How to Manage Feline Diabetics
PATHOPHYSIOLOGY OF DM
Diabetes mellitus (DM) is a common endocrine disease in cats characterized by an absolute or relative deficiency of insulin. This results in a decreased ability of cells to take up and utilize not only glucose, but also amino acids, fatty acids, and electrolytes. In addition the lack of insulin results in increased gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, and protein catabolism. Predisposing factors in cats include obesity, advancing age, and being male.
Two types of DM are recognized in humans, and these classifications can be applied to the disease in cats. Type I DM (insulin dependent diabetes mellitus) is due to an absolute deficiency of insulin. This form of diabetes is characterized by minimal secretory response to ß-cell secretagogues such as glucagons. Type II DM (non-insulin dependent diabetes) is characterized by abnormal insulin secretion and peripheral insulin resistance, and results in a stable reregulation of the blood glucose concentration at a higher concentration. The two types of diabetes are classically distinguished by characteristic responses to challenge by insulin secretagogues such as glucose, glucagons, or arginine. In type I DM, there is a decreased or negligible secretion of insulin compared to normal animals, whereas in type II DM, total insulin secretion may be normal or increased, although the pattern of secretion may be abnormal. The insulin concentration is still insufficient, however, to prevent hyperglycemia. The phenomenon of glucose toxicity complicates interpretation of glucagon tolerance tests, particularly in cats, and the test is of little clinical utility. Currently the true prevalence of type I versus type II diabetes mellitus in diabetic cats is unknown.
DIAGNOSIS
The diagnosis of DM is made based on characteristic clinical signs of diabetes mellitus (polyuria, polydipsia, polyphagia, and weight loss), and documentation of hyperglycemia and glycosuria. In cats diagnosis may be complicated by the occurrence of marked stress hyperglycemia. When making a diagnosis of DM in cats, it is therefore important not only to document persistent hyperglycemia and glycosuria, but also to rule out other diseases that may cause similar clinical signs. Measurement of fructosamine concentration or urine glucose on urine samples collected in the home environment allow the clinician to distinguish between stress induced hyperglycemia (and resultant glycosuria) and persistent hyperglycemia due to diabetes mellitus. Glycosuria may also occur secondary to ketamine anesthesia, chronic renal failure, and postobstructive diuresis. The presence of significant ketonuria together with hyperglycemia, is diagnostic for diabetes mellitus in cats.
Cats are also unique in that DM may be transient or intermittent. In one study, 10 diabetic cats were reported to go into spontaneous remission after 1 to 3 months of therapy. In other studies, up to 70% of cats with DM have been reported to go into spontaneous clinical remission, suggesting that up to 70% of cats may have type II DM. The glucagon tolerance test is not useful in predicting whether or not a cat is likely to go into remission.
TREATMENT OF DIABETES MELLITUS IN CATS
Most diabetic cats should be treated with insulin in conjunction with dietary modification. Oral hypoglycemic drugs such as glipizide can be considered in certain circumstances but are not effective for control of diabetes mellitus in the majority of diabetic cats.
INSULIN
Insulins may be classified by insulin source, insulin formulation, or duration of action of insulin. Not all forms of insulin are currently commercially available and product availability is likely to continue to change. Insulin formulations that are or have been available in the recent past include:
short duration regular insulin (designated R)
moderate duration NPH insulin (designated N)
moderate duration Lente insulin (designated L)
long duration Ultralente insulin (designated U)
long duration PZI insulin.
Insulin may be derived from bovine, porcine, or human recombinant sources and the concentration may be either 100 units/mL or 40 units/mL. A number of human recombinant insulin analogues are also available.
The types of insulin recommended for use in cats have been complicated by the recent disappearance of many insulin products from the market. The insulin products that are currently available and recommended for use in small animals are listed below:
Short acting:
Regular insulin (Zinc insulin crystals)
Products: Humulin R [Lilly], Novolin R [NovoNordisk] Both human recombinant. 100 U/mL
Moderate acting:
NPH insulin (neutral protamine hagedorn) Complexed with protamine zinc in phosphate buffer
Products: (Humulin N [Lilly], Novolin N [NovoNordisk] Both human recombinant 100 U/mL
Lente insulin (3 parts semilente, seven parts ultralente)
Mix of crystalline and amorphous in acetate buffer
Products: Vetsulin [Intervet] Pure pork insulin (40 U/mL)
Long acting:
PZI insulin
Insulin complexed with protamine and zinc.
