diabetes management made possible with Caninsulin

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1 Successful diabetes management made possible with Caninsulin Veterinary Technical Brochure 1

2 Diabetes Incidence and Etiology Diabetes mellitus due to pancreatic disease Introduction Diabetes mellitus is a common endocrine disorder of dogs and cats that results from an absolute or relative insulin deficiency. In general, the prognosis is good, provided that the diagnosis is made at an early stage and treatment is adequate. Insulin treatment is the cornerstone of successful management, but appropriate diet and a regular lifestyle are also important. First-rate communication between you, the veterinarian and the pet owner is of major importance. Your attitude to diabetes mellitus will largely determine the owner s motivation and compliance with treatment. Incidence Estimates of the incidence of diabetes mellitus in dogs and cats range from 1:100 to 1: Diabetes occurs most commonly in middle aged and older dogs and cats. In dogs, there is a genetic predisposition in Keeshonds and Samoyeds and a higher incidence in intact females. A higher incidence is seen in Burmese cats and in neutered male cats. Etiology Diabetes mellitus can originate from either pancreatic or non-pancreatic disease. Endocrine Destruction of endocrine pancreatic tissue can lead to diabetes mellitus. In dogs, there is some evidence that autoimmune destruction of the islets of Langerhans plays a role in the pathogenesis of diabetes. In cats, amyloid deposition may contribute to the destruction of the islets of Langerhans. Exocrine Severe inflammation or neoplasia of the exocrine pancreas can also lead to loss of islet function. In these cases, diabetes is complicated by exocrine pancreatic insufficiency. Vacuolar degeneration of islets of Langerhans in a dog, Hemaxtoxylin and eosin (HE) stain, 10x. Diabetes mellitus due to disease not primarily of pancreatic origin Overproduction of counteracting hormones and insulin resistance Growth hormone excess Progesterone-induced Progesterone produced during the luteal phase induces the production of growth hormone by the mammary gland. This counteracts the action of insulin. Pituitary origin - acromegaly Acromegaly (hypersomatotropism) is caused by growth hormone excess. This is not uncommon in cats where it is due to a growth hormone-secreting pituitary tumor. Cushing s syndrome Amyloidosis of islets of Langerhans in a cat, HE stain, 25x. Amyloidosis of islets of Langerhans in a cat, polarized light (left) and Congo red stain (right). Photographs courtesy of Pathology Department, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands. Corticosteroids stimulate gluconeogenesis, leading to an increase in the blood glucose concentration. This stimulates insulin synthesis, which can eventually result in exhaustion of the islets of Langerhans. 2 3 Reference: 1. Panciera DL et al. (1990) J Am Vet Med Assoc 197,

3 Diabetes pathogenesis and clinical signs Figure 1: intercellular energy shortage extracellular hyperglycemia Figure 2: extracellular hyperglycemia intracellular energy shortage Glucose toxicity Glucose toxicity occurs when insulin secretion is reduced by prolonged hyperglycemia. Prolonged hyperglycemia can be due to a number of causes including the ones listed below. Iatrogenic Corticosteroids The therapeutic use of corticosteroids can induce diabetes mellitus. Progestogens The use of exogenous progestogens can lead to growth hormone excess. Progestogens also have an affinity for glucocorticoid receptors. Obesity In obesity, tissue receptors have decreased insulin sensitivity. This leads to a greater demand for insulin, which can result in exhaustion of the islets of Langerhans. Potential diabetes mellitus Potential diabetes mellitus, defined as impaired insulin synthesis and/or decreased sensitivity of tissue receptors to the effects of insulin, results in an increased blood glucose concentration that does not yet exceed the renal threshold. This is seen in intact female dogs during metoestrus. At this stage, the problem may still be reversible by spaying (elimination of the progesterone source). Mild hyperglycemia may also be encountered in Cushing s syndrome (hyperadrenocorticism) and reversal of the cortisol excess may prevent the development of diabetes mellitus. Pathogenesis Diabetes mellitus is a paradox: simultaneous extracellular hyperglycemia and intracellular glucose deficiency. The consequences of this paradox are shown in Figs. 1 and 2. 2a hyperosmotic plasma dehydration of cells hyperglycemic coma blood glucose > renal threshold glucosuria polyuria Clinical signs osmotic diuresis polydipsia high urine specific gravity hypokalemia hyponatremia fat metabolism increase of fatty acid concentrations in plasma ketosis ketoacidosis; ketonuria There are three clinical scenarios in diabetes mellitus uncomplicated complicated by ketoacidosis hyperosmolar hyperglycemic non-ketotic syndrome Uncomplicated diabetes mellitus The classical signs are polyuria/polydipsia polyphagia cachexia increased susceptibility to infections (e.g. urinary tract infections) Complications, due to protein glycosylation, include cataracts (mainly in dogs) peripheral neuropathy (mainly in cats) gluconeogenesis increases protein synthesis decreases cachexia/lethargy polyphagia decreased gamma globulin concentrations increased susceptibility to infections impaired wound healing acidotic coma Fructosamine and glycated hemoglobin concentrations also increase due to protein glycosylation. Complicated by ketoacidosis Animals may become comatose if the ketoacidosis is severe. Hyperosmolar hyperglycemic non-ketotic syndrome When resistance of target tissues to insulin plays a role in the disease, insulin levels can be elevated. In these cases, ketosis is suppressed and blood glucose concentrations can become very high. These animals are usually comatose. 4 5 Reference: 2a. Rijnberk A. (1996) Clinical Endocrinology of Dogs and Cats, Kluwer Academic Publishers, The Netherlands;

