and growth hormone) or medications interfere with insulin action and cause glucose intolerance, which can lead to diabetes.

Etiology and Signalment

Canine

There are some distinct differences in the etiology of canine and feline diabetes. In dogs, it is generally thought to be an immune mediated disease with gradual destruction of beta cells. The progression from normal, to glucose intolerant, to diabetes, is generally slow so that most islets (over 90%) are lost before diabetes occurs. Other causes of diabetes in dogs include genetic predisposition, chronic pancreatitis and medication-induced diabetes (glucocorticoids and megestrol acetate).

Genetic predisposition to diabetes is most common in the following breeds: German Shepherd dogs, Schnauzers, Beagles, and Poodles. Golden Retrievers and Keshonds are more prone to juvenile diabetes.

Gender is a factor in dogs with females being three times more likely to develop diabetes than males. Generally, diabetes occurs in dogs in middle age (6-9 years) but can also present earlier for specific breeds, particularly the Golden Retriever and Keeshond.

Feline

The most common causes of diabetes in cats are obesity, pancreatitis and most commonly, amyloidosis of the pancreatic beta cells. There appears to be very little gender predisposition to this disease in cats, although it is slightly more common in males than females. As with dogs, the onset of diabetes in cats occurs most often in middle age.

Clinical Signs

The clinical signs of diabetes include PU/PD (polyuria and polydipsia) from hyperglycemia, resulting in glycosuria and a resultant osmotic diuresis. Polyphagia and weight loss is common although many animals will still be obese upon presentation. In addition to the polyphagia, there may be variable degrees of dehydration especially in the cat. Cataract formation is very common in dogs with diabetes, but rare in cats. Cats often present with icterus as a result of concurrent hepatic lipidosis and/or pancreatitis. Icterus is not common in dogs unless they have pancreatitis. Cats may also exhibit a plantigrade stance (peripheral neuropathy) that is directly related to the severity and duration of hyperglycemia. Clinical neuropathies do occur in dogs, but are extremely rare.

Differential diagnoses include: hyperthyroidism (in cats), gastrointestinal lymphoma, hepatic disease, renal disease, pancreatitis, hyperadrenocorticism, and acromegaly.

Diagnosis

Diagnosis involves testing for persistent fasting hyperglycemia, with fasting blood glucoses greater than 200mg/dl. Clinicians also will need to rule out transient hyperglycemia that may be due to: post-prandial hyperglycemia; diabetogenic hormones (endogenous or exogenous); and stress hyperglycemia. Stress hyperglycemia can be a problem in cats due to the release of epinephrine when stressed or handled.

Laboratory abnormalities include:

• Hemogram

o non-specific

o signs of dehydration

• Biochemistry profile

o hyperglycemia

o increased in SAP and ALT

o increased in bilirubin (usually in cats)

• hepatic lipidosis

• pancreatitis

• Urinalysis

o glycosuria

• renal threshold for glucose

• canine 180-220mg/dl

• feline 240-300 mg/dl

o ketonuria

o up to 40% of patients will have positive urine cultures in the absence of an active urine sediment.

Treatment

The number one cause of death in diabetic dogs and cats is not the disease itself, rather, it is the owner's frustration with the disease. This is an extremely important point to remember when treating diabetic animals. Good communication with the pet owner is perhaps the most important component of managing the disease.

It is recommended that clinicians schedule a 30-minute appointment with the client at the time of discharge before sending the diabetic patient home for the first time. During this appointment, clinicians should thoroughly discuss the care required for the patient. Include the following instructions in that discussion: how to give the animal injections; how to store insulin, what types of food to feed and how often; how to recognize the signs of hypoglycemia and how t react to this condition. Also include information on what clinical signs to look for in terms of monitoring water intake and urine production. The client should be give written instructions for use as a reference once they are caring for the patient at home. It is essential that the clinician and veterinary staff strive to educate the caregiver and motivate them to get involved in the care of their diabetic pet.

The goals of treatment include elimination of the clinical signs of diabetes, prevention or slowing of cataract formation and resulting blindness, prevention of potentially dangerous hypoglycemia, and prevention and/or treatment of concurrent illness.

Therapy for diabetes centers on four main areas: Treatment of concurrent illness (i.e., urinary tract infections, pydermas, etc.); oral hypoglycemic agents: insulin therapy, and dietary management.

Concurrent illness. Monitoring for concurrent illness is very important in effectively managing diabetic dogs and cats. Clinicians must effectively recognize and treat the other disorders because the concurrent illness will impact the diabetic regulation and many common diseases have similar clinical signs to diabetes mellitus. Even simple problems such as UTI's and pyodermas can result in activation of stress hormones and result in insulin resistance.

Oral Hypoglycemic Therapy

Diabetes mellitus affects dogs and cats with similar frequency varying from 1 in 100 to 1 in 500. Classification is generally based on the pancreatic beta cells ability to continue to produce and secrete insulin: 1)Insulin Dependent Diabetes Mellitus (IDDM) where loss or destruction of beta cells leads to a complete lack of insulin or, 2)Non-Insulin Dependent Diabetes Mellitus (NIDDM) in which beta cells still retain some functional ability. The majority of cases in veterinary medicine are IDDM but in some species, mainly cats, dietary management, oral hypoglycemic therapy, and/ or management with small doses of insulin suggests the possibility of NIDDM.

Oral hypoglycemic agents have been used in the treatment of NIDDM in humans for over 30 years. It is only in recent years however that these products have been seriously evaluated as an alternative to insulin therapy in animals. The medical literature provides an extensive amount of information on a variety of agents used in people while research in this field in veterinary medicine is still limited mainly to sulfonylureas (ie.glipizide). In this paper, we will review the various oral hypoglycemic agents commonly used in human medicine today, their mechanism of action, efficacy in humans and potential applications for use in veterinary medicine.

