Felipedia

Diabetes mellitus ("sugar" diabetes) is a complex and common endocrine disorder in the cat. It is caused either by insufficient production of the hormone, insulin, by the pancreas (Type 1 diabetes) or by inadequate response of the body's cells to insulin (Type 2 diabetes). Because diabetic cats are not able to utilize glucose properly, they ultimately develop hyperglycaemia (high blood sugar levels) and subsequent glucosuria (sugar in the urine). The glucosuria leads to polyuria (excessive urination) and polydipsia (excessive thirst). In spite of maintaining a good appetite, diabetic cats lose weight because the body's tissues are unable to utilize glucose properly. Progression of the disease ultimately leads to further metabolic disturbances and causes vomiting, loss of appetite, weakness, and dehydration. Although affecting cats of any breed, sex, or age, diabetes mellitus most often occurs in older, obese individuals; males are more commonly afflicted than females. The exact cause of the disease in cats is not known, although genetic predisposition, obesity, pancreatic disease, hormonal imbalances, and certain medications have all been incriminated. After a period of time, a small percentage of diabetic cats lose their requirement for specific therapy with either insulin or hypoglycaemic medications¹⁴.

In human diabetes, Type 1 refers to the condition seen in people who are generally lean, young and prone to ketogenesis. Type 2 DM usually occurs in older humans who are often obese but is less prone to the development of ketogenesis.. Type 1 DM patients require insulin therapy while Type 2 may be controlled at least initially with weight loss, diet and oral hypoglycaemic agents¹².

In cats, the classification is not as clear. Generally, diabetes is a disorder of the older, often overweight cat, more similar to the Type 2 DM in humans. However, often by the time the diagnosis of diabetes is made, the cats are insulin dependant although most are not prone to ketogenesis. In addition to these differences, cats may develop diabetes secondary to primary pancreatic disease, endocrinopathies (acromegaly or hyperadrenocorticism), or drug therapy (glucocorticoids and progestins). Insulin resistant diabetes may develop as a consequence of hyperadrenocorticism, acromegaly and pituitary adenomas.

In Type 1 DM, there is beta cell depletion, resulting in absolute insulin deficiency. In Type 2 DM, the problem is one of insulin receptor and post-receptor defects, causing impaired insulin uptake by tissues. This insulin resistance and associated hyperglycaemia causes the beta cells to produce more insulin. This state is one of relative insulin deficiency. Obese cats appear to have a defect in insulin secretion along with a lower tissue sensitivity to insulin. Weight loss results in an improvement in tissue sensitivity, thus weight loss is not only helpful but also imperative in treatment.

Another important feature about diabetes in cats is that pancreatic islet amyloid deposits are believed to interfere with insulin secretion and that oral hypoglycaemic drugs such as sulfonyl ureas and glucatrol may actually increase islet amyloid polypeptide (IAPP) deposition. IAPP is co-secreted with insulin. Islet amyloidosis occurs in 90% of humans with Type 2 DM.

Polyuria, polydipsia, increased appetite, and weight loss are hallmark signs of diabetes mellitus in cats. In the earlier stages of the disease, cats remain active and alert with few other signs of disease. However as the disease progresses, poor skin and hair coat, liver disease, and secondary bacterial infections become more common. An infrequent disorder called diabetic neuropathy may cause cats to become progressively weaker in the rear legs and assume a unique, plantigrade stance. A dangerous condition called ketoacidosis may develop in some cats. Signs of ketoacidosis include a loss of appetite, vomiting, diarrhoea, lethargy, weakness, dehydration, and breathing abnormalities. Without proper and prompt treatment, this condition ultimately proves fatal.

Risk factors include body weight >7kg, older age (>10 years), male gender and neutered. Unlike humans, cats do not normally have hypertension associated with DM.

What is the Somogyi Effect?