4 Successful Diabetes Management Diagnosis Diabetes mellitus is not the only cause of polyuria, polydipsia and weight loss. Cases should be investigated fully to rule out other causes before starting insulin treatment. 2b A preliminary diagnosis of diabetes mellitus based on clinical signs must be confirmed by urine and blood tests. Reference intervals for blood glucose in non-diabetic, healthy animals are approximately mmol/l ( mg/dl) in dogs and mmol/l ( mg/dl) in cats. The renal threshold is around 10 mmol/l (180 mg/dl) in dogs and around 14 mmol/l (252 mg/dl) in cats. If the blood glucose concentration exceeds this threshold, glucose is excreted in the urine (glucosuria). Transient hyperglycemia can occur particularly in cats in stress situations, usually where struggling is involved. Fructosamine concentrations are correlated with the average blood glucose concentration over the previous 1-2 weeks. Fructosamine measurement is a valuable tool in confirming a diagnosis of diabetes mellitus particularly in cats. Diabetes management General considerations Treatment of diabetes mellitus is likely to succeed only if the pet owner understands all aspects of its management, including the importance of diet and regular exercise. Investment of time in a careful explanation of all aspects of diabetes management is strongly recommended. Spaying If diabetes mellitus has been diagnosed in an intact female dog, immediate spaying (ovari(ohyster)ectomy) is advisable, to prevent further exposure to endogenous progesterone. In animals fit for surgery, this can be carried out prior to insulin treatment and intravenous fluid therapy administered. If the animal s condition is critical (dehydration, anorexia, uremia, severe hyperglycemia and glycosuria) and surgery is contraindicated, intravenous fluid therapy and insulin administration should be started. Spaying can then be carried out as soon as the dog s condition has improved sufficiently. On the day of surgery, pre-operative fasting will necessitate reducing the insulin dose, e.g. to around 30% and intravenous fluid therapy should be administered. Following surgery, regular monitoring is necessary until the animal s condition is stable. The response to insulin will often improve and the insulin demand will decrease accordingly. Diet and feeding schedule The volume and composition of meals should be identical from day to day to avoid changes in insulin requirements. As this is difficult to accomplish with home-prepared meals, commercial pet food is preferable. Commercial diets with a high quality, highly digestible protein source and a low fat content provide a more gradual intestinal uptake of glucose. In animals that are over- or underweight, the ideal body weight should be reached by gradual weight loss or gain. Very calorie-dense diets, especially those high in soluble carbohydrates, should be avoided in animals that are underweight. For dogs the daily food intake is usually divided into two meals. The timing and quantity of these meals varies, based in part on whether insulin is administered once or twice daily. The first meal is given around the time of the morning insulin injection and the second meal approximately 8 hours to 12 hours later. Cats are often very fussy eaters and usually prefer to eat when they choose. Free access to a measured amount of the food is often the best option. Diabetic cats can be stabilized on their usual diet if need be, but diets low in carbohydrate are usually preferred. Clean drinking water should be available at all times. A reduction in excessive water consumption indicates successful management of the diabetes mellitus. 6 7 Reference: 2b. Rijnberk A. (1996) Clinical Endocrinology of Dogs and Cats, Kluwer Academic Publishers, The Netherlands;