Sulfonylureas

Sulfonylureas were discovered as a treatment for diabetes quite accidentally when it was noted, in the 1940's, that antibacterial sulfonamides also caused a decrease in blood glucose levels. Since that time they have been extensively studied to determine their safety and efficacy. The most common sulfonylurea agents used today are called second generation sulfonylureas as they are larger, nonpolar and more lipid soluble formulations of their parent compounds. These drugs have replaced the first generation sulfonylureas as they tend to have greater hypoglycemic potency. This group of drugs includes glipizide (Glucotrol), glyburide (DiaBeta,Glynase PresTab) and glimeperide (Amaryl).

Mechanism of Action

Despite the fact that these drugs have been around the longest, their mechanism of action is still not entirely understood. They are thought to exert an insulinotropic effect by means of closing ATP-dependent potassium channels in pancreatic beta cells. The resulting depolarization causes an influx of calcium and stimulation of insulin release. There is no increase in insulin synthesis. In addition, these drugs are also thought to improve insulin receptor binding or enhance post-receptor activity, improve hepatic insulin sensitivity and inhibit hepatic glycogenolysis. The efficacy and mechanism of these extrapancreatic effects however, remains unclear. As with other oral hypoglycemic agents, the need for some degree of normal beta cell function and insulin release precludes the use of these drugs in patients with IDDM (i.e. dogs).

Efficacy

Dose ranges of 2.5-40 mg/day of glipizide and 1.25-20 mg/day of glyburide are commonly used when treating human diabetics. However, approximately 30% of human patients treated with sulfonylureas do not achieve adequate glycemic control. Of those who do initially respond, 5-10% will develop secondary failure requiring other forms of treatment. In these patients, poor dietary compliance as well as progressive beta cell dysfunction are thought to be the cause. Appropriate patient selection appears to greatly influence efficacy. Patients with NIDDM who have been unsuccessfully treated with diet and exercise alone, are otherwise healthy, and who have been diagnosed within the last 5 years are the best candidates for successful sulfonylurea therapy in people.

In veterinary medicine, the most extensively studied sulfonylurea has been glipizide. In one study, glipizide was effective in improving clinical signs and blood glucose concentrations in 65% of cats.

The degree of response in these cases varied greatly however, which is to be expected when the type of DM is unknown (IDDM vs. NIDDM). Unlike in people, distinguishing between the two forms of diabetes has proven difficult as routine insulin secretagogue testing in cats is unreliable although it is currently believed that 50-70% of cats are insulin dependent diabetics. In a more recent study, glycemic control in diabetic cats was monitored over a 50 week period in which glipizide monotherapy was instituted at a dose of 5 mg orally twice daily. Overall, 22 out of 50 cats (44%) treated were considered to have had a positive response to therapy. The effectiveness of the drug however, waned in 3 of these cats prior to the end of the study decreasing the success rate to 38%. Unfortunately, there were no consistent factors in either study which would indicate which patients would respond well to glipizide therapy. When considering treatment with oral hypoglycemics in our feline patients however, careful patient selection based on our knowledge of the disease as well as information from the medical literature, will ensure a better success rate (Table 1).

Current initial dose recommendations for treating cats with glipizide are 2.5 mg orally twice daily. Animals determined to be responding favorably to glipizide therapy typically show resolution of clinical signs, blood glucose levels <200 mg/dL and absence of glucosuria. These cases should be routinely evaluated as they may not require life-long therapy. Based on the severity of the underlying pancreatic pathology, complete response may not be seen in all cases and an initial favorable response does not preclude the possibility of insulin supplementation in the future. Glimperide (Amaryl) may also be used at 2 mg SID and monitored in a similar fashion to glipizide.

Adverse Effects

The overall incidence of adverse effects is relatively low with second generation sulfonylureas but hypoglycemia, skin reactions, hematologic abnormalities (i.e. thrombocytopenia, hemolytic anemia), vomiting and elevated liver enzymes have all been reported in human medicine. The main concern is hypoglycemia. In one human study, symptomatic hypoglycemia occurred in 20% of patients within the first six months of treatment. It is important to note however that this side effect tends to occur more frequently in patients being treated with long acting forms of the drug such as glyburide and the frequency is still less than that seen in patients treated with insulin. The risk of hypoglycemia is increased in patients with impaired hepatic and renal function as these are the main routes of clearance. Other risk factors include alcohol use, drug interactions and concurrent GI disorders.

In a 50 week study in which 50 cats were treated with glipizide, the most common side effects noted were jaundice, elevated liver enzymes, anorexia and vomiting. These signs were documented in 16% of cats and most signs resolved with discontinuation of the drug or a reduction in the dose. A decrease in the incidence of vomiting has also been noted in cats that are given the drug with a meal. Hypoglycemia has been reported as a potential side effect in 15% of cats. These cases never demonstrated clinical signs associated with hypoglycemia and blood glucose levels rose with discontinuation or attenuation of the glipizide. Hypoglycemia has also been noted in patients that were believed to have been transient diabetics. In these patients, euglycemia was achieved once the drug was discontinued.

Biguanides

The high incidence of primary and secondary failure of sulfonylurea therapy in humans has recently brought forth the potential use of biguanides as an alternative or adjunctive treatment for patients with NIDDM. The use of Galega officinalis (French lilac), the active component of which is guanidine, can be traced back to medieval Europe where it was prescribed as a treatment for diabetes. It was from guanidine that the two main biguanides, phenformin and metformin, were synthesized in the 1950's. Metformin (Glucophage) is the most commonly used biguanide today. Despite having been used in Europe and Canada for over 30 years, it was only recently (1994) approved by the FDA for use in the United States.

