Diabetes mellitus: Rule out administration problems first in uncontrolled cats
Q: Could you review the causes and management of diabetes mellitus in older cats?
A: To answer this important question I referred to the recent article: Rand J: Understanding feline diabetes and its management. Proc 20th Annual Forum ACVIM 20:29-30, 32-34, 2002. An abbreviated summary of this article follows.
Diabetes mellitus in animals may be type 1, type 2, or other specific types. Type 1 diabetes is an uncommon cause of diabetes mellitus in cats. Type 2 diabetes appears to be the most common form of diabetes mellitus in cats and is characterized by inadequate insulin secretion and impaired insulin action - commonly referred to as insulin resistance.
Altered pancreatic beta cell function is usually progressive and, in some cats, results in complete loss of insulin secretion. Few diabetic cats have other specific types of diabetes mellitus, previously called type 3 diabetes. Various diseases are causes of the other types of diabetes mellitus resulting in non-specific destruction of pancreatic tissue. The most frequent diseases are pancreatitis and pancreatic adenocarcinoma; neoplasia accounting for up to 19 percent of feline diabetes mellitus cases. Extremely rare causes of naturally occurring insulin resistance in cats include growth-hormone producing tumors resulting in acromegaly and hyperadrenocorticism.
Iatrogenic administration of megestrol acetate or long-acting steroids (such as commonly used depo-medrol) is associated with the development of diabetes mellitus in some cats. It is quoted that diabetic cats are approximately six times less sensitive to insulin than normal cats.
Obesity, related factors
Obesity is a recognized risk factor for the development of diabetes mellitus in cats. Obesity decreases insulin sensitivity by one-half and, in some obese cats, insulin sensitivity decreases to even lower levels. Low insulin sensitivity results in hyperinsulinemia and eventually leads to beta cell death. In some families of cats, there is strong evidence for a genetic basis for the disease.
Environmental influences interact with genetic influences and play an important role in the development of diabetes mellitus in cats. The lifestyle of many domestic cats has changed with physical inactivity and obesity increasing in urban cats.
Exclusively indoor cats are usually less active than outdoor domestic cats that hunt and defend their territory, and these cats are significantly less active than feral cats that have to hunt for all their nutrition. Neutered male cats outnumber neutered female cats with diabetes mellitus by 1.5:1. Male cats are at greater risk of obesity than females.
When fed ad lib, male cats gain more weight than female cats. In addition, male cats tend to have lower insulin sensitivity than female cats when lean that deteriorates further with weight gain. The propensity of male cats to have underlying low insulin sensitivity coupled with weight gain problems may explain their increased risk of diabetes mellitus.
In susceptible cats, the long-term demand for increased insulin secretion may lead to beta cell destruction and a decline in insulin secretory capacity.
Many, but not all, cats with type 2 diabetes have amyloid deposition replacing islets cells. Amyloid deposition does not appear to be an essential component of type 2 diabetes in cats but contributes to beta cell loss and failure of insulin secretion. Islet amyloid is formed from the beta cell hormone amylin, which is secreted along with insulin. Formation of intracellular amylin fibrils is toxic to beta cells. Cats with high amylin concentrations tend to have more profound amyloid deposition.
Obesity likely contributes to amyloid deposition in susceptible cats by stimulating hyperamylinemia and hyperinsulinemia.
Once persistent hyperglycemia occurs, insulin secretion is reduced through a phenomenon referred to as glucose toxicity. The severity of this glucose toxic effect is dependent on the degree of hyperglycemia and the duration. It is, therefore, vital that therapy be instituted as soon as possible to reduce hyperglycemia in diabetic cats if any beta cell function is to be preserved. Therapy is also important because a substantial number of cats will undergo remission of their diabetes mellitus if the effects of glucose toxicity are minimized.
Chronically elevated blood glucose also causes insulin resistance. When overt diabetes mellitus with persistent hyperglycemia occurs, the added insulin resistance further adds to the problem of inadequate insulin secretion. Once glucose concentrations are decreased with treatment, insulin sensitivity may improve.