Products: PZI Vet, [Idexx] 90% Beef, 10% Pork (40 U/mL)
Glargine insulin long-acting insulin analog
Products: Lantus [Lilly] human recombinant. 100 U/mL
INSULIN THERAPY IN CATS
Regular insulin should be used in any sick or ketoacidotic patient for short term control of the blood glucose until the cat can be transitioned to a longer acting insulin. Insulin products suitable for long-term control of diabetes mellitus in cats include Lente, PZI, and Glargine insulin. NPH insulin, although it can be used in cats, is typically too short acting to result in good long-term glycemic control in most cats.
PZI Insulin
In a study of 67 diabetic cats (34 cats with newly diagnosed DM, and 33 cats with poorly controlled DM), PZI insulin was effective in decreasing BG concentration in 85% of cats and improving clinical signs in 90% of the cats within 45 days of initiating treatment. In this study all cats were treated with PZI twice daily, and the starting dose was 0.4 U/kg/injection. By the end of the study (day 45) the mean insulin dose was 0.9 U/kg/injection. The nadir of the blood glucose occurred at 5 to 7 hours post injection. Hypoglycemia occurred in 31% of the cats and sometimes occurred even when very low insulin doses were used. For this reason it is recommended that the starting insulin dose should be conservative (1 U/cat/injection) with subsequent dose increase made based upon response to treatment. It is important to note that this study used the commercially available PZI insulin (PZI Vet), not compounded PZI insulin, and similar results should not be expected with the products supplied by compounding pharmacies. Because PZI insulin has a well established track record in cats and a large prospective study on response to PZI insulin in cats has been published, PZI insulin is my first choice for treatment of diabetes mellitus in cats although this may change when more data is published on other insulin products in cats. The main disadvantage of PZI insulin is the expense ($82/vial, 20c/unit).
Pork Lente insulin (Vetsulin)
Lente insulin is also a suitable product for use in diabetic cats. Although it is not yet licensed in the US for cats it has been used successfully for years in cats in Europe. The major disadvantage of lente insulin is that it may be ineffective because of short duration of action in some cats. Unfortunately most studies of lente insulin in feline diabetics have used human recombinant insulin which is no longer available. The current lente insulin that is available is a pure pork insulin and the pharmacokinetics of this insulin may differ from that of human recombinant lente insulin. Useful information regarding use of vetsulin in cats . The starting dose for lente insulin in cats (0.25 - 0.5 U/kg/injection) is similar to that of other insulins. Lente insulin should be administered twice a day in cats. Lente insulin is considerably cheaper than PZI insulin (approximately $20/vial, 5c/unit).
Insulin Glargine
Early studies of the long-acting insulin analogue (insulin glargine) have been very promising. In a study of 13 diabetic cats treated with either once daily Glargine insulin at a dose of 0.5 U/kg once a day or lente insulin (human recombinant) 0.5 U/kg, twice a day, there was a significant improvement in both groups of cats and no difference between the two insulin groups. All cats were fed a commercial high protein low carbohydrate diet. Of the 4 cats in remission at the end of the study, 3 had been treated with lente insulin and one with glargine. In a study of 24 newly diagnosed diabetic cats, treated with either glargine, PZI, or lente, and fed a low carbohydrate high protein diet, glargine treated cats tended to have lower blood glucose concentrations and fructosamine concentrations than those treated with PZI or Lente. Glargine insulin resulted in higher remisison rates than did the cats treated with PZI or lente insulin. Despite these promising preliminary results further studies are necessary in larger numbers of diabetic cats. The cost of glargine insulin is approximately $65 /vial, 6.5 c/unit).
General Recommendations for Insulin Treatment in Cats
The starting dose for insulin in a new feline diabetic patient is 0.25 - 0.5 U/kg or 1 - 3 U/cat. It is recommended that PZI insulin should be started at the lower end of this dose.