Mechanism of Action

Unlike sulfonylureas, biguanides act mainly by decreasing hepatic glucose output and increasing peripheral insulin sensitivity. These drugs do not stimulate insulin secretion or result in hypoglycemia and are therefore classified as anti-hyperglycemic agents. The exact mechanism through which metformin decreases production of glucose by the liver and ameliorates hepatic insulin resistance is unknown but is thought to involve alteration of hepatic enzyme activity as well as enhancement of insulin/glucagon- stimulated suppression of gluconeogenesis. Other proposed mechanisms of action include, decreased intestinal glucose absorption and decreased fatty acid oxidation.

In animal studies, metformin has been show to increase insulin-stimulated uptake of glucose by muscle without increasing lactate production, a fact which is important when discussing potential adverse effects. It is also thought to enhance insulin receptor binding. The importance of this effect however is unknown as there is a poor correlation between insulin binding and glucose homeostasis.

Efficacy

In one study conducted to monitor the effects of metformin vs placebo on glycemic control, it was found that fasting blood glucose as well as glycosylated hemoglobin (GHb) was better controlled in patients receiving metformin therapy. These patients however, required the maximal metformin dose of 2550 mg/day. The efficacy of the drug in reducing GHb and blood glucose has been attributed directly to a reduction in hepatic glucose output due to inhibition of gluconeogenesis. The most significant finding has been that, unlike sulfonylureas and insulin, metformin does not cause weight gain and rarely causes clinical hypoglycemia.

Combination therapy using metformin in conjunction with sulfonylureas has also been studied in patients who had minimal to no response with sulfonylureas alone. Compared to patients receiving glyburide monotherapy vs. metformin monotherapy, patients on the combined protocol had the lowest blood glucose levels and GHb levels of the three groups. However, 18% of patients receiving combination therapy did exhibit signs of hypoglycemia whereas less than 3% of patients in the other two groups exhibited these signs.

One potential application for the use of metformin in veterinary medicine, is in the treatment of cats who have failed or are only partially responding to glipizide therapy. As with humans, hypoglycemia would be the main concern in these cases when using the drugs in combination and owners should be warned of potential complications.

Adverse Effects

The most alarming side effect seen with the use of biguanides historically has been lactic acidosis. In patients treated with phenformin, decreases in hepatic gluconeogenesis as well as increased glycogen formation and glucose oxidation in peripheral tissue, caused an accumulation of lactate which in turn led to acidosis. This side effect seemed to be potentiated in patients with impaired renal function, liver disease, alcoholism, or other illness which could decrease metabolism and/or clearance of lactate. The severity and increased incidence of this effect caused the withdrawal of phenformin from the U.S. market in the 70's although it is still used in some countries. Metformin, on the other hand, has not been shown to cause significant acidosis. The two main reasons for this are: 1) metformin does not cause a significant increase in lactate production in peripheral tissues and 2) it has been shown to cause an increase in lactate oxidation unlike phenformin. The incidence of lactic acidosis in patients receiving metformin monotherapy is less than one-tenth of a percent while the risk of acidosis seen with phenformin therapy is approximately 10-20 times greater.

The more commonly reported side effects associated with metformin occur in approximately 20% of cases and include: diarrhea, abdominal discomfort, metallic taste, nausea, and anorexia. When used to treat human diabetics, many physicians recommend taking the drug with a meal to reduce the likelihood of GI disturbances. Treatment with metformin has also been shown to cause significant weight loss in obese patients with preferential loss of adipose tissue. This finding would exclude thin, NIDDM patients in veterinary medicine from treatment with this drug. Reduction in the absorption of vitamin ±2 and folate has also caused some concern about the possibility of anemia and, although only one case attributable to metformin has been reported, periodic hematocrit and hemoglobin measurements have been proposed by some.

α-Glucosidase Inhibitors

Dietary control of blood glucose levels has always been a cornerstone in the treatment of diabetes mellitus. One of the goals of dietary therapy has been to delay absorption of glucose in an effort to achieve better glycemic control. Unfortunately, many patients find these stringent dietary regimens difficult to follow spurring the development of drugs such as α-glucosidase inhibitors. The most commonly used drug in this family is acarbose (Precose) which was only recently approved by the FDA for the treatment of hyperglycemia in patients with NIDDM.

Mechanism of Action

α-Glucosidases (i.e. sucrase, maltase, lactase) are made in the brush border of the small intestine and are involved in the digestion of complex carbohydrates into monosaccharides (i.e. glucose). Acarbose acts by competitively and reversibly inhibiting these enzymes therefore delaying hydrolysis and subsequent absorption of ingested carbohydrates. It is also thought that acarbose may inhibit pancreatic α-amylase which is a catalyst in the digestion of starch . The overall effect of these actions is to reduce post-prandial hyperglycemia. Malabsorption and significant weight loss expected with this mechanism of action is uncommon as the small amount of carbohydrates that do reach the large intestine are metabolized by colonic bacteria into fatty acids which are then absorbed.

Efficacy

While other oral hypoglycemic agents have proven to be successful in controlling overall glucose levels, consistent, post-prandial hyperglycemia will sometimes necessitate the addition of an α-glucosidase inhibitor such as acarbose into the regime. For this reason, acarbose has been extensively studied both as a single agent as well as in conjunction with other forms of therapy for NIDDM.

In 1994 a multicenter, placebo-controlled study was conducted evaluating the efficacy of acarbose in 354 patients with NIDDM who had not been well controlled with diet alone, diet and metformin, diet and a sulfonylurea or diet and insulin. Doses ranged from 50 mg to 200 mg three times daily with doses adjusted based on postprandial glucose levels and patient tolerance. It was found that the postprandial plasma glucose levels, as well as glycosylated hemoglobin values, were significantly lower in all four groups for patients receiving acarbose vs. placebo after 1 year of treatment.