Glucagon and insulin are released by the pancreas. Glucagon and insulin have opposite effects: insulin makes the blood sugar go down and glucagon causes blood sugar to go up. They work together to balance blood glucose levels. Glucagon can increase blood glucose levels by causing the liver to release its stored glucose to the blood stream. Insulin lowers blood glucose by allowing tissues to use or store glucose.

When too much insulin is given the blood glucose drops rapidly and hypoglycaemia (low blood sugar) results. This can trigger the body to release glucagon (and other hormones) and the result is that glucose is dumped into the blood. This can lead to hyperglycemias (high blood sugar). So, you have hyperglycaemia induced by hypoglycemias, or the Somogyi effect. (Somogyi was a scientist who did research on glucose production by liver during times of stress.)

The method of determining if Somogyi effect is occurring is to do a blood glucose curve. Your cat will have a specific pattern of hyperglycaemia if the Somogyi effect is occurring. Although at first it seems odd, the treatment for this type of hyperglycaemia is to decrease the insulin dose. This prevents the hypoglycaemia from occurring and triggering the Somogyi effect.

Diagnosis

Diabetes mellitus is diagnosed based on the cat's clinical signs, physical examination findings, laboratory test results, and the persistent presence of abnormally high amounts of sugar in the blood and urine. In stressed patients, adrenalin release causes hyperglycaemia and glucosuria. It is essential to differentiate between stress response and diabetes.

A fructosamine test is conducted to determine if the elevated blood sugar is temporary or sustained (>72hrs). Fructosamine measures the protein bound glucose levels over the preceding 10-20 days. Similarly glycosylated haemoglobin is synthesised in red blood cells in an irreversible reaction between glucose and amino acids of the haemoglobin. As glycosylated haemoglobin levels reflect glycaemic control over the preceding 90 days, fructosamine detects successful management and changes to management earlier than glycosylated haemoglobin.


Figure 3. With normoglycemia, a relatively small amount of serum protein is glycosylated.	Figure 4. With persistent hyperglycemia, increased protein glycosylation occurs.

Fructosamine measurement also may be used to diagnose and monitor diabetes mellitus in dogs and cats¹³. It is a highly sensitive and specific laboratory test to distinguish hyperglycaemic, non-diabetic patients from diabetics with chronic hyperglycemia.¹ Fructosamines are stable complexes of carbohydrates and proteins that are produced by an irreversible, non-enzymatic glycosylation of protein (Figs. 3 and 4).¹¹ Glucose has a greater affinity for albumin in dogs and for globulins in cats.⁹ Determination of fructosamine concentration in the blood is performed using an adapted, commercially available, automated, colorimetric nitroblue tetrazolium technique. This laboratory test is fast, reproducible, inexpensive, easily automated, requires minimal labour, and provides greater precision than other tests.⁸

A single measure of fructosamine indicates the average glucose concentration over the previous 1-2 weeks.⁵ Fructosamine measurement may be used to assist in the diagnosis of diabetes mellitus as well as to monitor the effectiveness of insulin therapy in diabetic patients. There is very little evidence that fructosamine values are significantly influenced by acute or transient hyperglycaemia. Thus, fructosamine concentration may be used to assist in the diagnosis and monitoring of diabetic patients without interference from transient hyperglycemia.⁵ This is especially beneficial in cats that are highly affected by stress-induced hyperglycemia.⁹ Quantitative measurement of fructosamine depends on the level and duration of serum glucose concentration and the rate of turnover of specific plasma proteins in the patient.³ In dogs, the half-life of albumin is approximately 8 days.² Therefore, fructosamine values will change faster than glycosylated haemoglobin values in response to changes in blood glucose concentration.