It is difficult to predict in advance which cats will do better with which insulin formulation. The potency of different insulin formulations may vary from cat to cat, but this is not usually predictable in an individual animal, although longer acting insulins as a rule are less potent than shorter acting insulin. It is therefore important that a blood glucose curve is performed within 5 - 7 days of making any change in insulin formulation. Cats should also be carefully monitored for clinical signs of hypoglycemia, because of the possibility of remission of diabetes mellitus in the cat. Whatever insulin formulation is chosen, twice a day insulin therapy is most likely to result in ideal glycemic control. If this is not possible, once a day therapy with PZI Vet or glargine can result in effective control of clinical signs.
Switching from One Insulin Product to Another
The first step is to evaluate how well regulated the animal is on the current insulin product. Next the clinician should determine the potency of of the new insulin versus old insulin (long acting insulins are less potent than moderate acting insulins). Finally the proposed frequency of administration of the new insulin should be determined. In general better glycemic control can be established in cats (and the likelihood of remission increased) by using twice a day insulin. The new dose should then be determined based on these factors: If animal has good glycemic regulation, if switching to a more potent insulin or increasing the frequency of administration the dose should be decreased by 10 - 25%. If current glycemic control is poor and the potency of the new insulin is the same or less keep the same dose. The final dose should be adjusted based on clinical response, blood glucose curve concentrations (at least 5 - 7 days after the change in insulin formulation), and measurement of fructosamine (2 - 4 weeks after the change in insulin formulation). When switching insulins it is important to educate owners about obtaining and using U40 insulin syringes if you are switching to Vetsulin or PZI Vet. It is NOT recommended to use U100 syringes with U40 insulin by making a dose adjustment. This is liable to lead to serious dosage errors. The owner should also be educated about the clinical signs of hypo-and hyperglycemia, and taught how to manage an episode of suspected hypoglycemia.
DIETARY MANAGEMENT
Dietary management is an important adjunct therapy in management of diabetic cats. Options include a high fiber, moderate carbohydrate and fat diet; or a low carbohydrate/high protein diet; both types of diets have been demonstrated to improve glycemic control in feline diabetic patients. A prospective study comparing a low carbohydrate-low fiber diet to a moderate carbohydrate-high fiber diet in 63 diabetic cats showed improvements in glycemic control in both groups, but there was a higher rate of remission of diabetes mellitus in the low carbohydrate-low fiber diet. These findings support the clinical opinion that low carbohydrate diets in conjunction with good glycemic control increase the likelihood of diabetic remission. Which diet will be the most effective in improving glycemic control in individual patients is unpredictable, although it makes clinical sense to start with a low carbohydrate diet in most cats, and move to a high fiber diet if clinical remission is not achieved with the low carbohydrate diet and better glycemic control is needed. Other factors such as bodyweight of the cat, other concurrent diseases, and diet palatability should also be considered when choosing a diet for a diabetic cat.
POOR RESPONSE TO INSULIN
Clinical signs suggestive of inappropriate response to insulin therapy include recurrence or persistence of clinical signs of DM, disorientation or seizures due to hypoglycemia, or an insulin dose higher than 6U/injection in the cat. Adequate assessment of the cause of the problem requires performing a blood glucose curve. Measurement of fructosamine concentration may also be helpful. In cats receiving twice-daily insulin, most glucose curves can be performed during working hours (8 AM to 6 PM). Based on the results of the blood glucose curve and fructosamine concentration, appropriate recommendations for changes in treatment or further diagnostic testing can then be made. Common problems that may lead to a poor response to insulin include problems with owner administration, inappropriate insulin dose or formulation, insulin induced hypoglycemia, rapid metabolism of insulin, and insulin resistance. It is important , when interpreting the results of blood glucose curves to take into consideration the level of stress of the patient while in the hospital. Other factors such as clinical signs, results of urine blood glucose measurements at home, serum fructosamine concentrations, and changes in physical examination (especially body weight), should be taken into account when interpreting the blood glucose curves.
