Clinically, diabetes mellitus is classified as insulin-dependent (IDDM) or noninsulin-dependent (NIDDM) based on the cat's need for insulin treatment. Cats may have an apparent sudden and complete absence of insulin secretion and require insulin treatment beginning at the time diabetes is diagnosed (ie, IDDM). Alternatively cats may gradually lose the ability to secrete insulin as β cells are destroyed slowly by progressively worsening islet amyloidosis or vacuolar degeneration. Affected cats may have an initial period where hyperglycaemia can be controlled with treatments other than insulin (ie, NIDDM), however, β cell dysfunction eventually becomes severe and IDDM develops. Diabetes can be frustrating in cats, in part because of the variable severity of pancreatic β cell destruction between cats and the impact of concurrent glucose toxicity and insulin-antagonistic disorders (eg, obesity, chronic pancreatitis) on β cell function at the time diabetes is diagnosed. As a consequence, diabetic cats can initially appear to have NIDDM which progresses to IDDM, flip back and forth between IDDM and NIDDM as severity of insulin resistance and suppression of beta cell function waxes and wanes or revert to a subclinical diabetic state that does not require treatment. Apparent changes in the diabetic state (ie, IDDM and NIDDM) are understandable when one realises that islet pathology in diabetic cats may be mild to severe and progressive or static; that the ability of the pancreas to secrete insulin depends on the severity of islet pathology and can decrease with time; that responsiveness of tissues to insulin varies, often in conjunction with the presence or absence of concurrent inflammatory, infectious, neoplastic or hormonal disorders; and that all these variables affect the cat's need for insulin, insulin dosage and ease of diabetic regulation.
Initial insulin therapy in diabetic cats
Type of insulin
Protamine zinc insulin (PZI) has been the primary insulin used to treat diabetes mellitus in cats. Unfortunately, the manufacturer (Eli Lilly Co., Indianapolis, IN, USA) discontinued production and distribution of PZI in December 1991, and ultralente, lente and NPH insulin have subsequently been used in lieu of PZI. Ultralente is a less potent, longer-acting insulin than NPH and lente insulin. During the past decade, it has become apparent that establishing control of glycaemia in diabetic cats can be problematic with use of these insulins, in part because of slow absorption of ultralente insulin from the subcutaneous site of deposition and because of short duration of effect of lente and NPH insulin, even when administered twice a day. Inadequate absorption of ultralente insulin resulting in poor control of glycaemia despite insulin doses of 8–10 U per injection is a problem in approximately 20% of diabetic cats treated with ultralente insulin in our hospital. For these cats, a switch to lente or NPH insulin at an initial dosage of 1–2 U per cat twice a day is often effective in establishing better control of glycaemia. In contrast, duration of effect of lente and NPH insulin can be considerably shorter than 12 h, resulting in persistence of clinical signs of diabetes. For these cats, a switch to ultralente insulin at an initial dosage of 1–2 U per cat twice a day is often effective in establishing better control of glycaemia. Unfortunately, it is not possible to predict which type of insulin will work best in individual diabetic cats. The initial insulin of choice ultimately is based on personal preference and experiences. We initially use lente or ultralente of recombinant human origin at a dosage of 1–2 U per cat administered twice daily.
Antigenicity of recombinant human insulin
Insulin antibodies result from repeated injections of a foreign protein (ie, insulin). The more divergent the insulin molecule being administered from the species being treated, the greater the likelihood that significant or worrisome concentrations of insulin antibodies will be formed. The amino acid sequence of cat and beef insulin are similar, but differences exist between cat, pork and human insulin. Studies using an ELISA to detect insulin antibodies in serum of insulin-treated diabetic cats identified an approximately equal frequency of positive serum insulin antibody titres in diabetic cats treated with beef insulin, compared with recombinant human insulin. However, titres were weakly positive in most cats, prevalence of persistent titres was low, and presence of serum insulin antibodies did not appear to affect control of glycaemia. These results suggest that the prevalence of insulin antibodies causing problems with control of glycaemia similar to those identified in dogs is uncommon in cats treated with recombinant human insulin. Overt insulin resistance caused by insulin antibody formation occurs in less than 5% of cats treated with recombinant human insulin.