In another study, 18 women with NIDDM who were poorly controlled with sulfonylurea therapy alone were given either acarbose (900 mg daily) or metformin (1500 mg daily) in addition to sulfonylurea (240 mg daily) over an 8 week period. Glycosylated hemoglobin as well as fasting and postprandial blood glucose levels were assessed. Unlike the 1994 study, this study only found a statistically significant decrease in the postprandial blood glucose level; all other parameters remained about the same.

While the majority of studies of acarbose used in conjunction with other agents have shown it to be effective in significantly improving glycemic control, acarbose monotherapy is only comparable or slightly less effective than sulfonylureas. It is important to note as well that glycemic control in many of these trials was attained using doses that were much higher than currently approved FDA labeling.

Adverse Effects

The most commonly reported adverse effects of acarbose therapy involve the gastrointestinal tract which can be directly linked to its mechanism of action. In one study, 76% of patients reported flatulence, 33% experienced diarrhea and 25% complained of abdominal cramps. In most instances, these effects were mild and transient in nature. Slowly increasing dosage adjustments was shown to decrease the incidence of adverse events.

Based on efficacy trials in humans, it may be a viable alternative as adjunctive therapy in patients who cannot be controlled on other oral hypoglycemic agents alone. A recent study in dogs showed improved glycemic control in conjunction with insulin in 5 dogs with diabetes mellitus. The dose range was 25(dogs less than 10 kg) to 50 (dogs greater than 10 kg) mg for 2 weeks and the dose was then increased to 50 and 100 mg respectively for 6 weeks. Loose stool occurred in 3/5 dogs. A dose of 12.5 – 25 mg BID-TID with meals has been proposed for use in cats. Based on its mechanism of action, it is also possible to consider using acarbose in patients who are receiving daily insulin injections. Decreasing the post-prandial rise in glucose may help to stabilize the patients glucose levels throughout the day in conjunction with exogenous insulin.

Conclusion

While sulfonylureas have been the most extensively studied oral hypoglycemic drugs in veterinary medicine, acarbose, metformin and troglitazone all have potential benefits for the treatment of NIDDM. Due to the nature and progression of the disease in the cat, studies using felines hold the most promise. For example, as mentioned above, we know obese cats are more likely to develop insulin resistance and subsequent NIDDM. These animals are likely the ones to benefit the most from the use of drugs such as troglitazone to either prevent or slow the progression of the disease.

References

Feldman, E.C. et al: Canine and Feline Endocrinology and Reproduction. W.B. Saunders, Philadelphia, PA, 1996.

Ettinger, S.J. et al: Textbook of Veterinary Internal Medicine. W.B. Saunders, Philadelphia, PA, 1995.

Groop, L.C.: Sulfonylureas in NIDDM. Diabetes Care 15:737-748; 1992.

Melander, A.: Clinical Pharmacology of Sulfonylureas. Metabolism 28:12-16; 1987.

Tal, A.: Oral Hypoglycemic Agents in the Treatment of Type II Diabetes. American Family Physician 48:1089-1095; 1993.

Tan, G.H. et al: Concise Review for Primary Care Physicians. Mayo Clinic Proceedings 71:763-768; 1996.

Nelson, R.W. et al: Effect of an orally administered sulfonylurea, glipizide, for the treatment of diabetes mellitus in cats. JAVMA 203:821-827; 1993.

Ford, S.L.: NIDDM in the cat: Treatment with oral hypoglycemic medication, glipizide. Vet. Clinics of North America 25:599-614; 1995.

Feldman, E.C. et al: Intensive 50-week evaluation of glipizide administration In 50 cats with previously untreated diabetes mellitus. JAVMA 210:772-777; 1997.

Nelson, R.W. et al: Kirk's Current Veterinary Therapy. W.B. Saunders, Philadelphia, PA, 1995.

Heine, R.J.: Role of Sulfonylureas in NIDDM: Part II - "The Cons". Horm. Metab. Res. 28:522-526; 1996.

Bressler, R. et al: Pharmacological regulation of Blood Glucose Levels in NIDDM. Arch. Intern. Med. 157:836-846; 1997.

Harrower, A.D.B.: Pharmacokinetics of Oral Antihyperglycaemic Agents in Patients with Renal Insufficiency. Clin. Pharmacokinet. 2:111-118; 1996.

Bailey, C.J. et al: Traditional Plant Medicines as Treatments for Diabetes. Diabetes Care 12:553-563; 1989.

Melchior, W.R. et al: Metformin: An Antihyperglycemic Agent for the Treatment of Type II Diabetes. Annals of Pharm. 30:158-163; 1996.

Goo, A.K.Y. et al: Metformin: A New Treatment Option for NIDDM. The Journal of Family Practice 42:612-618; 1996.

Bailey, C.J. et al: Metformin. The New England Journal of Medicine 334:574-579; 1996.

Wollen, N. et al: Inhibition of Hepatic Gluconeogenesis by Metformin. Biochemical Pharm. 37:4353-4358; 1988.

Bailey, C.J.: Biguanides and NIDDM. Diabetes Care 15:755-771;1992.

Stumvoll, M. et al: Metabolic Effects of Metformin in NIDDM. The New England Journal of Medicine 333:550-554; 1995.

Martin, A.E. et al: Acarbose: An -glucosidase inhibitor. Am. Journal Health-Syst. Pharm. 53:2277-2290; 1996.