PATHOPHYSIOLOGY OF DM
Diabetes mellitus (DM) is a common endocrine disease in cats characterized by an absolute or relative deficiency of insulin. This results in a decreased ability of cells to take up and utilize not only glucose, but also amino acids, fatty acids, and electrolytes. In addition the lack of insulin results in increased gluconeogenesis, glycogenolysis, lipolysis, ketogenesis, and protein catabolism. Predisposing factors in cats include obesity, advancing age, and being male.
Two types of DM are recognized in humans, and these classifications can be applied to the disease in cats. Type I DM (insulin dependent diabetes mellitus) is due to an absolute deficiency of insulin. This form of diabetes is characterized by minimal secretory response to ß-cell secretagogues such as glucagons. Type II DM (non-insulin dependent diabetes) is characterized by abnormal insulin secretion and peripheral insulin resistance, and results in a stable reregulation of the blood glucose concentration at a higher concentration. The two types of diabetes are classically distinguished by characteristic responses to challenge by insulin secretagogues such as glucose, glucagons, or arginine. In type I DM, there is a decreased or negligible secretion of insulin compared to normal animals, whereas in type II DM, total insulin secretion may be normal or increased, although the pattern of secretion may be abnormal. The insulin concentration is still insufficient, however, to prevent hyperglycemia. The phenomenon of glucose toxicity complicates interpretation of glucagon tolerance tests, particularly in cats, and the test is of little clinical utility. Currently the true prevalence of type I versus type II diabetes mellitus in diabetic cats is unknown.
DIAGNOSIS
The diagnosis of DM is made based on characteristic clinical signs of diabetes mellitus (polyuria, polydipsia, polyphagia, and weight loss), and documentation of hyperglycemia and glycosuria. In cats diagnosis may be complicated by the occurrence of marked stress hyperglycemia. When making a diagnosis of DM in cats, it is therefore important not only to document persistent hyperglycemia and glycosuria, but also to rule out other diseases that may cause similar clinical signs. Measurement of fructosamine concentration or urine glucose on urine samples collected in the home environment allow the clinician to distinguish between stress induced hyperglycemia (and resultant glycosuria) and persistent hyperglycemia due to diabetes mellitus. Glycosuria may also occur secondary to ketamine anesthesia, chronic renal failure, and postobstructive diuresis. The presence of significant ketonuria together with hyperglycemia, is diagnostic for diabetes mellitus in cats.
Cats are also unique in that DM may be transient or intermittent. In one study, 10 diabetic cats were reported to go into spontaneous remission after 1 to 3 months of therapy. In other studies, up to 70% of cats with DM have been reported to go into spontaneous clinical remission, suggesting that up to 70% of cats may have type II DM. The glucagon tolerance test is not useful in predicting whether or not a cat is likely to go into remission.
TREATMENT OF DIABETES MELLITUS IN CATS
Most diabetic cats should be treated with insulin in conjunction with dietary modification. Oral hypoglycemic drugs such as glipizide can be considered in certain circumstances but are not effective for control of diabetes mellitus in the majority of diabetic cats.
INSULIN
Insulins may be classified by insulin source, insulin formulation, or duration of action of insulin. Not all forms of insulin are currently commercially available and product availability is likely to continue to change. Insulin formulations that are or have been available in the recent past include:
short duration regular insulin (designated R)
moderate duration NPH insulin (designated N)
moderate duration Lente insulin (designated L)
long duration Ultralente insulin (designated U)
long duration PZI insulin.
Insulin may be derived from bovine, porcine, or human recombinant sources and the concentration may be either 100 units/mL or 40 units/mL. A number of human recombinant insulin analogues are also available.
The types of insulin recommended for use in cats have been complicated by the recent disappearance of many insulin products from the market. The insulin products that are currently available and recommended for use in small animals are listed below:
Short acting:
Regular insulin (Zinc insulin crystals)
Products: Humulin R [Lilly], Novolin R [NovoNordisk] Both human recombinant. 100 U/mL
Moderate acting:
NPH insulin (neutral protamine hagedorn) Complexed with protamine zinc in phosphate buffer
Products: (Humulin N [Lilly], Novolin N [NovoNordisk] Both human recombinant 100 U/mL
Lente insulin (3 parts semilente, seven parts ultralente)
Mix of crystalline and amorphous in acetate buffer
Products: Vetsulin [Intervet] Pure pork insulin (40 U/mL)
Long acting:
PZI insulin
Insulin complexed with protamine and zinc.