5 Diabetes Management with caninsulin Due to differences in metabolism, the duration of activity of a particular insulin will vary from animal to animal. The source of the insulin can be also different. Caninsulin is an aqueous suspension of 40 IU highly purified porcine insulin per ml, consisting of 35% amorphous and 65% crystalline zinc insulin. Caninsulin is available in vials and cartridges. Caninsulin is administered using a U40 insulin syringe or VetPen. Pharmacokinetics of Caninsulin In dogs the amorphous fraction has peak activity approximately 3 hours after subcutaneous administration, and its effects last for about 8 hours. This effect is maintained by the crystalline fraction, which has a slower onset of action and peak effects from 7 to 12 hours following injection. 3,4 The total duration of effect ranges from 14 to 24 hours depending on the individual dog (Fig. 3). In cats, the maximum effect is seen around 4 hours after administration and the total duration of action is around 12 hours. 5 Dogs The duration of activity of Caninsulin may be sufficient to treat dogs once daily. However, in many cases, injections have to be given twice daily. Cats activity of Caninsulin Figure 3: Schematic representation of Caninsulin concentration in dogs showing biphasic activity amorphous (30%) crystalline (70%) time in hours The duration of action of Caninsulin is shorter in cats than in dogs. As a result, all cats require twice daily injections. Twice daily injection of Caninsulin can provide sufficiently good glycemic control that can result in remission of the clinical signs. 6 Initial regulation Dogs The initial dose for dogs is 0.5 IU/kg once daily. Many dogs need twice daily insulin. The dose per injection is often the same whether the insulin is administered once or twice daily. When changing a dog from once daily to twice daily insulin, a dosage reduction of 25% per injection is recommended. For example, a dog on 20 IU once daily would receive an initial daily dose of 15 IU twice daily. Even after stabilization it is not uncommon for a dog s insulin requirements to change suddenly, often after a period of months or even years. Cats The initial dose for cats is 1 to 2 IU per injection twice daily, depending on the initial blood glucose concentration (Table 1). The starting dose should ideally not exceed 2 IU per cat twice daily in the first 3 weeks of treatment. After several weeks or even months it is not unusual for either insulin to be no longer required (clinical remission) or a major change in the dose to be required. Baseline blood glucose concentration <20 mmol/l or <360 mg/dl 20 mmol/l or 360 mg/dl Initial Caninsulin dose (round down to nearest whole unit) 1 IU twice daily 2 IU twice daily Table 1. Guide to starting twice daily Caninsulin treatment in cats 8 9 References: 3. Graham PA, Nash AS & McKellar QA. (1997) J Small Anim Pract 38, Horn B & Mitten RW. (2000) Aus Vet J 78, Martin GJ & Rand JS. (2001) J Feline Med Surg 3, Michiels L et al. (2008) J Feline Med Surg 10,

6 Diabetes incidence and Etiology Dose Adjustment and monitoring Dose adjustment In dogs, dose adjustment should be managed in steps of 10%. In cats, the dose should be adjusted in steps of 0.5 to 1 IU according to an algorithm (Fig. 3). 5,6 Following adjustment, full evaluation should not take place before the new dose has been given for days to weeks, particularly in cats. Maintaining a blood glucose concentration within the reference interval for nondiabetics throughout the entire day is not a treatment goal per se. The aim is to try to maintain blood glucose concentrations between around 5 and 15 mmol/l (90 and 270 mg/dl) for a substantial part of the day. This will result in the disappearance of most of the clinical signs - the goal of therapy. Urine monitoring Urine monitoring is a quick and easy method of detecting ketones (ketonuria). Urine only tests positive for glucose if the blood glucose concentration remains above the renal threshold for a substantial period. Monitoring of urine for glucose can be useful in diabetic animals that are not yet stable or in those that have problems with recurrent hypoglycemia. Here it is used to identify the absence of glucose. Blood glucose (mmol/l) Time (hours) Figure 3. Blood glucose curve from a stable diabetic dog Recheck: After 1 week Every 3 weeks If hypoglycemia is suspected then: Every 2 4 months Increase the insulin by 0.5 or 1 IU Blood glucose nadir of <54 mg/dl (<3 mmol/l) No Blood glucose nadir of >162 mg/dl (>9.0 mmol/l) Perform a 12 hour blood glucose curve Are there clinical signs of hypoglycemia? 5 7 days later No Yes Biochemical hypoglycemia Blood glucose nadir of <90 mg/dl (<5.0 mmol/l) Yes Blood glucose nadir of mg/dl ( mmol/l) Yes Reduce the insulin dose by at least 1 IU Does the cat have a total water intake of <100 ml/kg/day? No Urine monitoring can be used for animals that are known to have a blood glucose concentration in an acceptable range. In this case it is a quick, easy method of detecting hyperglycemia. This should then be investigated further by measuring blood glucose concentrations. Blood glucose curves The most accurate way to assess the response to treatment is by making a blood glucose curve (Figs. 3-6). The procedure is as follows: The first blood sample should ideally be taken just prior to the insulin administration. The procedure is: The animal should be given its first meal followed by its morning Caninsulin injection. Blood samples should then be taken approximately every 2 hours throughout the day (at least 9 to 12 hours). It is important to record the time that the samples are taken! Blood glucose (mmol/l) Blood glucose (mmol/l) Figure 4. Insulin resistance Time (hours) (hyperglycemia) (see Fig. 6): If hyperglycemia persists with dosage reduction, try increasing the dose Decrease the insulin dose by 0.5 or 1 IU Figure 5. Short duration of action: 10 Figure 3. Guide to monitoring stabilization and making dose rate changes in diabetic cats change to twice daily 11 Time (hours)