Coniff, R.F. et al: A Double-Blind Placebo-Controlled Trial Evaluating the Safety and Efficacy of Acarbose for the Treatment of Patients with Insulin-Requiring Type II Diabetes. Diabetes Care 18:928-932; 1995.

Chiasson, J.L. et al: The Efficacy of Acarbose in the treatment of Patients with NIDDM. Annals of Int. Med. 121:928-935; 1994.

Bayraktar, M. et al: A Comparison of Acarbose Versus Metformin as an Adjuvant Therapy in Sulfonylurea-Treated NIDDM Patients. Diabetes Care 19:252-254; 1996.

Greco, D.: Treatment of NIDDM with oral hypoglycemic agents. Proceedings of the Fifteenth Annual Veterinary Medical Forum 1997. Pgs. 252-255.

Kuehnle, H.F.: New Therapeutic Agents for the Treatment of NIDDM. Exp. Clin. Endocrinol. Diabetes 104:93-101; 1996.

Insulin Therapy. There has been a considerable amount of confusion over the various insulin preparations that are available. In general, animal origin insulins are being discontinued as the desire and ability to treat people with human derived insulin preparations has progressed.

There is concern that animals receiving human insulin will develop antibodies resulting in decreased insulin activity and/or effectiveness. Dogs receiving any insulin product that is not derived from pork may make antibodies. However, studies have shown that those antibodies do not interfere with the glucose control. In fact, dogs that made antibodies against insulin had a longer duration of insulin action, which actually enhanced the effect of the insulin rather than decreased its efficacy. A recent study in cats should that 13% developed anti-insulin antibodies. None of the cats should signs of insulin resistance.

The options with human insulin include ultra short acting, short acting, intermediate acting, and long-acting insulins. The short acting insulins are primarily used for ketoacidosis, and therefore, are not covered in this article. The intermediate acting insulins are classified as either NPH or Lente. It is important to note however, that even though they are classified as intermediate, they do not behave the same way in the dog or cat. Lente is actually a mixture of semi-lente and ultra lente, which results in a bimodal onset of actions. This is helpful in some patients because is helps block post- prandial hyperglycemia. Conversely, a lente insulin is not recommended for use in an animal that does not develop post prandial hyperglycemia. It is recommended that NPH be used in the majority of dogs and cats with diabetes and it is also understood that most patients will require two injections a day to achieve glycemic control.

On July 6, Eli Lilly announced that it was discontinuing 4 of its insulin products: Humulin L Lente insulin, Humulin U Ultralente insulin, Iletin II Regular pork insulin, and Iletin II NPH pork insulin (see attached announcement). Less than 2% of human patients with diabetes mellitus will be affected by the change since most have been switched to newer insulins and/or insulin analogs.

To meet this challenge we will need to switch patients currently taking these products to comparable insulin preparations and change the way we approach the newly diagnosed dog or cat with diabetes. Therefore, we have put together the following suggested guidelines:

Canine Patients

Newly Diagnosed Patients

1. Vetsulin (porcine origin lente): A zinc, porcine, intermediate acting insulin. Canine and porcine insulin have an identical amino acid sequence thereby eliminating the theoretical complication of anti-insulin antibodies and their effect on glycemic control. The suggested, initial starting dose is 0.5 units/kg BID. This insulin is only available at a concentration of 40 IU/ml (U-40) so please make sure that proper insulin syringes are provided to the owner. Re-assessment of clinical signs and a serial blood glucose curve should be performed 1 week after starting therapy. For additional information see: www.vetsulin.com.

2. Humulin N or Novolin N; These are both intermediate acting, human origin insulins. Suggested starting doses are 0.5 units/kg BID. Re-assessment of clinical signs and a serial blood glucose curve should be performed 1 week after starting therapy.

3. Glargine: To date, no information on the use of glargine in the dog is available (see discussion below regarding glargine and cats)

Transitioning Canine Patients

If you have canine patients currently taking Humulin L lente insulin, I would switch them to either Vetsulin or Humulin N. The initial dose of Vetsulin or Humulin N will remain the same with re-assessment of clinical signs and a serial blood glucose curve performed 1 week after changing insulin preparations.

Feline Patients

Newly Diagnosed Patients

1. Insulin glargine (Lantus): Glargine is a modified, recombinant, long acting insulin analog. A study presented at ACVIM in 2005 showed a very high rate of remission (8/8 in remission within 4 months with 6/7 still in remission at 1 year) in feline diabetics with the use of glargine and a low carbohydrate-high protein diet. The recommended starting dose is 0.5 units/kg BID if the fasting blood sugar is greater than 360 mg/dl and 0.25 units/kg BID if the initial fasting blood glucose is less than 360 mg/dl. For additional product information see: www.lantus.com. Glargine highlights:

a. Should not be diluted or mixed as this will affect pH

b. Should be kept refrigerated. Once open the vial has a shelf life of 4 weeks at room temperature. I would discard any remaining insulin after 8 weeks of refrigeration pending further clinical data.

2. PZI: As with dogs we only recommend the use of PZI Vet from Idexx. The initial starting dose

3. Humulin N and Novolin N: Similar to PZI with remission rates of 40-50 % when used with a low carbohydrate-high protein diet. Starting doses are generally 1-3 units/cat once a day.

4. Vetsulin: Again similar to PZI and Humulin N with remission rates of 40-50 % when used with a low carbohydrate-high protein diet. Starting doses are generally 1-3 units/cat once a day.

Transitioning Feline Patients

If you have patients currently taking either Humulin L or Humulin U, I would switch them to either Vetsulin or Humulin N. The initial starting dose will remain the same with re-assessment of clinical signs and a serial blood glucose curve performed 1 week after changing insulin preparations. If you wish to transition them to glargine, I would follow the dosage recommendations as outlined above under newly diagnosed patients. It is important to note that remission rates will be much lower with glargine and a low carbohydrate-high protein diet in long standing diabetic patients (cats with diabetes for more than 6 months) than in newly diagnosed patients.