Products: PZI Vet, [Idexx] 90% Beef, 10% Pork (40 U/mL)
Glargine insulin long-acting insulin analog
Products: Lantus [Lilly] human recombinant. 100 U/mL
INSULIN THERAPY IN CATS
Regular insulin should be used in any sick or ketoacidotic patient for short term control of the blood glucose until the cat can be transitioned to a longer acting insulin. Insulin products suitable for long-term control of diabetes mellitus in cats include Lente, PZI, and Glargine insulin. NPH insulin, although it can be used in cats, is typically too short acting to result in good long-term glycemic control in most cats.
PZI Insulin
In a study of 67 diabetic cats (34 cats with newly diagnosed DM, and 33 cats with poorly controlled DM), PZI insulin was effective in decreasing BG concentration in 85% of cats and improving clinical signs in 90% of the cats within 45 days of initiating treatment. In this study all cats were treated with PZI twice daily, and the starting dose was 0.4 U/kg/injection. By the end of the study (day 45) the mean insulin dose was 0.9 U/kg/injection. The nadir of the blood glucose occurred at 5 to 7 hours post injection. Hypoglycemia occurred in 31% of the cats and sometimes occurred even when very low insulin doses were used. For this reason it is recommended that the starting insulin dose should be conservative (1 U/cat/injection) with subsequent dose increase made based upon response to treatment. It is important to note that this study used the commercially available PZI insulin (PZI Vet), not compounded PZI insulin, and similar results should not be expected with the products supplied by compounding pharmacies. Because PZI insulin has a well established track record in cats and a large prospective study on response to PZI insulin in cats has been published, PZI insulin is my first choice for treatment of diabetes mellitus in cats although this may change when more data is published on other insulin products in cats. The main disadvantage of PZI insulin is the expense ($82/vial, 20c/unit).
Pork Lente insulin (Vetsulin)
Lente insulin is also a suitable product for use in diabetic cats. Although it is not yet licensed in the US for cats it has been used successfully for years in cats in Europe. The major disadvantage of lente insulin is that it may be ineffective because of short duration of action in some cats. Unfortunately most studies of lente insulin in feline diabetics have used human recombinant insulin which is no longer available. The current lente insulin that is available is a pure pork insulin and the pharmacokinetics of this insulin may differ from that of human recombinant lente insulin. Useful information regarding use of vetsulin in cats . The starting dose for lente insulin in cats (0.25 - 0.5 U/kg/injection) is similar to that of other insulins. Lente insulin should be administered twice a day in cats. Lente insulin is considerably cheaper than PZI insulin (approximately $20/vial, 5c/unit).
Insulin Glargine
Early studies of the long-acting insulin analogue (insulin glargine) have been very promising. In a study of 13 diabetic cats treated with either once daily Glargine insulin at a dose of 0.5 U/kg once a day or lente insulin (human recombinant) 0.5 U/kg, twice a day, there was a significant improvement in both groups of cats and no difference between the two insulin groups. All cats were fed a commercial high protein low carbohydrate diet. Of the 4 cats in remission at the end of the study, 3 had been treated with lente insulin and one with glargine. In a study of 24 newly diagnosed diabetic cats, treated with either glargine, PZI, or lente, and fed a low carbohydrate high protein diet, glargine treated cats tended to have lower blood glucose concentrations and fructosamine concentrations than those treated with PZI or Lente. Glargine insulin resulted in higher remisison rates than did the cats treated with PZI or lente insulin. Despite these promising preliminary results further studies are necessary in larger numbers of diabetic cats. The cost of glargine insulin is approximately $65 /vial, 6.5 c/unit).
General Recommendations for Insulin Treatment in Cats
The starting dose for insulin in a new feline diabetic patient is 0.25 - 0.5 U/kg or 1 - 3 U/cat. It is recommended that PZI insulin should be started at the lower end of this dose.