7 Challenges Diabetes incidence and Etiology in diabetes management Somogyi effect An insulin dose that is slightly too high may bring about the Somogyi effect (rebound hyperglycemia) (Fig. 8). This is a chain of reactions through which the body attempts to counteract a decline in blood glucose. If the blood glucose concentration falls rapidly or approaches hypoglycemia (less than 5 mmol/l or 90 mg/dl), clinical signs of hypoglycemia may also develop. In response to a declining glucose concentration in the brain, adrenaline and subsequently cortisol, glucagon and growth hormone are released. These hormones bring about an increase in the blood glucose (through gluconeogenesis, release of glucose from hepatic glycogen stores and increased peripheral resistance to insulin). Polyuria and polydipsia are seen and this can easily be misinterpreted. Hyperglycemia can sometimes persist for days after a single hypoglycemic episode. If the Somogyi effect is suspected, an alternative approach involves decreasing the dose by 20% and closely observing the clinical signs. If the polyuria or polydipsia worsen following dose reduction, it is unlikely that the Somogyi effect was the problem. Hypoglycemia If the insulin dose is too high, clinical signs of hypoglycemia may be observed. These include hunger, restlessness, shivering, ataxia, disorientation, convulsions and coma. However, some animals just become very quiet and stop eating. This serious and potentially fatal condition (which can also be triggered by anorexia, vomiting or excessive exercise) may occur at any stage, even after stabilization has been achieved. Blood glucose (mmol/l) Immediate oral administration of a glucose source (1 g glucose per kg body weight, approximately one heaped teaspoonful per 5 kg body weight) by the owner can alleviate these signs. Owners need to keep a glucose source readily available. Following emergency administration of glucose, food must be given repeatedly at intervals of 1-2 hours until all the effects of the extra insulin have been counteracted. Problems with regulation If the response to insulin therapy is poor, a blood glucose curve should be made and every effort made to rule out other concurrent or underlying disorders. Problems with administration Caninsulin has been specially developed for use in animals and has a concentration of 40 IU/mL, making the dose easy to measure and dilution unnecessary. Caninsulin should be stored upright in a refrigerator and must be mixed before use. To obtain a homogeneous, uniformly milky suspension, shake vials thoroughly or invert cartridges, which contain mixing beads, ten times. Problems with resorption from the injection site This has been reported in cats, especially with ultralente insulin. Antibodies Antibodies may be directed either against the insulin or against other foreign proteins in a preparation. The presence of antibodies is common in diabetic dogs and does not frequently lead to poor regulation. Insulin antibodies appear to be less common in diabetic cats. Antibody production is less likely in dogs if homologous insulin is given - the porcine insulin in Caninsulin has exactly the same structure as canine insulin Time (hours) Figure 6. Rebound hyperglycemia: reduce the dose 12 13

