Pathophysiology

The pancreas is a bilobed organ which sits in the cranial abdomen, between the stomach and the duodenum. The pancreas is an organ of both exocrine and endocrine functions – the pancreatic acinar cells are responsible for the formation and secretion of digestive enzymes, and the endocrine cells within the Islets of Langerhans are responsible for glucose homeostasis. This is mainly achieved through the hormones glucagon and insulin.

Glucagon is secreted from alpha cells, and increases blood glucose levels by converting stored glycogen in the liver into glucose. Insulin is released from beta cells in response to elevated blood glucose levels. This hormone reduces blood glucose by stimulating fat, liver and muscle tissue to store glucose, reducing circulating glucose levels. Glucagon and insulin are released as required based on the body’s blood glucose level, and counteract each other to maintain normoglycaemia in a healthy patient.

In a diabetic patient, this balance is disrupted and blood glucose levels rise. In 80-90% of cats, this is caused by a combination of insulin resistance (reduced efficacy of insulin action in the liver, adipose and muscle tissue) and beta cell failure (‘Type 2’ diabetes). The remaining 10-20% of cats have other, more specific causes of diabetes mellitus. These include conditions such as acromegaly (where a benign, pituitary gland mass causes excessive release of growth hormone, which causes insulin-resistant diabetes), hyperadrenocorticism (Cushing’s disease), pancreatitis and pancreatic lesions. Certain medications, particularly steroids and progestogens, are also linked to diabetes mellitus as they cause insulin resistance.

As diabetic cats have insulin resistance and beta cell failure, as opposed to an absolute insulin deficiency, a cat can achieve diabetic remission if their disease is identified early and tightly controlled from an early stage.

The pathophysiology of diabetes mellitus in cats differs significantly to dogs, the majority of whom have an absolute insulin deficiency due to immune-mediated destruction of the beta cells (‘Type 1’ diabetes). This results in an absolute deficiency of insulin, meaning they will require lifelong treatment with no ability to enter diabetic remission. Specific other causes of canine diabetes include pregnancy/oestrus (e.g. gestational diabetes), the use of certain medications, and hyperadrenocorticism (5% of Cushingoid dogs are reportedly also diabetic, compared with 80% of Cushingoid cats).

Certain factors have been established as risk factors for the development of diabetes. In cats, these include obesity, which causes insulin resistance; increasing age; indoor-only access and physical inactivity; male gender; neutering; breed; and administration of steroids/progestagens. In dogs, these include middle-to-older age (7+), female dogs, and certain breeds (Schnauzer breeds, Siberian Huskies, Finnish Spitzes, Samoyeds, Golden Retrievers and some terrier breeds).

The hyperglycaemia we see in our diabetic patients in turn causes further damage to the beta cells; decreasing insulin secretion and increasing insulin resistance even further. This is known as glucose toxicity, and this cycle of hyperglycaemia → glucose toxicity → insulin resistance & decreased secretion →hyperglycaemia can cause irreversible pancreatic damage, preventing the opportunity to achieve diabetic remission in cats.

When glucose levels exceed the renal threshold (14-16mmol/L), glucose spills from the bloodstream into the urine. It is at this point we see the clinical signs commonly associated with DM.

Clinical Signs

The classic signs we see in diabetic patients are polyuria, polydipsia and polyphagia +/- weight loss. As glucose spills into the urine, osmotic diuresis ‘pulls’ additional water into the urine to balance out the concentrated glucose. This increased water content causes the polyuria seen in these patients. As these patients lose more water, they become polydipsic to compensate for the increased fluid losses. As glucose is lost in the urine, our diabetic pets may eat more to compensate for the energy/calorie losses, causing polyphagia. Additionally, as protein breakdown increases in cases of insulin resistance, we see weight and muscle loss in these patients.

Other signs we may see in diabetic cats include a plantigrade stance (where the metatarsals and hock are flat to the ground when walking) caused by hyperglycaemia-associated nerve injury (diabetic neuropathy). Though less common, hypertension has also been reported in diabetic cats, and so target organ damage (particularly ocular changes) may be seen. In dogs, visual deficits and diabetic cataract formation is common.

Diabetic Ketoacidosis

If diabetes remains undiagnosed for some time, ketone bodies are formed from lipids as an alternative energy source. Metabolic acidosis and ketosis results, and patients may present with signs of diabetic ketoacidosis (DKA) initially. These signs include vomiting, anorexia, weight loss, dull mentation and dehydration, and patients with DKA require prompt stabilisation and intensive nursing care prior to long-term diabetic management.

Diagnostic Tests

When investigating a potential case of diabetes mellitus, a number of diagnostic tests may be performed. These typically include a full biochemistry, electrolytes, haematology and urine analysis, alongside other specific tests. Parameters of particular importance include:

Glucose

Consistent hyperglycaemia is seen. Acute, transient, increases may be seen with stressed cats, and these increases can be severe (>16mmol/L).

