Diabetes mellitus in the dog and cat

Diabetes mellitus is undoubtedly one of the most common endocrine disorders in dogs and cats. There are many studies on the epidemiology of this pathology and some of these have found incidences of approximately 0.5% in both species. Diabetes mellitus is a disease characterized by hyperglycaemia due to a deficiency in the secretion of insulin and/or a defect in the action of this hormone. It is the consequence of an absolute or relative lack of insulin caused, in its turn, by inefficiency of the pancreatic endocrine β cells. Being a chronic disease, diabetes mellitus necessitates continuous treatment and periodic controls by a veterinarian. Animals affected by this disease usually require life-long treatment; however, careful management of the diabetic patient can ensure the animal a good quality of life.

CLASSIFICATION

In human medicine, diabetes mellitus is currently classified on the basis of aetiology into four categories. In veterinary medicine, in contrast, although there are not yet internationally accepted criteria, the disorder is commonly divided into:

• type I diabetes mellitus: previously defined as “insulin-dependent diabetes”, this is the more common form in dogs.
• type 2 diabetes mellitus: previously defined as “non-insulin-dependent diabetes”, this is the more frequent form in cats.

Cases of what are defined as “other types of diabetes” in human medicine are extremely rare in dogs and cats. As far as concerns human gestational diabetes mellitus,a similar form of diabetes may occur during dioestrus in the bitch; this type of diabetes has not, however, been described in cats.

AETIOLOGY

TYPE 1 DIABETES MELLITUS IN THE DOG

The aetiology of the destruction of β cells in the diabetic dog is still unknown; however, genetic predisposition, immune-mediated mechanisms and environmental factors seem to play the major roles in the pathogenesis and development of diabetes mellitus in the dog (Tab. 1). Type 1 diabetes is characterized by complete destruction of the pancreatic β cells with progressive and absolute lack of insulin.

Table 1: Factors potentially involved in the aetiopathogenesis of diabetes mellitus in the dog and cat.

OTHER TYPES OF DIABETES IN THE DOG

The occurrence of type 2 diabetes mellitus in the dog has not be scientifically demonstrated. Obesity creates insulin resistance but no studies have proven the real correlation between obesity and diabetes mellitus in the dog, in contrast to the situation in the cat.

The high concentrations of progesterone during dioestrus and pregnancy cause glucose intolerance, increasing the risk of development of dioestrous or gestational diabetes. Furthermore, progesterone stimulates breast tissue to produce growth hormone, which causes considerable insulin resistance. For this reason, if diabetes mellitus develops during pregnancy or dioestrus it can be classified as gestational diabetes, equivalent to that occurring in women. If the diabetes persists after the pregnancy or at the end of the dioestrus, it is classified as type 1 diabetes. 

Juvenile diabetes in the dog is extremely rare and presumably has a genetic basis. All the cases of diabetes mellitus described in puppies and kittens are type 1 diabetes mellitus. The onset of juvenile diabetes mellitus occurs between 3 and 6 months of age and the clinical signs, including diabetic cataract, develop rapidly.

TYPE 2 DIABETES MELLITUS IN THE CAT

Type 2 diabetes accounts for 80-95% of cases of diabetes in cats. It has a complex aetiology involving a combination of genetic and environmental factors. The risk increases with age. The underlying cause of this form of diabetes is insulin resistance, which can have various causes (Tab. 1). The hyperglycaemia deriving from the insulin resistance damages the pancreatic β cells (glucose toxicity) to the point of causing complete functional exhaustion of these cells.

EPIDEMIOLOGY

Age: diabetes mellitus in the dog and cat is generally diagnosed in animals aged between 4 and 14 years old, with the highest prevalence between 7 and 10 years. Juvenile diabetes is manifested in animals under 1 year old and is extremely rare in both species.

Sex: the incidence of diabetes in the dog is two times higher in females than in males. In cats, on the other hand, the incidence is higher in males.

Breed: genetic, breed and family predispositions seem to play an important role in the establishment of diabetes in the dog. Studies have been carried out in many countries to determine which breeds are more predisposed to this endocrine disorder. In Italy the breeds that seem to be at greatest risk are the Irish Setter, Poodle, Yorkshire Terrier and English Setter. As far as concerns cats, there does not seem to be a predisposition in any particular breed, although Burmese cats are the breed most frequently reported to be affected in Australia and in New Zealand.