Beef/pork-source protamine zinc insulin (PZI)
Protamine zinc insulin (PZI) is a long acting preparation of beef/pork-source insulin used to treat diabetes mellitus in cats. Since the original manufacturer (Eli Lilly) discontinued production of PZI, beef/pork-source and recombinant human ultralente, lente and NPH insulin have been used to treat diabetes in cats. Recently, compounded PZI preparations have been provided by pharmacists at the request of veterinarians for use in diabetic cats that have been poorly responsive to ultralente, lente and NPH insulin. In our experience, these preparations have been inconsistent in improving control of glycaemia in diabetic cats. In 1998, an animal health pharmaceutical company (Blue Ridge Pharmaceuticals Inc., Greensboro, NC, USA) resumed production of PZI using the same methods as the original manufacturer. It is currently under review by the United States FDA for treating diabetes mellitus in cats. To date, only absorption kinetics of PZI administered to healthy and a small number of diabetic cats and a retrospective study evaluating the response of 14 diabetic cats to treatment with PZI have been published. Marked variability in absorption kinetics of PZI has been identified in cats. Time to peak blood insulin concentration ranged from 4 to 12 h, time of the blood glucose nadir from 1 to 12 h, and time for blood insulin concentration to return to baseline from 8 to 24 h after SC administration of PZI to healthy and diabetic cats. Historically, PZI was typically administered only once per day to diabetic cats; a frequency of administration that was based more on clinical perceptions of response to treatment than absorption kinetic studies.
A multicentre study evaluating PZI for the treatment of diabetes mellitus was recently completed. Newly-diagnosed diabetic cats and previous insulin-treated diabetic cats with poor control of glycaemia were entered into the study. Most of the previous insulin-treated diabetic cats were treated with ultralente or NPH insulin. Beef/pork-source protamine zinc insulin was administered twice daily in this study because of prior clinical experience suggesting that control of glycaemia is best for most diabetic cats when PZI is administered twice a day.
Beef/pork-source PZI was effective in decreasing blood glucose concentrations and establishing control of glycaemia within 45 days of initiating treatment in 85 and 90% of 67 diabetic cats enrolled in the study when control of glycaemia was based on serum fructosamine concentration and owner perception of response to therapy, respectively. Results of blood glucose measurements obtained throughout the day suggest that twice daily PZI administration is appropriate for most diabetic cats. The only adverse effect associated with PZI treatment was hypoglycaemia. Considerable overlap in the range of PZI dosages that induced hypoglycaemia, established control of glycaemia, and had not established control of glycaemia by day 45 of treatment was identified in this study. These findings suggest the dosage at the time PZI is initiated should be low (eg, 1 U/cat/injection) to avoid hypoglycaemia, and subsequent increases in the PZI dosage should be based on owner perception of their cat's response to PZI treatment, changes in the physical examination and bodyweight, and results of blood glucose and serum fructosamine measurements. Results of this study also suggest that PZI may become the initial insulin of choice for treating diabetic cats, once it becomes readily available. However, as with the other types of insulin, response to PZI insulin is unpredictable.
Identification and control of concurrent disorders
Identification and treatment of concurrent disease plays an integral role in the successful management of the diabetic cat. Any concurrent inflammatory, infectious, hormonal or neoplastic disorder can cause insulin resistance by stimulating secretion of one or more of the diabetogenic hormones (ie, glucagon, epinephrine, cortisol, growth hormone). The most common concurrent disorders interfering with insulin effectiveness in cats include severe obesity, chronic pancreatitis, renal insufficiency, hyperthyroidism, oral infections, acromegaly and hyperadrenocorticism. Some disorders (eg, hyperadrenocorticism, acromegaly) cause obvious severe insulin resistance while others (eg, chronic pancreatitis, gingivitis) cause subtle insulin resistance that results in erratic control of glycaemia. A thorough physical examination and complete diagnostic evaluation (including CBC, serum biochemistry panel serum T4, urinalysis and abdominal ultrasound) are imperative in any newly-diagnosed or poorly-controlled diabetic cat. Improvement in insulin resistance and control of glycaemia often occurs after resolution or control of concurrent disorders.