Reference intervals for fructosamine concentration have been proposed in many publications since this test was introduced for use in diabetic veterinary patients, and these reference intervals vary greatly from manuscript to manuscript. This variation in fructosamine reference intervals is most likely due to different populations of animals, different methods of performing the assay, different statistical procedures, and different environmental conditions and feeding protocols.¹¹ For example, the clinical pathology laboratory used by the University of Georgia Veterinary Medical Teaching Hospital uses fructosamine reference intervals of 175-400 µmol/L in cats and 258-343 µmol/L in dogs. It is important to know that reference intervals are variable between laboratories and that each laboratory should establish their own reference intervals. Reference intervals are not affected by the age or sex of the animal.^1,11

Proper treatment of diabetes mellitus is based on the severity of the disorder. Cats with ketoacidosis require intensive care. Treatment includes fluid therapy to correct dehydration and electrolyte abnormalities, and short acting insulin. Diabetic cats that are not ill usually require insulin injections to be given once or twice daily under the skin, and a carefully controlled diet. As an alternative to insulin, treatment with an oral hypoglycaemic drug (see below) may be attempted.

Insulin

Adequate control of most diabetic cats requires long-acting insulin injections to be given once or twice daily. Each cat responds differently to insulin, so the proper choice of insulin type, dose, and frequency of administration needs to be individually determined. Selection of the appropriate insulin type, dose, and frequency of administration for an individual diabetic cat is ideally based on 18- to 24-hour blood glucose profiles. In order to perform a glucose profile, the cat is hospitalised, and following insulin administration, frequent determinations of blood glucose values are made throughout the day. The proper dose of insulin may change with time and may need to be adjusted based on blood glucose profiles, intermittent blood and urine sugar measurements, and response to therapy.

Over-dosage of insulin causes hypoglycaemia (low blood sugar). Signs of this potentially dangerous complication include weakness, listlessness, incoordination, convulsions and coma. Left untreated, death may result. If hypoglycaemia develops, the cat should immediately be offered its normal food if it is able to eat. Alternatively, a tablespoon of Karo syrup should be rubbed on the gums or, if the cat can swallow, given slowly by syringe into the mouth. Never force fingers, food, or fluids into the mouth of a convulsing or comatose cat. Your veterinarian should be contacted immediately if your cat experiences an episode of hypoglycaemia so that further treatment instructions can be given and a modification of insulin administration, if necessary, can be made.

Cats requiring excessively high insulin doses (greater than one to two units of insulin per pound per day) should be evaluated further. Other diseases may be underlying or complicating the diabetes mellitus and as a result, necessitate high insulin dosages. Problems with insulin injection, poor absorption or too rapid metabolism of insulin, or even insulin overdose are potential causes of an apparently excessive insulin requirement.

Oral Hypoglycaemic Medications

Healthy diabetic cats can sometimes be successfully treated with a hypoglycaemic medication, e.g. glipizide. Glipizide acts by lowering blood glucose, but unlike insulin, it is given orally. Adverse side effects are not common but include vomiting, loss of appetite, and liver damage. If hyperglycaemia persists after one or two months of therapy, or if the cat becomes ill or ketoacidotic, glipizide therapy should be discontinued and insulin therapy instituted.

Diet

Obese diabetic cats should lose weight gradually, with no more than 3 percent of their body weight lost per week. Your veterinarian will help in tailoring a safe weight-loss program for your cat. High fibre, high complex carbohydrate diets are useful, not only by assisting in weight loss, but by helping to control blood glucose levels after eating. Underweight diabetic cats should be fed a high fibre diet only after reaching their ideal body weight after being fed a high calorie diet.

Cats receiving insulin once daily should be fed half the daily food requirement at the time of the injection and the remaining half at the time of peak insulin activity (as determined by a blood glucose profile). If receiving twice daily insulin injections, cats should be fed half the daily ration at each administration. Cats receiving oral hypoglycaemic medication should be fed a high fibre diet, but ideally as multiple small meals consumed throughout the day.

While the ideal combination of macronutrients (protein, fat, and carbohydrate) to feed diabetic cats is not known, diets low in carbohydrates and high in protein reduce post-prandial hyperglycemia and insulin concentrations in healthy cats . Initial data from diabetic cats also suggest that low carbohydrate–high protein diets result in better clinical control, reduced insulin requirements and increased rates of diabetic remission . Thus a commercial low carbohydrate should be used in diabetic cats, unless contraindicated by other disease . During the first few weeks of treatment, diabetic cats may have a reduced appetite, and if they refuse these low carbohydrate diets, they should be offered any palatable food.