CLINICAL SIGNS

The four classical signs of diabetes mellitus are polyuria, polydipsia, polyphagia and weight loss. The lack of insulin leads to less use of glucose, amino acids and fatty acids, increased hepatic gluconeogenesis and glycogenolysis and, consequently, a state of hyperglycaemia.

Polyuria and polydipsia (Pu/Pd): the increased circulating glucose abundantly exceeds the capacity of the renal tubular cells to reabsorb the glucose present in the glomerular ultrafiltrate and glucose is, therefore, lost in the urine. Glycosuria usually occurs when the level of glycaemia is over 180-200 mg/dl in the dog and 200-300 mg/dl in the cat. A state of osmotic diuresis is created which causes polyuria and a compensatory polydipsia.

Polyphagia and weight loss: the incapacity of cells in peripheral tissues to use glucose causes a progressive loss of weight. An interaction between the hypothalamic satiety centre and the hunger centre is responsible for the amount of food an individual eats. The hunger centre functions constantly but can be temporarily inhibited by the satiety centre after food intake. Glucose enters the cells of the satiety centre only in the presence of insulin and, therefore, in subjects with diabetes mellitus, glucose is not able to activate the satiety centre and inhibit hunger. Thus, despite the hyperglycaemia, subjects with diabetes mellitus overeat.

Clinical examination: the clinical examination may reveal hepatomegaly due to hepatic lipidosis and a variable degree of dehydration (in 48% of animals). Another very common finding in the dog is bilateral cataract (68% of animals), which is not found in cats. Cats may, however, sometimes have a dull coat and scurf. Furthermore, some individuals develop difficulty in jumping, weakness/ataxia of the posterior limbs or a plantigrade posture (diabetic neuropathy) (Fig. 1]). In some cases clinical signs related to hypertension may be present.

LABORATORY FINDINGS

A minimum set of laboratory tests for a patient with diabetes mellitus should include a full blood count, basic biochemistry screen, and physicochemical and bacterial studies of the urine.

Full blood count
In patients with uncomplicated diabetes, the full blood count does not usually show any abnormalities. If the animal is dehydrated there may be a mild relative polycythemia. An increase in white blood cells may indicate an ongoing inflammatory process, in particular if there is concomitant pancreatitis.

Biochemical profile
The biochemical alterations depend on the time passed between the onset of the disease and the moment of diagnosis and may reveal the presence of possible concomitant disorders. In an animal in a good clinical state often the only findings are hyperglycaemia and hypercholesterolaemia. In fact, uncontrolled diabetes is accompanied by increased blood levels of triglycerides, cholesterol, lipoproteins, chylomicrons and fatty acids. Other common findings are raised levels of alkaline phosphatase and alanine transaminase, both usually with values below 500 IU/L. Higher values should trigger investigations to determine whether there is a concomitant disorder such as hypercortisolism or a liver disease. Electrolyte and acid-base imbalances occur during diabetic ketoacidosis.

Physicochemical examination of the urine
On examination of the urine, findings compatible with diabetes mellitus are: glycosuria, ketonuria, proteinuria and, sometimes, bacteriuria associated or not with pyuria or haematuria. Proteinuria can be the consequence of an infection of the urinary tract or of glomerular damage secondary to destruction of the basement membrane. In the case of uncomplicated diabetes, it is common to find only glycosuria, without ketonuria. At the time of diagnosis it is good practice to carry out bacterial studies of the urine, sampled by cystocentesis, to exclude any infection of the urinary tract, since such infections are common in subjects with diabetes mellitus (incidence of about 20%). 

Despite the polyuria that occurs in diabetes, the specific gravity of the urine is high, usually with values above 1.025, because of the presence of glucose. In cases in which the specific gravity is below 1.020 it is worth investigating for the existence of  a concomitant disorder characterized by polyuria-polydipsia, such as renal failure or hypercortisolism.