Perhaps the most significant disorder deleteriously affecting glycaemic control in diabetic cats is chronic pancreatitis, which has been identified at necropsy in approximately 50% of diabetic cats seen at our hospital. Most of these cats have a similar history, characterised by poorly-controlled diabetes, fluctuating insulin requirements, blood glucose concentrations often >17 mmol/l, intermittent lethargy and inappetence, and owner concerns that their pet is ‘just not doing well’. An inability to correct these problems has ultimately led to euthanasia of many of these cats. Documentation of chronic pancreatitis can be difficult and must rely on a combination of clinical signs, physical examination findings, routine blood work and, most importantly, ultrasound evaluation of the pancreas. There are no classic alterations identified on the CBC, serum biochemistry panel and urinalysis which consistently support chronic pancreatitis. The most common findings have been a mild neutrophilic leukocytosis (total WBC, <25 000/μl) and increase in total bilirubin concentration (0.5 to 1.0 mg/dl). However, failure to identify these abnormalities does not rule out chronic pancreatitis. Serum amylase and lipase concentrations have not been helpful in establishing the diagnosis and results of serum trypsin-like immunoreactivity (TLI) have been inconsistent. Normal serum TLI concentrations are common in diabetic cats with chronic pancreatitis. Identification of pancreatic enlargement and either a mixed hypo- and hyperechoic or predominant hyperechoic pattern to the pancreas have been the most reliable findings in diabetic cats with chronic pancreatitis. Treatment revolves around intravenous fluids, diet and anti-inflammatory doses of prednisone but a successful outcome is difficult to maintain and many affected cats continue to suffer relapses.
Monitoring glycaemic control—what constitutes poor control of glycaemia?
The basic objective of insulin therapy is to eliminate the clinical signs of diabetes mellitus while avoiding the common complications associated with the disease. Common complications in cats include weight loss, peripheral neuropathy of the hind limbs causing weakness and ataxia, hypoglycaemia, and poor control of glycaemia secondary to concurrent infection, inflammation, neoplasia or hormonal disorders. The devastating chronic complications of human diabetes (eg, nephropathy vasculopathy, coronary artery disease) take 10–20 years or longer to develop and are uncommon in diabetic cats. As such, the need to establish near normal blood glucose concentrations is not necessary.
Recent studies on response of diabetic cats to insulin therapy suggest that owners are happy and cats are healthy and relatively asymptomatic if most blood glucose concentrations are kept below 14 mmol/l. Our initial determination of good vs poor control of glycaemia is based on owners’ subjective opinion of severity of clinical signs and overall health of their pet, findings on physical examination, and stability of body-weight. If the owner is happy with results of treatment, the physical examination is supportive of good glycaemic control, and the body-weight is stable, the diabetic cat is usually adequately controlled. Poor control of glycaemia should be suspected and additional diagnostics (ie, blood glucose curve) considered if the owner reports clinical signs (ie, polyuria, polydipsia, lethargy, signs of hypoglycaemia), the physical examination identifies problems consistent with poor control of glycaemia (eg, thin, lack of grooming, poor hair coat, peripheral neuropathy) or the cat is losing weight.
Identifying a blood glucose concentration between 6 and 14 mmol/l at the time of the physical examination also supports insulin effectiveness. Documenting an increased blood glucose concentration (ie, >17 mmol/l) does not, by itself, confirm poor control of glycaemia. Stress can cause marked hyperglycaemia which does not reflect the cat's responsiveness to insulin and can lead to the erroneous belief that the diabetic cat is poorly controlled. If a discrepancy exists between the history, physical examination findings and blood glucose concentration or if the cat is fractious and blood glucose concentrations are known to be unreliable, measurement of serum fructosamine concentration should be considered to further evaluate status of glycaemic control. Fructosamines are glycated proteins found in blood that are used to monitor glycaemic control. Fructosamines result from an irreversible, non-enzymatic, insulin-independent binding of glucose to serum proteins. The extent of glycosylation of serum proteins is directly related to the blood glucose concentration; the higher the serum fructosamine concentrations, the poorer the glycaemic control of the patient, and vice versa. Serum fructosamine concentrations are not affected by acute stress-induced hyperglycaemia. Serum fructosamine concentrations can be measured to clarify the impact of stress on results of blood glucose measurements and discrepancies between the history, findings on physical examination, and results of blood glucose measurements. Ideally, serum fructosamine concentrations should be less than 450 μmol/l in the well-controlled diabetic cat. The higher the serum fructosamine concentration above 450 μmol/l, the worse the control of glycaemia. Serum fructosamine values greater than 600 μmol/l are very high and consistent with complete lack of control of the diabetic state. Increased serum fructosamine concentrations suggest poor glycaemic control and a need for insulin adjustments; however, fructosamine concentrations do not identify the underlying problem. Adjustments in insulin therapy should be based on a review of historical information regarding prior response to various insulin treatments utilised in the cat, critical evaluation of the current insulin treatment regimen for possible problems (eg, excessive dose causing the Somogyi effect, once a day insulin administration, poor absorption of ultralente insulin) and, if valid, interpretation of serial blood glucose measurements following insulin administration.