Care should be taken with cats diagnosed with renal disease, as diets high in protein may have a deleterious effect . For these cats, dietary management of renal disease using a restricted protein diet should take precedence over dietary management of diabetes.

Obesity in cats markedly reduces insulin sensitivity and hence calories should be restricted so weight loss occurs in obese cats at a rate of 1% to 2% loss of body weight per week . Because of the decreased postprandial hyperglycemia with a low carbohydrate diet, it is suggested that diets with less than 20% of calories from carbohydrate (eg, Hill’s m/d, Purina DM) should be used for obese diabetic cats during the calorie restriction phase . Currently, most feline weight loss diets are low fat, high carbohydrate diets . Weight loss improves insulin sensitivity, and may reduce insulin requirements . In some cats, diabetic remission is obtained after weight loss and short-term insulin or oral hypoglycemic therapy.

The alpha-glucosidase inhibitors (eg, acarbose) reduce intestinal glucose absorption (Greco 1999) and are generally not effective in the treatment of feline diabetes alone, but can be used in conjunction with insulin and/or other oral agents to gain better glycemic control . Cats given acarbose and fed a low carbohydrate diet had a reduced insulin requirement and improved glycaemic control, but similar results were achieved feeding the low carbohydrate diet alone.

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 1 to 4 months to stabilize; thus, the temptation to “over adjust” the insulin dose must be avoided . It is unrealistic to expect excellent control after only 2 to 4 weeks of treatment, except in cats going into early remission.

The most common problems resulting in poor control are excessive dose, miscalculation of dose, too short duration of insulin action, or poor absorption of insulin . Some cats are mistakenly labelled problem cats when the clinical signs are well controlled, but blood glucose measurements are less than ideal . This usually occurs when there are unrealistic goals for glycemic control when using lente, NPH or ultralente . If the glucose nadir is below 10 mmol/L (182 mg/dL) after each insulin injection, peak action occurs >3 hours after administration, and hypoglycaemia is not occurring, glycemic control is usually adequate . These cats usually have good clinical control (stable body weight, good coat condition, active, alert, water drunk <100 mL/kg/24 h) . Swapping to a longer acting insulin such as glargine will usually improve glycemic control.

Problem cats have persistent clinical signs including polydipsia (water drunk > 100 mL/kg/24 h), low body condition score, polyphagia, lethargy, and a poor hair coat; an insulin dose higher than normal (1.5–2 or more IU/kg/injection); and either a nadir glucose >180 mg/dL (10 mmol/L) or hypoglycemia . For problem-solving in problem cats, it is important to first rule out administration problems . Expired insulin, heat-affected insulin (eg, left in a car in summer), poor mixing of suspensions, failure of administration (eg, injecting through the skin pinch onto the hair-coat), and the presence of air bubbles in the syringe causing a lower administered dose, all occur regularly in practice . 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 occur when using 40 IU/mL insulin in a 100 IU/mL syringe, because the cat is only getting 40% of the dose indicated by the markings on the syringe . Watch the owner administer the insulin . If it is an old bottle of insulin, change to a new one . If the cat has been treated for at least 8 to 12 weeks and insulin is being correctly administered but poor control is still evident, measure water intake over consecutive days at home (measure fructosamine concentration if water intake cannot be measured), and obtain a blood glucose curve.