DIAGNOSIS

The diagnosis of diabetes mellitus is made on the basis of the clinical signs and the finding of persistent hyperglycaemia and concomitant glycosuria. Mild hyperglycaemia (130-180 mg/dl) is clinically asymptomatic and is usually found incidentally. There are various causes (Table 2). Stress-induced hyperglycaemia is common in cats, but only occasionally found in dogs and does not usually cause glycosuria. In order to confirm the diagnosis in the cat it is, therefore, essential to determine the concentration of fructosamine: high levels indicate a state of persistent hyperglycaemia although the levels may be within the normal reference values if the diabetes has developed only within the preceding 2 or 3 weeks.

Table 2: Causes of mild hyperglycaemia in the dog and cat.

At the time of the diagnosis, a clinical examination and laboratory investigations should be performed to look for any concomitant disorders that could render the insulin therapy ineffective (Table 3).

Table 3: Common concomitant conditions in dogs and cats with diabetes mellitus.

TREATMENT

The aim of treatment is to eliminate clinical signs, limit fluctuations in blood glucose levels and maintain the concentration of glucose in the blood close to the reference values. In this way it is possible to avoid the complications that occur during poorly controlled diabetes. These objectives can be reached through correct insulin therapy, an appropriate diet, constant, moderate physical exercise and good management of any concomitant disorders. Another important therapeutic aim in the cat is to obtain a remission of the disease.

INSULIN THERAPY

Mixed-action or long-acting insulin can be used for the management of diabetic dogs and cats. The insulin must be given twice daily, 12 hours apart, together with a meal. Ideally the dose of insulin and amount of food in the morning should be identical to those in the evening. There are currently numerous types of commercially available insulin. They are classified on the basis of their speed of action, duration and intensity of effect and origin. The forms of insulin commonly used in Italy for the long-term management of diabetes are the following:

Compound insulin zinc suspension

• Category: this is classified as a slow-acting insulin, although it is a mixture of 30% amorphous zinc and 70% crystalline zinc;
• Concentration: 40 IU/ml;
• Origin: a porcine insulin which, from a structural point of view, is identical to that of canine insulin so the probability of antibody reactions developing in dogs is very low;
• Characteristics: a suspension, so it must be mixed every time it is used by gently rolling the bottle in the hands. Since its concentration is different from the insulin used for humans it is important that it is administered exclusively with the green syringes provided with the product. It is the only insulin that has been registered for dogs and cats and numerous scientific studies have demonstrated its good efficacy and safety;
• Dose: the recommended starting doses are 0.25-0.5 IU/kg subcutaneously every 12 hours in the dog and 1 IU/cat every 12 hours for cats weighing <4 kg or if the glycaemia is <360 mg/dl on admission or  2 IU/cat every 12 hours for cats weighing >4 kg or if the glycaemia on admission is >360 mg/dl;
• Pharmacokinetics and pharmacodynamics:
  • onset of effect: at 3 hours (peak at 3-4 hours and at 9-11 hours);
  • maximum effect: 4-8 hours;
  • mean duration: 15-17 hours.  

Glargine

• Category: long-acting insulin analogue;
• Concentration: 100 IU/ml;
• Origin:recombinant human;
• Characteristics:does not need to be mixed before administration. It is an aqueous solution with a pH=4. The interaction between the acid pH of the insulin and the relatively neutral pH of the subcutaneous tissues leads to the formation of microprecipitates at the site of injection from which small amounts of glargine are gradually released. For these reasons glargine should not be diluted or mixed with other substances. In humans the slow and constant release of glargine from the microprecipitates provides a steady blood concentration for about 24 hours, without particular peaks of serum insulin concentration occurring;
• Dose: the recommended starting dose is 0.25-0.5 IU/kg subcutaneously every 12 hours both in the dog and in the cat;
• Pharmacokinetics and pharmacodynamics:
  • onset of effect: 1.3 ± 0.5 hours;  
  • maximum effect: 5.3 ± 3.8 hours;  
  • mean duration: 11.3 ± 4.5 hours.  

In the dog: the efficacy of glargine in the dog has yet to be demonstrated. Preliminary studies indicate that it is slightly inferior to compound insulin zinc suspension, while the risk of it causing hypoglycaemia is lower.