The diagnosis of diabetes mellitus in cats is not simple. Clinical signs, such as polydipsia/polyuria, weight loss or polyphagia are non-specific and cannot be confirmed by physical examination. Diagnosis in cats is also complicated by stress hyperglycemia, which in sick, non-diabetic cats may lead to glycosuria or blood glucose levels in excess of 360 mg/dl.
Blood glucose concentration in non-diabetic, unstressed cats is usually less than 180 mg/dl. When sampling blood, it is very important to avoid struggling with the cat, because this will cause a transient hyperglycemia. Blood glucose concentration should be measured several hours after the first sample to confirm persistent hyperglycemia, especially if the blood glucose concentration is 360 mg/dl or greater.
Signs of diabetes mellitus occur once blood glucose concentration exceeds the renal threshold, which is approximately 288 mg/dl for most cats. If there is doubt whether the hyperglycemia is transient, associated with stress or from diabetes mellitus in sick cats, it is prudent to begin insulin therapy and monitor glucose concentrations carefully for the next few days. Reducing glucose concentrations with exogenous insulin reduces the suppressive effect of glucose toxicity and makes recovery of beta cells more likely.
The approach outlined next is much more controversial. Because glucose toxicity can reduce insulin secretion in normal cats to levels of insulin-dependent diabetic cats within three to seven days, do not wait to begin insulin therapy if blood glucose concentration is 270 mg/dl or higher. Likewise, in cats with iatrogenic or spontaneous hyperadrenocorticism or acromegaly, begin insulin therapy immediately to preserve remaining beta cells. Therapy for the underlying disease can then be instituted and glucose concentrations monitored to adjust insulin dose. Do not wait to see if the diabetes resolves once the underlying disease process is treated or the exogenous hormone eliminated, because this makes permanent diabetes mellitus more likely.
Treatment of diabetic cats is to control the clinical signs of diabetes mellitus, such as weight loss, polydipsia/polyuria, and polyphagia or inappetence, and to prevent diabetic ketoacidosis. Additionally, one wants to reduce the risk of hypoglycemia by appropriate dose adjustment of insulin or oral hypoglycemic agents. Although currently it is not possible at diagnosis to predict which cats are more likely to go into remission, appropriate therapy may lead to diabetic remission.
In cats, postprandial hyperglycemia is mild but very prolonged, up to 18-24 hours, in cats fed typical cat foods. The initial increase in blood glucose concentration occurs about two to four hours after eating. Therefore, it is not necessary to match the timing of the insulin administration to meals. Once eating normally, a diabetic cat with a healthy body weight should be fed a good quality feline diet free choice to maintain its healthy body weight. A high protein, low carbohydrate diet is advantageous, such as a feline growth diet, in the hyperglycemic cat. When the diabetes mellitus becomes stabilized with therapy, body weight often increases. If the cat starts to become overweight, calories should be restricted to maintain ideal body weight.
Alternatively, the cat could be changed to a moderately calorie-restricted diet, such as a geriatric diet, or a diet for less-active cats, although these tend to have higher levels of carbohydrate.
About 5-30 percent of diabetic cats achieve good clinical control with oral hypoglycemic drugs. Glipizide is the only hypoglycemic drug with well-documented effectiveness in the treatment of diabetic cats. The dosage of glipizide is 2.5 mg twice daily, regardless of the body weight of the cat. Because glipizide may cause transient elevation of serum liver enzymes and in some cases icterus, monitoring of serum liver enzymes is recommended during glipizide treatment.
The preferred treatment in diabetic cats is injectable insulin. The choice of insulin for the diabetic cat centers around minimizing the number of injections required each day while still achieving adequate diabetic control.
Insulins used for daily maintenance are those either of intermediate duration (lente or NPH) or long-acting duration [ultralente or protamine zinc insulin (PZI)]. Despite the variation in insulin types used, no correlation has been found between the type of insulin and diabetic control.