With the recent introduction of the AlphaTrak Blood Glucose Monitoring System (Abbott) we have the ability to very accurately measure blood glucose concentrations in both dogs and cats using very small quantities of blood. This will allow both veterinarians and pet owners to obtain very reliable results in both the hospital and home setting. This information can then be used to make informed decisions regarding the management of diabetic patients. These decisions impact the type and dose of insulin selected, the frequency of insulin administration, aid in the assessment of glycemic control, help in preventing hypoglycemic episodes and monitor for remission of diabetes especially in feline patients.

Glycemic control can be evaluated in a numbers of ways. Owner assessment of clinical signs (polyuria, polydipsia, weight gain or loss), progression of diabetic cataracts (dogs), presence of peripheral neuropathy (cats), and episodes of hypoglycemia are often the best indicators of glycemic control. Changes in insulin dosage or documenting remission of diabetes, is best determined by blood glucose measurement. Recognizing that the measurement of blood glucose concentrations can be problematic in the hospital setting (especially in cats as a result of stress induced hyperglycemia) recent work has evaluated the practicality and value of at home blood glucose monitoring in dogs and cats. At home blood glucose monitoring is essential in the management of human patients with diabetes given that a number of the complications associated with long term diabetes are directly related to persistent hyperglycemia. While diabetic retinopathy, nephropathy, painful neuropathies and cardiovascular disease are rare in our veterinary patients, adequate glycemic control is required to eliminate clinical signs and decrease morbidity and mortality in dogs and cats. Control of clinical signs does not require the restoration of euglycemia but rather involves keeping the blood glucose levels below renal threshold for the majority of the day. Renal threshold for glucose is 180 mg/dl in the dog and approximately 280 mg/dl in the cat. It is very important that we remember the owners of diabetic dogs and cats are being asked to do a great deal to help in the management of their pet's chronic illness and we need to do whatever we can to make the clients job easier while at the same time taking steps to assure maximal diabetic control.

Blood Glucose Monitoring

Reliability of the AlphaTrak system depends of course on proper use. Please review the materials supplied with your system to ensure optimal performance. We will review a number of important points here that should be followed by veterinarians, technicians and pet owners. Following these easy steps will help ensure accurate test results.

1. Insert the top of the test strip into the meter until it stops. Note: The butterfly is at the bottom of the strip and should face up.

2. Press the "m" button to power on the meter.

3. Check/adjust the code number using the "m" button to scroll down and the "c" button to scroll up. The code number on the display must match the CODE DOG or CODE CAT on the side of the test strip vial.

4. Wait for blood drop and test drip symbol to appear on screen.

5. Obtain a blood sample from the pet (See below). Dispose of lancet in biohazard sharps container. The owner should be disposing of insulin needles and lancets in a similar manner.

6. Gently touch only 1 sample area of the test strip to the blood sample (sample size is only 0.3 ul). Make sure to apply the blood to the side of the test strip. Do not put blood on the top or bottom of the strip. The meter will beep when it has an adequate sample.

7. Wait for result. The test is complete when the blood glucose concentration is shown on the display screen.

Monitoring of blood glucose concentrations should be done in the following situations and may be performed in the clinic or preferably at home by the pet owner:

1. One week after initiating insulin treatment or changing insulin dosage.

2. At any time hypoglycemia is suspected.

3. At any time a change in clinical status is observed. For instance, return of pu/pd, weight loss, cataract progression, etc.

In general, we are interested in obtaining blood samples at the following times to assess glycemic control:

1. Pre-prandial and pre insulin

2. Every 2 hours (dogs; cats on NPH, lente or ultralente) or 4 hours (cats on glargine or PZI) post prandial/insulin

3. Samples should be obtained for 12 hours or until the nadir (lowest glucose concentration) is observed. It is rare that a curve will need to be performed for a full 24 hours.

Obtaining At Home Blood Glucose Samples

Most pet owners can be taught and are in fact eager to learn how to obtain blood samples at home. Obviously if the pet is too fractious or will not tolerate blood collection other methods of assessing glycemic control will have to be employed (clinical signs, fructosamine levels, urine glucoses, etc).

Dogs: The easiest location seems to be the oral buccal mucosa (similar to performing a buccal mucosal bleeding time (BMBT). Before starting glucose testing on a diabetic dog at home, have the owner run through a mock scenario to get the dog accustomed to the procedure. A lot of the "ease" of home testing depends on a calm and pleasant atmosphere and patient. To do an actual test, have the pet lie on its side on the floor. Roll back the upper lip and gently wipe the buccal mucosa dry with facial tissue. Then using an AlphaTrak sterile lancet, stick the buccal mucosa close to the lip edge. Wait a couple of seconds for a spot of blood to appear gently massaging the area if necessary to produce a large enough drop. Apply the blood drop to the test strip as outlined above. After a reading is obtained, the result is recorded and positive reinforcement provided.

Other sites that may also work in dogs include the foot pads, calloused areas and a shaved an area in the skin near the dorsal tail head. The site that is ultimately chosen will inevitably depend on the individual preferences of the pet and the owner.

Cats: In cats the lateral ear veins seem to work the best although we have also had success with the carpal and tarsal pads. For the ear veins and pads do not wash the site or apply alcohol prior to using the lancet as it can make obtaining a sample very difficult. The site can be wiped with an alcohol swab following sample collection.