In the cat: recent studies have shown that this type of insulin is an effective treatment for diabetes mellitus in the cat, providing good control of blood glucose levels, limiting the peaks of hyperglycaemia during the day with a low risk of episodes of hypoglycaemia.

Glargine insulin, administered twice daily and associated with a protein-rich, carbohydrate-poor diet, seems to produce a higher percentage of remissions compared with other types of insulin.

Detemir

• Category: long-acting insulin;
• Concentration: 100 IU/ml;
• Origin: recombinant human;
• Characteristics: this is an ultraslow-acting insulin. Acetylation of the molecule confers longer binding with albumin, a prolonged duration of action and contemporaneously has enabled the preparation of a neutral, liquid formulation. As of present the literature on this insulin is scarce, although its efficacy seems similar to that of glargine;
• Dose: the recommended starting dose is 0.25-0.5 IU/kg subcutaneously every 12 hours; 
• Pharmacokinetics and pharmacodynamics:
  • onset of effect: 1.8 ± 0.8 hours;
  • maximum effect: 6.9 ± 3.1 hours;
  • mean duration: 13.5 ± 3.5 hours.  

DIETARY TREATMENT

Diet plays an important role in the management of the diabetic patient and must be considered an integral part of the therapeutic protocol. The daily food intake should be divided into two identical meals given 12 hours apart at the same time as the insulin dose is given.

In the dog: a fibre-rich diet leads to slower intestinal absorption of glucose and better control of glycaemia. Food stuffs that contain at least 12% of insoluble fibre and at least 8% of soluble and insoluble fibres seem to be the most effective in improving blood glucose trends in diabetic dogs. Problems that can be related to a fibre-rich diet include: increased number of stools passed during the day, constipation, flatulence, hypoglycaemia 1 or 2 weeks after the increase in the fibre content and refusal to eat the food because it is unpalatable. Furthermore, fibre-rich diets should not be prescribed to underweight animals. The ideal protein content is controversial; nevertheless, it is advisable to prescribe a diet that does not contain more the 30% of proteins (expressed as percentage of energy that can be metabolised). The lipid content of the diet must be relatively low and remain below 30% (expressed as percentage of energy that can be metabolised). A higher lipid content can be prescribed for underweight patients who need to reach optimal nutritional status. It should be remembered that obesity makes successful insulin therapy difficult, so the obese diabetic patient should be given a high-fibre, low-calorie diet.

In the cat: different studies have shown that a protein-rich diet extremely low in carbohydrates improves glycaemic control and allows the dose of insulin to be reduced significantly.

PHYSICAL EXERCISE

Moderate, constant physical exercise helps good control of blood glucose levels in diabetic patients, promotes loss of weight and eliminates insulin resistance due to obesity. Furthermore, exercise mobilises insulin from its site of injection. Intense physical exercise can cause hypoglycaemia; in the case in which intense physical exercise is foreseen (for example, hunting) the dose of insulin given prior to the physical activity should be halved.

CONTROLS AND MONITORING

Having diagnosed diabetes mellitus in an animal, it is important to inform the owner that it will take 2-3 months to reach stable blood glucose control. The first controls should be carried out 1, 3, 8, and 12 weeks after the diagnosis and then about every 4 months. Every time insulin therapy is modified, the patient should be re-evaluated 7-14 days after the change in dose.

The controls should include:

1) history

2) clinical examination

3) evaluation of fructosamine

4) a blood glucose curve (BGC)

5) home monitoring.

1) History: it is important to ask the owner for information about whether or not clinical signs are present: whether Pu/Pd continues or not, whether the animal’s weight is stable and its appetite maintained. If there is a history of episodes of vomiting and/or diarrhoea and/or altered appetite, investigations of possible diabetic ketoacidosis and/or concomitant pathologies should be made.

2) The control clinical examination should include a careful clinical examination and monitoring of the subject’s weight.

3) Measurement of fructosamine levels gives an indication of the mean blood glucose levels over the preceding 2-3 weeks.

Table 4: Fructosamine concentrations in normal and diabetic subjects.