Hypoglycemia most likely occurs in the first four months after beginning insulin therapy. It can be life threatening. Cats should be carefully watched for evidence of hypoglycemia (dazed, trembling, weakness, wobbly gait, seizures and coma) and the insulin dosage decreased.
The lente insulins have a more predictable onset and duration of effect in cats than the longer-acting insulins.
Porcine lente insulin is available in many countries as a proprietary veterinary product. Porcine lente insulin is administered twice daily in all diabetic cats. The recommended starting dose is 0.25-0.5 unit per kg body weight.
NPH insulin has a similar but slightly shorter duration of action than lente insulin and usually is administered twice daily. Human ultralente insulin can be used once daily in many cats, but most cats will require treatment twice daily. The long-acting insulin PZI insulin is available as a veterinary product (40 U/ml, IDEXX). It can be used once daily in some cats, but should typically be administered twice daily. As with other long-acting insulins, it has a more variable onset and duration of action than shorter-acting insulins. Prolonged marked hypoglycemia may occur in some cats on PZI insulin, and in some cats, glycemic control is poor. PZI insulin is particularly useful for cats in which the duration of action of lente insulin is too short to give adequate glycemic control, and when owners are unwilling to give twice-daily injections.
Many cats have reasonable clinical control with PZI insulin, but cats that do not achieve good control should be tried on shorter-acting insulin such as lente insulin, before the poor control is attributed to insulin resistance.
In some cats, blood glucose concentration does not decrease significantly and control of clinical signs is poor when using the longer-acting insulins (human or bovine ultralente or PZI insulin), even when dosages of 1 U/kg or greater are used. A change to a better absorbed, shorter-acting insulin (lente or NPH) may improve diabetic control in these cats.
The new insulin analogue, insulin glargine (Lantus), is long-acting and released for human use. Initial information shows that like other long-acting insulins, there is considerable variation between cats and within the same cat in onset, duration and degree of action. Also, prolonged hypoglycemia is a risk. In cats, insulin glargine is not peakless. Initial information indicates it is likely useful in diabetic cats and can be given once or twice daily depending on the individual cat. However, duration of action is not significantly different from PZI insulin in normal cats. Starting dose rates are 0.25 U/kg twice daily or 0.5 U/kg daily. Prolonged hypoglycemia is possible with long-acting insulins, and cats should be monitored carefully to avoid hypoglycemia.
The type of insulin chosen and baseline blood glucose concentration of the cat determine the initial dose of insulin. Insulins that have a longer duration of action do not tend to lower the blood glucose concentration as much as the same dose of shorter-acting insulin.
The recommended starting dose is 0.25-0.5 unit per kg body weight. The blood glucose response should be re-evaluated every two to four weeks (or immediately if clinical hypoglycemia occurs) until good control is attained. If clinical hypoglycemia occurs, the insulin dose should immediately be decreased by 50 percent, and a serial blood glucose curve performed for the new dose. If lente or NPH insulin is being used and diabetic control is poor, two circumstances may warrant a change to longer-acting insulin (ultralente or PZI insulin). Consider the change if:
* the insulin is having a rapid peak of action (within two to three hours) and a short duration of effect (six to seven hours),
* and/or if a low nadir blood glucose is occurring despite the average blood glucose concentration remaining high.
Monitoring diabetics cats
Evidence for good clinical control includes an active cat with a healthy appearance, a stable body weight, and levels of polydipsia and polyuria acceptable to the owner and veterinarian. Water intake can be measured at home or in the hospital, and is a better indicator of average blood glucose concentration than serum fructosamine concentration.
Water intake may vary substantially from day to day; therefore, measurement of water intake for more than a single day, preferably over a week, should be done. A water intake of less than 20 ml/kg body weight daily indicates exemplary diabetic control.
Most cats with good control drink less than 80 ml/kg body weight daily. Other clinical signs, such as a stable body weight and the presence or absence of lethargy, should also be monitored. Making insulin dosage rate changes on the basis of serum fructosamine measurements should be done with caution, as the serum fructosamine level does not give an indication of the nadir blood glucose concentration.