Poor control may result from an excessive dose of intermediate acting insulin, which may cause apparent insulin resistance (dose >1.5–2 IU/injection with persistent hyperglycemia), or short duration of insulin action . In many cats treated with the intermediate-acting insulins such as lente and isophane, these potent insulins rapidly lower blood glucose . This stimulates counter-regulatory responses, even when blood glucose concentration is not in the hypoglycemic range. The resulting counter-regulatory response increases blood glucose concentration, and causes an apparent short duration of insulin action and insulin resistance. This can be very frustrating for veterinarians when managing diabetic cats. This response happens because of the action of the hypothalamic neurons that sense blood glucose concentration and initiate counter-regulation. The hypothalamic neurons control entry of glucose into their cytoplasm, and actively maintain a large concentration gradient with plasma glucose when blood glucose concentrations are high. When potent insulin such as lente insulin is given and blood glucose concentration decreases rapidly, the intracellular glucose concentration of the hypothalamic neurons decreases more quickly into the range perceived by the neurons as hypoglycemic and a counter-regulatory response is triggered, even before hypoglycemia develops. The resultant secretion of glucagon, epinephrine, cortisol and growth hormone increases blood glucose concentration, and causes an apparent short duration of insulin action. Because the glucose lowering effect of lente in cats is less than 8 hours, most diabetic cats have blood glucose concentrations of 360 to 430 mg/dL (20 to 24 mmol/L) at the time of the next insulin dose, predisposing them to premature counter-regulation. The result is that in some cats, lente and NPH insulins may only lower blood glucose for 2 to 3 hours. This inherent short duration of action of lente, NPH and ultralente insulins, coupled with the response of the hypothalamic neurons can be very frustrating for practitioners. It also is dangerous for diabetic cats, because their insulin dosage often is wrongly increased. The end result is that the effect of lente, NPH and ultralente is often too short to achieve good glycemic control, and insulin resistance and signs of hyperglycemia and hypoglycemia ensue.

For cats on potent insulins such as lente or NPH, 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, there are two options . Either swap to glargine or first try lowering the dose of insulin to 0.3 to 0.5 IU/kg for 10 to 14 days to see if blood glucose or water intake improves towards the end of the period . If clinical control is not improved with a lower dose, check the glucose response to a standard dose of 0.5 IU/kg of insulin, to determine the duration of effect . If the glucose nadir occurs 2 to 3 hours after injection, switch to a longer acting insulin, or increase the frequency of administration to TID . Similarly with PZI, if the nadir occurs at <6 hours, change to BID administration, if the cat is receiving insulin once daily . With PZI or ultralente, if there is little response to insulin, try swapping to glargine and slowly increasing the dose until glycemic control is achieved, which may require a dose of 5–6 U/cat twice daily . If there is still polydipsia (water drunk >100 mL/kg/24 h) and little glycemic response after 1–2 months at a dose of 5–6 U/cat twice daily, check the cat for hyperthyroidism, hyperadrenocorticism, acromegaly or other systemic disease such as renal failure, if there are clinical signs which suggest concomitant disease . We have seen improved glycemic control in cats with periodontal disease, following dental surgery in combination with short-term antibiotics . In the meantime, increase the dose by 1 IU every 1–2 weeks until some glycemic response is achieved . Control is achieved in most difficult cats, with the exception of cats with acromegaly, once glargine dose is 5–6 U/cat twice daily . Warn the owner that a severe hypoglycaemic episode can occur with this protocol, and to be particularly vigilant regarding the early signs of hypoglycemia (lethargy, mental dullness, wobbliness, trembling and dilated pupils) . In some cats which appear insulin resistant, but no cause can be found, admitting them to hospital for carefully observed intensive insulin therapy to normalize blood glucose for several days, may substantially reduce the subsequent insulin doses that achieve control . Most cats are eventually controlled on 1–3 U/cat BID of glargine, even if they required a dose as high as 5–6 U/cat BID in the first 1 to 3 months to control blood glucose.


Blood glucose measurements can be done at home, reducing ongoing costs for pet owners

Managing a diabetic cat requires good communication between you and your veterinarian. A diabetic cat may live many healthy years with owners who are willing to put forth the effort of monitoring the cat's condition daily. Cats tend to be difficult to maintain on the same regimen for long periods of time, and increases or decreases may need to be made in drug dosages.

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