Diabetes mellitus is a chronic metabolic disorder characterised by high blood glucose caused by insulin deficiency or insulin resistance. It can be:
Diabetes insipidus is caused by an absolute or relative deficiency of antidiuretic hormone, and is usually treated with thiazide diuretics. It is rare.
Insulin is a complex protein made and stored in the B cells of the islets of Langerhans in the pancreas. The amino acid sequence of the protein differs slightly between species. Insulin is produced initially in the form of preproinsulin, a single chain precursor. This is converted to proinsulin, and then insulin and is packaged in granules ready for release by exocytosis. Increased blood glucose increases insulin secretion via increased ATP in the B cells which blocks ATP-sensitive K+ channels and depolarises the cells. This causes Ca++ influx and exocytosis of insulin. Other stimuli for insulin release include gastrin, secretin, cholecystokinin and glucagon-like peptide - all released by eating. Vagal stimulation will do the same. α2 adrenoreceptor agonists (including adrenaline and noradrenaline) reduce, and antagonists increase insulin release, probably by an action at the imidazoline I3 receptor.
Insulin is degraded in the liver, kidney and muscles.
Insulin stimulates the uptake and metabolism of glucose, amino acids and fatty acids in fat and muscle. It inhibits hepatic glycogenolysis and gluconeogenesis, and the catabolism of protein and fat. It is also anabolic, especially in the foetus.
Treatment involves a combination of dietary and exercise management, and either oral hypoglycaemics or insulin.
A high fibre, high complex carbohydrate diet is desirable in dogs. Avoid foods containing simple sugars, which will be rapidly absorbed from the gastrointestinal tract and elevate blood glucose. Acarbose is sometimes used in diabetic people to slow sugar absortion. Fibre slows carbohydrate absorption and dampens the post prandial rise in blood glucose.
Cats should be given a high protein diet. Slow weight loss is needed in obese cats. At least two meals a day is advisable.
Diabetic patients classically present with polydipsia, polyuria, polyphagia and weight loss. There are several different situations you will have to manage:
•the fat diabetic cat - diet & insulin, or, if owner unable to give injections, diet & oral hypoglycaemics
•the thin, sometimes ketotic, diabetic cat - diet & insulin
•diabetic dogs - diet & insulin
•insulin resistant cases - ?
•diabetic ketoacidosis - soluble insulin iv infusion
•diabetic coma - soluble insulin by iv infusion
•insulin overdose - hypoglycaemic seizures/coma - iv glucose
These drugs are not often effective in dogs but sometimes are in cats. The two main groups of drugs are the sulphonylureas (glipizide (best in cats), glibenclamide, gliclazide, chlorpropamide (rarely used now) and tolbutamide (most widely used in vet medicine)) and biguanides (metformin). A promising new group of drugs (glitazones) includes rosiglitazone, pioglitazone, ciglitazone and troglitazone (since withdrawn - worked in diabetes but caused liver failure), which are thought to decrease insulin resistance.
Sulphonylureas work by direct stimulation of insulin secretion by the B cells by binding to the ATP-sensitive K+ channels and blocking them. In the longer term, they also cause increased tissue sensitivity to circulating insulin by an unknown mechanism.
Biguanides do not require functioning B cells. Their exact mechanism of action is unknown but they cause inhibition of hepatic glycogenolysis and increased peripheral glucose utilisation.
Non insulin dependent diabetes
Approximately 25% of cats will respond to these drugs, so insulin may not be required.
•hypoglycaemia
•vomiting shortly after administration - usually subsides with time
•increased hepatic enzymes (but clinical liver disease has not been reported)
Sulphonylureas may contribute to the progression of type 2 diabetes. The response isusually slow, and in the meantime, hyperglycaemia can cause B cell death. Glipizide can also cause cats to deposit more amylin (co-released with insulin) in their pancreas, also resulting in B cell death.
In people side effects reported include cytopaenias, nausea and vomiting, cholestasis and hypersensitivity. Sulphonylureas can promote weight gain.
Most animals with diabetes mellitus will require insulin. A variety of insulin formulations are available in NZ but all except one are human recombinant insulin. The other is pig insulin marketed for dogs - nb, it is 40iu/mL as opposed to the standard human 100iu/mL.
Insulin has traditionally been conjugated with a number of adjuvants to alter its solubility and thus speed of onset and duration of action. A newer approach is to alter the protein itself to change its duration of action. Beware; the nomenclature is confusing!
an insulin analogue in which a lysine and a proline residue have been swopped. It is the most rapid and shortest acting. Insulin aspart is similar. These are relatively new and there is not much information on effects in animals.