It is difficult to predict in advance which cats will do better with which insulin formulation. The potency of different insulin formulations may vary from cat to cat, but this is not usually predictable in an individual animal, although longer acting insulins as a rule are less potent than shorter acting insulin. It is therefore important that a blood glucose curve is performed within 5 - 7 days of making any change in insulin formulation. Cats should also be carefully monitored for clinical signs of hypoglycemia, because of the possibility of remission of diabetes mellitus in the cat. Whatever insulin formulation is chosen, twice a day insulin therapy is most likely to result in ideal glycemic control. If this is not possible, once a day therapy with PZI Vet or glargine can result in effective control of clinical signs.
Switching from One Insulin Product to Another
The first step is to evaluate how well regulated the animal is on the current insulin product. Next the clinician should determine the potency of of the new insulin versus old insulin (long acting insulins are less potent than moderate acting insulins). Finally the proposed frequency of administration of the new insulin should be determined. In general better glycemic control can be established in cats (and the likelihood of remission increased) by using twice a day insulin. The new dose should then be determined based on these factors: If animal has good glycemic regulation, if switching to a more potent insulin or increasing the frequency of administration the dose should be decreased by 10 - 25%. If current glycemic control is poor and the potency of the new insulin is the same or less keep the same dose. The final dose should be adjusted based on clinical response, blood glucose curve concentrations (at least 5 - 7 days after the change in insulin formulation), and measurement of fructosamine (2 - 4 weeks after the change in insulin formulation). When switching insulins it is important to educate owners about obtaining and using U40 insulin syringes if you are switching to Vetsulin or PZI Vet. It is NOT recommended to use U100 syringes with U40 insulin by making a dose adjustment. This is liable to lead to serious dosage errors. The owner should also be educated about the clinical signs of hypo-and hyperglycemia, and taught how to manage an episode of suspected hypoglycemia.
DIETARY MANAGEMENT
Dietary management is an important adjunct therapy in management of diabetic cats. Options include a high fiber, moderate carbohydrate and fat diet; or a low carbohydrate/high protein diet; both types of diets have been demonstrated to improve glycemic control in feline diabetic patients. A prospective study comparing a low carbohydrate-low fiber diet to a moderate carbohydrate-high fiber diet in 63 diabetic cats showed improvements in glycemic control in both groups, but there was a higher rate of remission of diabetes mellitus in the low carbohydrate-low fiber diet. These findings support the clinical opinion that low carbohydrate diets in conjunction with good glycemic control increase the likelihood of diabetic remission. Which diet will be the most effective in improving glycemic control in individual patients is unpredictable, although it makes clinical sense to start with a low carbohydrate diet in most cats, and move to a high fiber diet if clinical remission is not achieved with the low carbohydrate diet and better glycemic control is needed. Other factors such as bodyweight of the cat, other concurrent diseases, and diet palatability should also be considered when choosing a diet for a diabetic cat.
POOR RESPONSE TO INSULIN
Clinical signs suggestive of inappropriate response to insulin therapy include recurrence or persistence of clinical signs of DM, disorientation or seizures due to hypoglycemia, or an insulin dose higher than 6U/injection in the cat. Adequate assessment of the cause of the problem requires performing a blood glucose curve. Measurement of fructosamine concentration may also be helpful. In cats receiving twice-daily insulin, most glucose curves can be performed during working hours (8 AM to 6 PM). Based on the results of the blood glucose curve and fructosamine concentration, appropriate recommendations for changes in treatment or further diagnostic testing can then be made. Common problems that may lead to a poor response to insulin include problems with owner administration, inappropriate insulin dose or formulation, insulin induced hypoglycemia, rapid metabolism of insulin, and insulin resistance. It is important , when interpreting the results of blood glucose curves to take into consideration the level of stress of the patient while in the hospital. Other factors such as clinical signs, results of urine blood glucose measurements at home, serum fructosamine concentrations, and changes in physical examination (especially body weight), should be taken into account when interpreting the blood glucose curves.