However, serum fructosamine level may be a useful marker where stress or fractiousness makes an accurate serial blood glucose curve unobtainable.
Urine glucose also does not give information about how an insulin dosage should be changed, and is most useful for indicating or predicting diabetic remission. If the cat becomes aglycosuric, this may indicate diabetic remission has occurred. And, the insulin administration can be discontinued for several days while the urine glucose is monitored daily. If glycosuria recurs, it may be necessary to perform a serial blood glucose curve to determine the subsequent insulin dose.
When cats treated with insulin fail to stabilize, a number of underlying causes and approaches to treatment should be considered. It is important to remember that many cats take one to four months to stabilize. The temptation to "over-adjust" the insulin dosage should be avoided.
It is unrealistic to expect good glucose control after only two to four weeks of diet and insulin treatment. The most common problems resulting in poor glucose control are excessive dose, miscalculation of dose, too short duration of insulin action or poor absorption of insulin. Some cats are mistakenly labeled problem cats when the clinical signs are well controlled, but blood glucose measurements are less than ideal.
If the glucose nadir is below 182 mg/dl after each insulin injection, peak action occurs more than three hours after administration and hypoglycemia is not occurring, glycemic control is usually adequate. These cats usually have good clinical control (stable body weight, good coat condition, active, alert, water intake less than 100 ml/kg daily).
Uncontrolled cats have persistent clinical signs including polydipsia (water intake of more than 100 ml/kg daily), low body condition score, polyphagia, lethargy and a poor hair coat; an insulin dose higher than normal (1.5-2.0 or more U/kg per injection); and either a nadir glucose more than 180 mg/dl or hypoglycemia.
For problem-solving in uncontrolled cats, it is important to first ruleout administration problems - expired insulin, heat-affected insulin (such as left in a car in summer), poor mixing of suspensions, failure of administration (injecting through the skin pinch onto the hair coat), and the presence of air bubbles in the syringe causing a lower administered dose. Insulin syringes can be difficult to manage for elderly owners with arthritic hands and poor vision. These owners are often better able to cope with insulin pens. Misunderstandings between the owner and veterinarian regarding the number of units to be administered can cause problems.
If the cat has been treated for at least eight to 12 weeks and insulin is being correctly administered but poor control is still evident, measure water intake over consecutive days at home (measure serum fructosamine concentration if water intake cannot be measured), and obtain a blood glucose curve.
Poor control may result from an excessive insulin dosage, and cause apparent insulin resistance (dosage is greater than 1.5-2.0 units per injection with persistent hyperglycemia) or short duration of insulin action.
If the cat is polydipsic and insulin seems to have little effect, especially when previously it caused substantial lowering of glucose, or the duration of action seems to be short, it is safer to first try lowering the dose of insulin to 0.3-0.5 U/kg for 10-14 days to see if blood glucose or water intake improve. This is particularly useful in cats on potent insulins such as lente or NPH insulin.
If clinical control is not improved with a lower dose, check the blood glucose response to a standard dose of 0.5 U/kg of insulin, to determine the duration of effect. If the blood glucose nadir occurs two to three hours after injection, switch to a longer-acting insulin or increase the frequency of administration to three times daily.
Similarly with PZI insulin, if the nadir occurs at less than six hours, change to twice-daily administration if the cat is receiving insulin once daily. With PZI or ultralente insulin, if there is little response, try using lente or NPH insulin as some cats seem to have poor absorption with the longer-acting insulins.
If there is still polydipsia (water intake is more than 100 ml/kg daily) and little glycemic response to a more potent insulin, check the cat for hyperthyroidism, hyperadrenocorticism, acromegaly or other systemic disease such as renal failure. Glycemic control may improve in cats with periodontal disease following dental procedures in combination with short-term antibiotics.
In the meantime, increase the dosage by one unit every two weeks until some glycemic response is achieved. Warn the owner that a severe hypoglycemic episode can occur with this approach and to be vigilant regarding the early signs (lethargy, mental dullness, wobbliness, trembling and dilated pupils).