To see the lateral ear vein, look carefully around the outer (haired) edge of the ear. Shining a flashlight from under the ear increases its visibility even on dark haired cats. It is much easier to get blood from a warm ear than from a cold one so gently massing the ear or applying a warm cloth or heated rice sock will help dilate the vessel. Have a folded tissue or gauze pad, the AlphaTrak lancet, and the AlphaTrak meter ready. Use the lancet to prick the ear near the vein. If you hit the vein directly you easily obtain a large enough sample. Remember you only need a 0.3 ul of blood. Put the tissue underneath the ear so you do not prick yourself and contaminate the blood sample. You may need to prick more than once to get enough blood and gentle massage around the site will also encourage the blood to form at the surface. Apply the blood drop to the test strip as outlined above. After a reading is obtained, the result is recorded and positive reinforcement provided. After you have done a series of tests in the same area it becomes slightly swollen and it appears easier to obtain a sample.

The same general procedure is followed when using the larger carpal or tarsal pads.

Using the Information Derived Using At Home or In Hospital Glucose Monitoring

The data obtained with at home blood glucose monitoring in conjunction with clinical signs is used to adjust the dose of insulin and to monitor for remission of diabetes. We will look at scenarios for both cats and dogs. The recommendations for cats are based on our experience as well as the data generated by Dr Jacquie Rand at the University of Queensland.

Cats

1. Cats on Glargine and PZI Insulins

a. If the preinsulin blood glucose concentration is > 360 mg/dl and/or the nadir blood glucose concentration is > 180 mg/dl the dose of insulin is increased by 0.5 to 1 unit BID.

b. If the preinsulin blood glucose concentration is 270 to 360 mg/dl and/or the nadir blood glucose concentration is 90 - 180 mg/dl the dose of insulin is maintained.

c. If the preinsulin blood glucose concentration is 190 - 270 mg/dl and/or the nadir blood glucose concentration is 54 - 90 mg/dl use the nadir, clinical signs and the next preinsulin glucose concentration to determine if the dose is decreased or maintained.

d. If the preinsulin blood glucose concentration is < 180 mg/dl and/or the nadir blood glucose concentration is < 54 mg/dl the dose of insulin is decreased by 0.5 to 1 unit BID. If the total insulin dose is already 0.5 – 1 unit BID, stop the insulin and check for diabetic remission.

2. Cats on NPH, Lente or Ultralente Insulins

a. If preinsulin blood glucose is < 210 mg/dl withhold insulin and check for diabetic remission.

b. If preinsulin blood glucose is 234 - 288 mg/dl total insulin dose should not be higher than 1 unit BID.

c. If nadir blood glucose is < 54 mg/dl insulin dose should be reduced by 50%.

d. If nadir blood glucose is 54 - 90 mg/dl dose should be reduced by 1 unit BID.

e. If nadir blood glucose is 91 - 162 mg/dl insulin dose should remain the same.

f. If nadir blood glucose is > 180 mg/dl insulin dose should be increased by 1 unit BID.

Dogs

1. Dogs on NPH or Lente Insulins

a. If the preinsulin blood glucose concentration is > 360 mg/dl and/or the nadir blood glucose concentration is > 180 mg/dl the dose of insulin is increased by 25%..

b. If the preinsulin blood glucose concentration is 270 to 360 mg/dl and/or the nadir blood glucose concentration is 90 - 180 mg/dl the dose of insulin is maintained.

c. If the preinsulin blood glucose concentration is 190 - 270 mg/dl and/or the nadir blood glucose concentration is 54 - 90 mg/dl use the nadir, clinical signs and the next preinsulin glucose concentration to determine if the dose is decreased (50%) or maintained.

d. If the preinsulin blood glucose concentration is < 180 mg/dl and/or the nadir blood glucose concentration is < 54 mg/dl the dose of insulin is decreased by 50%.

The use of the AlphaTrak Blood Glucose Monitoring System both in the clinic and at home will greatly improve our ability to assess glyemic control and improve insulin therapy. In conjunction with close observation of clinical signs, at home glucose monitoring should go a long way towards improving the quality of life of diabetic pets and their owners.

References

Martin GJ, Rand JS. Pharmacology of a 40 IU/ml Porcine Lente Insulin Preparation in Diabetic Cats: Findings During the First Week and After 5 or 9 Weeks of Therapy. J Feline Med Surg 3:1; 23-30; 2001

Nelson,R.W., Lynn,R.C., Wagner-Mann,C.C. & Michels,G.M. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 218, 38-42 (2001).

Marshall R, Rand J. Comparison of the Pharmacokinetics and Pharmacodynamics of Glargine, Protamine Zinc and Porcine Lente Insulin in Healthy Cats. Australian College of Veterinary Scientists Science Week, 2003.

Stenner,V.J., Fleeman,L.M. & Rand,J.S. Comparison of the pharmacodynamics and pharmacokinetics of subcutaneous glargine, protamine zinc and lente insulin preparations in healthy dogs. J Vet Int Med 18, 444-445. 2004 (abstract).

Marshall RD and Rand JS. Treatment with glargine results in higher remission rates than Lente or protamine zinc insulins in newly diagnosed diabetic cats. J Vet Int Med 19, 425, 2005 (abstract).

Diet. There is a considerable amount of reliable research data showing that diets high in carbohydrates, low in fat and high in fiber are helpful in regulating diabetic dogs. These types of diets lower the average insulin dose, the average blood sugar, the amount of urine being produced and glycosolated hemoglobins and fructosamine levels.

The carbohydrates in these diets are complex carbohydrates. It is important to avoid diets high in simple sugars, which includes any commercial semi-moist food, primarily those packaged in foil packets. Diets high in simple sugars are absorbed very rapidly before the insulin has time to work. The goal with diet is to balance the absorption of sugar with the onset of action of the insulin. A high carbohydrate/low fat diets also decreases plasma free fatty acid and cholesterol concentrations, and increases the number and activity of insulin receptors.