(crystalline / neutral / regular insulin) is rapid acting, short duration and is used iv in emergencies, onset of action - minutes, maximum effect 30 mins - 2 hours, duration 1 - 4 hours (prolonged to 4 - 10 hr if given sc)
(NPH insulin) (complexed with protamine) is intermediate acting, only given sc - onset 30 min - 3 hr, duration 4 - 24 hr depending on preparation
a mixture of soluble and amorphous crystals complexed with zinc chloride. Small lumps / crystals are absorbed slowly (lente insulin), big lumps / crystalls are absorbed more slowly (ultra lente insulin). These are only given sc and last about 24 hours.
Mixtures of these are also sold to get a fast onset and long duration. The insulin in these preparations is the same; the formulation is merely adjusted to alter its rate of release.
insulin glargine is another longer acting analogue (24 hours in people). It has not reached NZ yet.
The price of insulin is approximately $50 for 10 mls of a 100 IU/ml suspension. Insulin must be given parenterally as it is inactivated by proteolytic enzymes.
An animal’s requirement for insulin will vary throughout the day, depending on feeding and exercise. Once the animal has stabilised on insulin (usually about a week) it is usual to measure blood glucose every 1 - 2 hours and plot a glucose curve for 24 hours to reasess the dose. A single blood glucose can be misleading.
Insulin resistance is defined as persistent hyperglycemia, glucosuria and clinical signs, despite receiving more than 2.2 iu of insulin/kg per injection. Possible causes include the Somogyi overswing, problems with insulin administration/storage/mixing of different insulins, concurrent disease such as hyperadrenocorticism, acromegaly and urinary tract infections, the development of antibodies to insulin. The first step is to evaluate the glucose curve and assess the owner's technique (see medicine notes).
These animals are always dehydrated and usually have intercurrent disease. Glucose spilling over into the urine causes an osmotic diuresis and consequent sodium and potassium depletion, so these animals have hyperosmolality, hypovolaemia, metabolic acidosis and prerenal azotaemia.
Correct fluid and electrolyte deficits (0.9% NaCl with added potassium (40mmol/L)) and monitor ECG. Give soluble insulin (0.1iu/kg/h in fluids) to reduce the ketone bodies, avoiding a rapid decline in blood glucose. Check blood glucose every hour and give iv gluccose if necessary. Then correct acid base imbalance (give bicarbonate) if pH is low. Phosphate supplementations may also be necessary (potassium phosphate iv), but this can cause hypocalcaemia.
Depression and coma result from intracellular dehydration of neurones due to increased osmolality. A vicious cycle is set up as depression leads to reduced water intake, further hypovolaemia and hyperosmolality. Treatment is as for ketoacidosis but the animal should be given lots of fluid first as insulin will result in potassium and water moving into the cells.
Treat circulatory collapse with fluids as an emergency. Replace sodium and fluid deficits with 0.45% NaCl plus potassium. Slowly correct the glucose as above - start after 6 hours fluid therapy. Once the animal has improved (blood glucose 10mM), begin stabilisation with isophane insulin.
These can occur with insulin overdose or unusually strenuous exercise. In these situations, severe hypoglycaemia may occur.
If the animal is at home get the owner to rub or pour sugar syrup onto the gums. Once the animal regains conscious a small meal should be fed and the pet should be taken to the vet clinic. 50% dextrose should be administered iv slowly to effect (2-15 mLs), preferably added to an infusion, and the animal should respond in approximately 2 minutes. If inappetance is a problem the animal should be maintained on a 5% dextrose iv drip.
A lot of work is going into ways to deliver insulin orally, but there is nothing nearing commercial release yet. Insulin sprays for inhalation or absorption across nasal or buccal membranes are in clinical trials in people. These would be difficult to use in animals. Transdermal delivery is another possibility.
An artificial pancreas is still some way off - present implantable glucose detectors are not reliable enough.
Some zinc complexes mimic the effects of insulin and are being investigated.
An islet neogenesis gene associated protein has been found which makes islet cells regrow. This has possibilities in the distant future.
This occurs mainly in German Shepherds. It is usually treated by providing a highly digestible diet (low fat and fibre) and giving pancreatin, which contains a mixture of protease, lipase and amylase enzymes. The most effective form is a powder or granules which are sprinkled on the food. It may be necessary to give a H2 blocker such as cimetidine to stop acid breakdown of the enzymes in the stomach.