This parameter has the advantage of not being affected by stress-induced hyperglycaemia or lack of food intake, conditions which often alter the outcome of the blood glucose curves measured in the clinic. However, other factors can influence its blood concentration (Tab. 5) and sometimes there are discrepancies between fructosamine levels on the one hand and the clinical signs and blood glucose curve on the other.

Table 5: Factors that can influence the concentration of fructosamine in the dog and cat.

4) Blood glucose curve. Monitoring patients by serial measurements of blood glucose levels is fundamental for the long-term management of the disease. Blood glucose curves show the efficacy of insulin therapy, the nadir and the duration of the effect of the insulin; furthermore, they enable the veterinarian to establish the correct dose of insulin for the patient. The blood glucose levels can be measured using automated analysers or portable blood glucose monitors (PBGM).

Protocol: in order to construct a blood glucose curve, the level of glucose in the blood is measured immediately in the morning with the patient fasting and before the insulin is administered. After this measurement the usual meal and the prescribed dose of insulin are given. Following this the blood glucose level is measured every 2 hours over a total of 12 hours (seven measurements). In the case in which the patient refuses to eat in the clinic, the animal can be given the meal and insulin at home and the blood glucose curve started only after the meal.

Interpretation of the results: ideally, the glucose levels should remain between 100 mg/dl and 250 mg/dl.

• Glucose differential: this is the difference between the highest and the lowest blood glucose levels and provides an indication of the efficacy of the insulin.
• Nadir: this represents the peak activity of the insulin. Ideally it should be between 100 and 125 mg/dl. If the nadir is greater than 150 mg/dl, the dose of insulin should be increased. If the nadir is below 80 mg/dl, the dose should be decreased by about 10-25%.
• Duration of effect of the insulin: this is defined as the time between administration of the insulin and the moment at which the glycaemia exceeds 250-270 mg/dl. If the duration of effect is shorter than 8-10 hours, the patient usually manifests clinical signs of diabetes mellitus. If the effect of the insulin lasts more than 14 hours, there is an increased risk of hypoglycaemic crises or Somogyi’s effect.

In the case in which monitoring by fructosamine and/or a blood glucose curve shows that the insulin dose is insufficient, the dose should be increased by 10-25%. If, on the other hand, the amount of insulin is too high (fructosamine <300 μmol/l and/or nadir <80 mg/dl) the dose should be reduced by 10-50%.

The blood glucose curve can reveal a possible Somogyi’s effect (paradoxical hyperglycaemia): excessive doses of insulin can cause hypoglycaemia with consequent release of hormones that promote the increase of blood glucose levels, thereby raising these levels considerably. Subjects usually continue to show clinical signs, despite high doses of insulin. The hyperglycaemic state can even persist for some days and a single evaluation of the blood glucose level would erroneously lead the veterinarian to increase the dose of insulin. The blood glucose curve, however, shows the swinging course of the glycaemia during the day, with periods of hypoglycaemia followed by notable peaks of hyperglycaemia. In the case in which Somogyi’s effect is suspected, the dose of insulin should be decreased by at least 50%.

In order to avoid establishing this type of effect, the insulin therapy must always be started at the doses indicated above and increased gradually, only after having controlled the situation correctly with a blood glucose curve and/or fructosamine assay. In addition, it is important not to increase the dose of insulin until at least 4-5 days after the previous dose modification.

5) Home monitoring. Blood glucose curves are usually produced in the clinic by the veterinarian; however, the cost of this procedure for the owner, in terms of both time and money, should not be undervalued. Furthermore, blood glucose levels can be affected by the stress animals (in particular cats) feel in an unfamiliar environment. In order to overcome these problems, some authors have suggested that the monitoring could be carried out at home by the animal’s owner. This is possible by pricking the capillaries of the internal surface of the pinna or labial mucosa and testing the collected blood in a portable device for measuring glycaemia. There is a good correlation between the levels of glucose measured in venous blood and capillary blood. The procedure is quick and easy for the veterinarian, but also for the animal’s owner.