Fructosamine

Fructosamine is a glycated protein which reflects the mean blood glucose concentration over the previous 2-3 weeks. This test is not affected by stress hyperglycaemia, unlike blood glucose concentrations3.

Biochemistry

A full biochemistry panel is typically performed to assess for any concurrent renal or hepatic disease, as both can cause insulin resistance3.

Total +/- Free T4

Total T4 levels are performed to assess for any concurrent thyroid disorders which could be causing insulin resistance.

Pancreatic Lipase (PLi)

PLi may also be checked to assess for pancreatitis which could be causing insulin resistance.

Urinalysis On dipstick analysis, we see glucosuria, and may see ketonuria if the patient is ketotic. Specific gravity may be reduced in cases of PU/PD, or concurrent chronic kidney disease.

A urine culture should always be performed, since diabetic patients are at increased risk of a urinary tract infection (due to glucosuria +/- dilute urine). A cystocentesis sample should always be obtained for culture to avoid external contamination.

Venous Blood Gas Analysis

If available in practice, a venous blood gas can be performed to assess the patient’s acid/base status, and ideally should be performed in all patients where DKA is suspected.

Treatment

The main goals of diabetic treatment are to resolve the patient’s clinical signs, whilst avoiding hypoglycaemia. Resolution of clinical signs is achieved by maintaining the patient’s blood glucose level below the renal threshold (14-16 mmol/L) as much as possible, or below 11mmol/L to prevent further glucose toxicity. Ideally, patients should return to a normal appetite and water intake, and maintain a stable bodyweight.

In cats, reverting the patient back to a subclinical state (achieving diabetic remission) should also be a treatment goal, though this may not be possible if the patient has been hyperglycaemic for some time.

Treatment typically consists of exogenous insulin administration, alongside dietary modifications, weight loss in overweight patients, management of any concurrent diseases, and withdrawal of any diabetogenic medications such as steroids.

Insulin

Administration of insulin is the main component of treatment in diabetic patients. Many different insulin types are available for use; each have different indications, durations of action and nadirs, both in dogs and cats:

Neutral or regular insulin has a short duration of effect and a rapid onset of action. It is used only in DKA patients, and is administered either via intermittent intramuscular injections, or as a constant rate infusion. It is not suitable for long-term use, and is not licensed.

Lente insulin or Caninsulin has an intermediate duration of effect. It is a porcine insulin given subcutaneously (SC) every 12 hours. The duration of effect is typically 8-10 hours, resulting in poor control in some cats, and the nadir (point of lowest blood glucose/peak effect) is typically 2-6 hours post-injection1. Caninsulin is licensed for veterinary use and available as a 40IU/ml concentration.

Protamine Zinc (PZI) insulin contains protamine and zinc, which crystallises with insulin to release insulin gradually. It is a long-acting insulin given SC every 12 hours. The duration of effect is reported to be 13-24 hours, with the nadir reported 2-6 hours post injection. PZI is licensed for veterinary use (ProZinc), and is available as a 40IU/ml concentration.

Glargine insulin is a long-acting, slow onset insulin analogue given SC every 12 hours. The duration of effect and nadir can be variable, with durations reported from 12->24 hours, and the nadir reported 12-14 hours post injection1. With glargine, the glucose curve ‘flattens out’ after 7-10 days of treatment as blood glucose levels remain more consistent. It is not licensed for veterinary use.

Diet

The main goal of dietary therapy is to reduce the impact of a meal on blood glucose levels. As carbohydrates are converted to glucose, high-carbohydrate diets increase insulin demand. Diabetic cats should therefore be fed a high protein, low carbohydrate diet (carbohydrate content less than 12% of metabolisable energy) to reduce the demand on the pancreatic beta cells to release insulin. Dogs should be fed a complete, balanced, palatable diet high in complex carbohydrates and free of simple sugars.

The diet should begin at the time of treatment initiation, and the patient transitioned gradually onto the new diet. The diet should be continued long-term,. Cats, can be fed as per their previous normal routine, whereas dogs should be fed 50% of their resting energy requirement every 12 hours, at the time of insulin injection.

Inpatient Care

Glucose Curves

Diabetic patients are commonly hospitalised in practice for glucose curves. These can be a useful tool in assessing a patient’s response to insulin, but are not without limitations. In cats, stress hyperglycaemia can significantly affect glucose curve results. In addition, blood glucose levels can significantly vary day-to-day and an 8-10-hour window may not give us a true representation of the patient’s overall glycaemic control.

In some cases, it may be better to perform curves at home, by teaching clients how to use a glucometer. This minimises stress, and maximises normal food intake and routine. More data can also be gained by regular testing at home if needed, rather than less regular appointments for day hospitalisation.

If you are performing glucose curves in the clinic, use a glucometer validated for use in veterinary patients. Glucose distribution differs between human, feline and canine blood, and inaccuracies of 1-2mmol/l lower are reported when human glucometers are used. Keep the sampling site consistent, to avoid any differences in BG concentration between sites. Capillary blood (such as an ear or paw pad) is preferred as many glucometers are calibrated for this, rather than venous blood. Additionally, avoid using peripheral or central veins if possible, to preserve them for larger sample volumes and catheterisation.