8 Diabetes incidence and Etiology Diabetic pets can enjoy Healthy, CLIENT participation Normal lives Most clients quickly learn to give daily insulin injections. It is best to confirm that the animal is eating normally, before giving the insulin injection. Get More Information about Caninsulin online During therapy the pet owner needs to actively participate in regularly monitoring their pet s progress. Many clients can be successfully instructed to take capillary blood samples and use a handheld glucometer. If this is not feasible, an alternative is to have the owner test the urine for the presence of glucose and ketones. Before dose changes are made, blood glucose concentrations should be confirmed. Prognosis in diabetes mellitus The prognosis for a diabetic animal depends to a large extent on the level of confidence, knowledge and dedication of its owner. These factors can be favorably influenced by your attitude and the quality of the information you, the veterinarian, provide. It should be made clear that treating a diabetic animal is interesting, rewarding and certainly not as complicated as is sometimes thought. More information to help you manage diabetes in dogs and cats is available at You can also visit the website that provides more information for owners of diabetic pets at

9 Product INFORMATION PRESENTATION Caninsulin is an aqueous suspension of insulin containing 40 IU per ml of highly purified porcine insulin, 30% is amorphous zinc insulin and 70% crystalline zinc insulin. USES Caninsulin, an intermediate acting insulin containing porcine insulin, is structurally identical to canine insulin. It is indicated in the treatment of diabetes mellitus in dogs and cats. DOSAGE AND ADMINISTRATION Invert the insulin vial a few times to resuspend the Caninsulin. Caninsulin should be administered by subcutaneous injection. An insulin syringe with unit markings for a 40 IU/ml insulin should be used. A once daily injection is sufficient to stabilise the blood glucose level in many dogs. However, the duration of action may vary, making it necessary to administer insulin twice daily to some dogs. In cats, it is necessary to administer Caninsulin twice daily. The dose depends on the degree of deficit in the animal's own insulin production and therefore is different in each case. In dogs, the initial daily dose is 1 IU per kg bodyweight plus a body weight dependent supplement dose. In cats, the initial daily dose is IU/kg twice daily. Especially in obese cats, an unduly high starting dose may be dangerous. Subsequent adjustment to establish the maintenance dose should be made by increasing or decreasing the daily dose by approximately 10% per day according to the results of measurement of the blood glucose concentrations. Once the maintenance dose has been established and the animal is stabilised a long term management programme needs to be implemented. The aim should be to manage the animal in such a way as to minimise the variations in its insulin requirement. This includes monitoring to detect under or overdosage of insulin and adjustment of dose if required. Careful stabilisation and tight monitoring and control during maintenance will help to limit the chronic problems associated with diabetes, such as cataracts. Various approaches to maintenance have been described. The most clinically rational approach is for the owner to monitor and record the animal's general health and urine ketones (including well-being, thirst and appetite) and check urine glucose at least daily. The veterinary surgeon checks the case every 2-4 months (or more often if there are problems) including its health and urine glucose and ketones record. Blood glucose is also measured at this time. Adjustments to the insulin dose are made by the veterinarian based on full analysis of the clinical data and on blood glucose measurement. The ability for owners to recognise the signs of hypo- or hyperglycaemia and respond approprately is important if control is to be achieved during maintenance therapy. Polyuria, polydipsia and polyphagia in combination with weight loss, general bad condition, and lethargy are the most common clinical signs of diabetes mellitus and require administration of insulin to restore blood glucose concentrations to the normal range. CONTRAINDICATIONS, WARNINGS, ETC. 1. Caninsulin is a an intermediate acting insulin and is not intended for the treatment of animals with severe acute diabetes presenting in a ketoacidotic state. Caninsulin must not be administered by the intravenous route. 2. The use of progestogens in patients suffering from diabetes mellitus should be avoided. Ovari(ohyster)ectomy may have to be considered. 3. Stress and irregular exercise must be avoided. Care must be taken with the use of corticosteroids. 4. It is important to establish a strict feeding schedule with minimal fluctuations and changes in consultation with the owner. 5. Administration of Caninsulin must be carried out by an adult responsible for the welfare of the animal. For animal treatment only. Keep out of the reach of children. STORAGE Store refrigerated at 2-8ºC. Do not freeze. Protect from light. Store in an upright position. Following withdrawal of the first dose use the product within 20 days. Discard unused material. PACKAGING Vials containing 10 ml or 2.5 ml in single and multiple packs. Intervet International BV - P.O. Box 31, 5830 AA Boxmeer - The Netherlands Phone: +31 (0) Fax: +31 (0) Intervet International B.V., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 2013_GAH_CA_056