Portable blood glucose meters
There are numerous devices for measuring blood glucose levels in humans; these devices have the advantage of being small and requiring minimal amounts of blood for the measurements (3-4 µL). Most portable blood glucose meters (PBGM) can use capillary blood or venous blood (fresh blood, blood collected into EDTA and blood in lithium heparin) without substantial differences in the values obtained, although they are subject to errors caused by the user, the environmental conditions and the blood used for the measurements. It is important to use the most accurate glucose meters and those that have been reported in recent literature to provide reliable results in veterinary medicine (Tab. 6).

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20. - Insulin resistance in dogs. Vet Clin North Am Small Anim Pract. 40(2): 309-16, 2010.
21. Gilor C, Ridge TK, Attermeier KJ, Graves TK- Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats.J Vet Intern Med. 24(4): 870-4, 2010.
22. Sako T, Mori A, Lee P, Oda H, Saeki K, Miki Y, Kurishima M, Mimura K, Nozawa S, Mizutani H, Makino Y, Ishioka K, Arai T.- Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2010.
23. Eisenbarth G.S.– Type 1 Diabetes Mellitus. A chronic autoimmune disease. The New EnglandJournal of Medicine 314: 1360-1368, 198
24. Rijnberk A, Kooistra HS, Mol JA- Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans. Growth Hormone & IGF Research13: S158–S164, 2003.
25. Rand JS, Fleeman LM, Farrow HA, Appleton DJ, Lederer R– Canine and Feline Diabetes Mellitus: Nature or Nurture? - WALTHAMInternational Science Symposium: Nature, Nurture, and the case for Nutrition. The Journal of Nutrition 2072-2080, 2010.
26. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus- Report of the expert committee on the diagnosis and classification of Diabetes Mellitus. Diabetes Care 26: 5-20, 2003.
27. Montgomery TM, Nelson RW, Feldman EC, Robertson K, Polonsky KS- Basal and glucagon-stimulated plasma C-peptide concentrations in healthy dogs, dogs with diabetes mellitus, and dogs with hyperadrenocorticism. J Vet Intern Med 10: 116-22, 1996.
28. Davison LJ, Herrtage ME, Steiner JM, Williams DA, Catchpole B– Evidence of anti-insulin autoeactivity and pancreatic inflammation in newly diagnosed diabetic dogs.J Vet Int Med 17: 395, 2003.
29. Davison LJ, Ristic JME, Herrtage ME, Catchpole B-  Cloning and sequencing of two potential canine pancreatic autoantigens: GAD65 and IA-2. J Vet Int Med 16: 360, 2002.
30. Alejandro R, Feldman EC, Shienvold FL, Mintz DH- Advances in canine diabetes mellitus research: etiopathology and results of islet transplantation. J Am Vet Med Assoc.193: 1050-5, 1988.
31. Hess RS, Kass PH, Shofer FS, Van Winkle TJ, Washabau RJ- Evaluation of risk factors for fatal acute pancreatitis in dogs.  J Am Vet Med Assoc. 214: 46-51, 1999.
32. Williams DA– Diagnosi and management of pancreatitis. J Small Anim Pract. 35: 445-454, 1994.
33. Ling GV, Lowenstine LJ, Pulley LT, Kaneko JJ- Diabetes mellitus in dogs: a review of initial evaluation, immediate and long-term management, and outcome.  J Am Vet Med Assoc.170: 521-30, 1977.
34. Simpson KW– Current concepts of the pathogenesis and pathophysiology of acute pancreatitis in the dogs and cat. Compendium on Continuing Education fot the Practing Veterinarian. 15: 47-253, 1993.
35. Peterson ME, Altszuler N, Nichols CE - Decreased insulin sensitivity and glucose tolerance in spontaneous canine hyperadrenocorticism.  Res Vet Sci.36: 177-82, 1984.
36. CampbellKL, Latimer KS– Transient diabetes mellitus associated with prednisolone therapy in a dog. J Am Vet Med Assoc 185: 299-301, 1984.