Ask clients to bring in their pet’s own food, bowls and bedding +/- litter tray and litter. Schedule the pet's food and insulin timings at hospital to match those at home, and keep feeding patterns consistent with their normal routine wherever possible.

In addition, promoting a fear-free and relaxing environment is important to reduce stress and minimise its effect on blood glucose concentrations in cats.

An alternative to blood glucose monitoring is a continuous glucose monitor . These measure interstitial fluid glucose (not blood glucose) via a small needle in a sensor applied to the skin via an applicator ‘stamp’. Each sensor lasts up to 14 days and the data is recorded via a reader, and uploaded to the cloud where it can be accessed by the practice.

These readers provide considerably more information than a glucose curve, and avoid handling-associated hyperglycaemia. Patients can also be discharged with them in situ for clients to read at home.

General Inpatient Care Considerations

As previously discussed, steps should be taken to minimise stress as much as possible during hospitalisation. In addition to any routine examinations and vital parameter checks, careful attention should be paid to the patient’s weight and body condition score, food intake and water intake. Resting energy requirements should be calculated daily based on the bodyweight that day, and food offered and consumed should be measured and recorded. Water intake should be monitored and sufficient water offered to meet the needs of a polydipsic patient.

The patient’s diet in hospital should be kept as consistent as possible, as should the timing of any food and insulin administration.

Hypoglycaemia

Diabetic patients should be monitored for signs of hypoglycaemia; this is most relevant around the time of the nadir, and when concurrent disease or illness causes vomiting, anorexia or other signs which may impact blood glucose levels. Signs of hypoglycaemia include lethargy or changes in mentation, ataxia, muscle twitching, weakness, disorientation and seizures. Where hypoglycaemia is considered a risk, an emergency plan should be clearly available on the kennel. This should include pre-calculated doses for bolus administration, and instructions on how to prepare a glucose infusion if required. Glucose injection, needles and syringes should be stored next to the emergency plan, allowing rapid intervention in an emergency.

Outpatient Care

Outpatient support is a key area of diabetic management, and is an especially rewarding area for veterinary nurses.

In a study performed at the Royal Veterinary College, 69% of diabetic pet owners reported a negative impact on their animal’s quality of life. The participants in the study also listed a number of concerns about managing diabetes at home, including provisions for holiday boarding, adjustments to work and social life, increased treatment costs. Interestingly, the only concern raised in the study relating specifically to the animal was the concern about diabetic control and the risk of hypoglycaemia. This demonstrates how much difference client support can make; by providing this at an early stage, treatment outcomes can be maximised.

Nurse support should begin at patient discharge, with support and advice on: insulin storage, handling, transport and disposal; injection training and technique, with practice on a cuddly toy or similar; and a discussion on diet, including the diet type, timings of feeding, and any weight loss support required. The treatment plan should, as far as is possible, remain consistent with the client and patient’s normal routine, to minimise any obstacles to treatment. Patients should be discharged with a ‘diabetic diary’ for the clients to fill in each day, allowing the team to review the patient’s daily management at-a-glance in follow-up appointments.

The provision of regular diabetic nurse consultations is a key area of support. This provides familiarity and comfort for the client as they see a familiar face, encourages them to discuss freely without feeling rushed, increases clinic utilisation of registered veterinary nurses, and increases the available time for veterinary surgeon consultations.

Nurses can use these consultations to obtain a recent history (including activity level, urination, drinking and food intake), review the patient’s diabetic diary, weigh the patient and provide dietary or weight loss (if required) advice. As far as we are able to as veterinary nurses, medications can be discussed, and further support on insulin use and injection technique can be provided.

Where required, diagnostics can also be performed at that consultation, if requested by the veterinary surgeon. These regular diagnostics typically include urine analysis, blood pressure measurement and blood sampling.

Any ‘red flags’ from the nurse consultation can then be brought to the veterinary surgeon’s attention easily and quickly, allowing prompt investigation.

References

1. Merrill L. 2012. Small Animal Internal Medicine for Veterinary Technicians and Nurses. Iowa: Wiley-Blackwell.

2. Niessen S, Powney S, Guitian J, et al. 2010. Evaluation of a Quality-of-Life Tool for Cats with Diabetes Mellitus. Journal of Veterinary Internal Medicine, 24, pp. 1098-1105.

3. Sparkes A, Cannon M, Church D, et al. 2015. ISFM Consensus Guidelines on the Practical Management of Diabetes Mellitus in Cats. Journal of Feline Medicine and Surgery, 17, pp. 235-250.

4. Taylor S, Sparkes A, Briscoe K, et al. 2017. ISFM Consensus Guidelines on the Diagnosis and Management of Hypertension in Cats. Journal of Feline Medicine and Surgery, 19, pp. 288-303.