High fiber diets reduce insulin resistance. The fiber acts to decrease post prandial hyperglycemia, primarily because it delays gastric emptying. A high fiber diet also decreases absorption of glucose and increases insulin action at the receptor.

It has recently been suggested that diabetic cats be fed a high protein/low carbohydrate diet. This can be accomplished with several commercially available canned diets (Hill's M/D, IVD Development, Purina DM, many other canned kitten diets). These diets may result in remission of the diabetes and elimination of the need for exogenous insulin and/or oral hypoglycemic agents. High protein/low carbohydrate diets more closely resemble the diet of felines in the wild and may help reduce glucose intolerance, insulin resistance and obesity.

Feeding. Ideally, the feeding schedule should be coordinated with the onset of action of the insulin. With dogs, this is fairly easy to regulate, but with cats, it is nearly impossible due to their "grazing" style of eating. For cat owners who may not be able to follow a strict feeding schedule or those with multiple pet households, insulin therapy will have to be adjusted to meet the owner's needs. The most important component of the dietary plan is to stress consistency in the diet. The following feeding schedule can be used for dogs and some cats. With insulin given once a day, feed three meals a day (of equal calories) at six-hour internals. Give the first meal at the time of the insulin injection. For animals receiving insulin twice a day, feed four meals a day. Schedule them to coincide with the insulin injections and feed mid-afternoon and late evening.

If the owner is unable to follow this schedule, advise them to feed twice a day, at the time of injection and 8-10 hours later (for once a day insulin patients); or at the times of insulin injections (for twice a day insulin patients).

Home Management

1. Instruct owner on proper injection techniques, injection locations, storage and handling of insulin.

2. Instruct owner on how to monitor clinical signs.

3. Continue feeding schedule and dietary therapy.

4. Instruct owners to initially monitor urine glucose/ketone levels daily, usually in the morning or evening prior to feeding. If persistent glycosuria or ketonuria is observed, ask owner to contact the veterinary hospital.

5. Advise owners of the signs of and treatment for hypoglycemia. Have owners keep a bottle of Karo syrup on hand if signs occur (i.e., weakness, ataxia, seizures) so they can rub syrup on the gums immediately. Instruct them to call the veterinary hospital.

6. Home monitoring of a diabetic cat is frequently based on observance of clinical signs only.

7. Serial sugars after the first week of home management.

Re-check Evaluations

1. Obtain owner assessment of clinical signs.

2. Serial blood sugars are helpful due to:

a. Variability of insulin action in a given patient.

b. Inaccuracy of random blood or urine sugars in monitoring the degree of glycemic control.

c. Not particularly helpful as a routine procedure in animals that are well controlled clinically.

3. Body weight

4. Physical examination/ophthalmic exam

5. Discuss urine log book with owner

6. Laboratory work as clinically indicated

7. Role of glycosylated hemoglobin and frustosamine:

a. Fructosamine may be helpful in distinguishing stress-induced hyperglycemia from diabetes in cats. These tests can be used every 3 – 4 months as an indicator of long term (2-3 weeks fructosamine; 4-6 weeks glycosylated hemoglobin) glucose control. Rising values indicate the need for further evaluation.

Problems with Insulin Therapy

1. Insulin induced hyperglycemia (Somogyi phenomenon)

- Hypoglycemia (<65mg/dl) followed by hyperglycemia (>300mg/dl) within 24 hours of insulin injection.

- Suspect when insulin requirements exceed 2 U/kg and clinical signs persist.

- Suspect when animal has signs of hypoglycemia in afternoon.

- Diagnosis with serial sugars.

- Treat by decreasing insulin dose 25-50% and review insulin administration with the owner to rule out management problems.

- Re-check serial sugars in one week.

2. Rapid insulin metabolism

- Duration of insulin less than 18 hours.

- Signs return in the evening.

- Diagnosis is with serial sugars. Hyperglycemia (>250) within 18 hours of insulin injection without previous hypoglycemia.

- Treatment:

• Review management with owner

• Switch to twice daily insulin administration. Most dogs and cats require insulin twice a day to achieve adequate glycemic control. Consider switching to PZI in cats.

3. Insulin Resistance

- Hyperglycemia (>300) throughout the day, despite insulin dosages > 2 U/kg.

- Diagnosis based on serial sugars.

- Potential causes of insulin resistance:

• Management problems

• Hyperadrenocoticism

• Steroid or Ovaban administration

• Diestrus or pregnancy

• Acromegaly

• Concurrent illness, infection

• Anti-insulin antibodies

• Hypothyroidism (dogs), hyperthyroidism (cats)

- If insulin dose exceeds 2U/kg, the animal should be evaluated for one of these causes of resistance.

4. Hypoglycemia

- Insulin overdosage

- Suspect if animal shows weakness, shaking, ataxia, seizures at time of insulin's peak effect.

- Therapy (instructions for owners)

• Mild signs - give food and call veterinarian

• Moderate signs - apply Karo syrup to the mouth, offer food when alert and then notify veterinarian.

• Comatose - apply Karo syrup to mouth and take animal to hospital.

- When hypoglycemia occurs, serial sugars should be performed to re-assess insulin dose

Summary

Diabetes mellitus is a common endocrine disorder in both the dog and the cat. An understanding of the pathogenesis of diabetes is crucial to understanding how to best manage the disease in both dogs and cats. Diet is playing an even larger role in the management of diabetes in cats. While oral hypoglycemic agents may have a place in both dogs and cats, the mainstay in treatment remains exogenous insulin administration.