37. Eigenmann JE, Eigenmann RY, Rijnberk A, van der Gaag I, Zapf J, Froesch ER- Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly.  Acta Endocrinol (Copenh).104: 167-76, 1983.
38. Scaramal JD, Renauld A, Gómez NV, Garrido D, Wanke MM, Márquez AG- Natural estrous cycle in normal and diabetic bitches in relation to glucose and insulin tests.Medicina (B Aires).57: 169-80, 1977.
39. Rand JS- Current understanding of feline diabetes mellitus: Part 1, pathogenesis. J Feline Med Surg 1: 143-153, 1999.
40. Goossens MMC, Nelson RW, Feldman EC, Griffey SM - Response to treatment and survival in 104 cats with diabetes mellitus (1985-1995). J Vet Int Med 12: 1-6, 1998.
41. Buscher H, Jacobs M, Ong G, Van Goor H, Weber R, Bruining H- β-cell function of the pancreas after necrotizing pancreatitis.  Dig Sur 16: 496-500, 1999.
42. Porte D- β-cells in type 2 diabetes mellitus. Diabetes 40: 166-180, 1991.
43. Panciera DL, Thomas CB, Eicker SW, Atkins CE- Epizootiological patterns of diabetes mellitus in cats: 333 cases (1980-1986). J Am Vet Med Assoc 197: 1504-1508, 1990.
44. Rand JS, Bobbermein LM, Hendrikz JK– Over-representation of Burmese in cats with diabetes mellitus in Queensland. Aust Vet J 75: 402-405, 1997.
45. Wade C, Gething M, Rand JS- Evidence of a genetic basis for diabetes mellitus in Bumese cats. J Vet Int Med 13: 269, 1999.
46. Baral R, Rand JS, Catt M, Farrow HA- Prevalence of feline diabetes mellitus in a feline private practice. J Vet intern Med 17: 433, 2003.
47. Greco DS- Pediatric endocrinology. Vet Clin Small Anim Prac 36: 549-556, 2006.
48. Crenshaw KL- CVT update: monitoring treatment of diabetes mellitus in dogs and cats. In: Bonagura JD, ed. Kirk’s current veterinary therapy XIII. Philadelphia: WB Saunders, 348-350, 1999.
49. Wess G, Reusch C- Capillary blood sampling from the ear of dogs and cats and use of portable meters to measure glucose concentration. J Sm Anim Pract 41: 60-66, 2000.
50. Casella M, Wess G, Reusch C- Measurement of capillary blood glucose concentrations by pet owners: a new tool in the management of diabetes mellitus.  J Am Anim Hosp Assoc.  38: 239-45, 2002.
51. Cohn LA, McCaw DL, Tate DJ, Johnson JC– Assessment of five portable blood glucose meters, a point-of-care analyzer, and color test strips for measuring blood glucose concentration in dogs. JAVMA216: 198-202, 2000.
52. Wess G, Reusch C- Assessment of five portable blood glucose meters for use in cats. AJVR61: 1587-1592, 2000.
53. Link KR, Rand JS, Hendrikz JK- Evaluation of a simplified intravenous glucose tolerance test and a reflectance glucose meter for use in cats. Vet Rec. 140: 253-6, 1997.
54. Hadar GS, Fracassi F, Pietra M, Famigli-Bergamini P- Assessment of two portable blood glucose meters for use in cats and dogs. Poster n°59 ECVIM-CA congress 8th-10^th September 2009.
55. Lederer R, Rand JS, Hughes I, Fleeman LM- Chronic or recurring medical problems, dental disease, repeated crticosteroid treatment and lower phisical activity are associated with diabets in Burmese cats. J Vet Int Med 17: 433, 2003.
56. Elliot DA, Nelson RW, Reusch CE, Feldman EC, Neal LA – Comparison of serum fructosamine and blood glycosylated hemoglobin concentration for assessment of glycemic control in cats with diabetes mellitus. J Am Vet Med Ass214: 1794,1999.
57. Niessen SJ, Petrie G, Gaudiano F, Khalid M, Smyth JB, Mahoney P, Church DB – Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Int Med21: 299-905, 2007.
58. Niessen SJ– Feline Acromegaly: An essential differential diagnosis for the difficult diabetic. Journal of Feline Medicine and surgery 12: 15-23, 2010.Scott-Moncrieff JC- Insulin resistance in cats. Vet Clin Small anim40:241-257, 2010.
59. Reusch CE, Shellenberg S, Wenger M- Endocrine Hypertension in small animal. Vet Clin Small Anim40: 335-352, 2010.