Monitoring your diabetic patients (Proceedings)

Pathogenensis

Dogs typically develop insulin dependent, or type I, diabetes mellitus. Their pancreas is not able to produce insulin so they have an absolute requirement for insulin to maintain euglycemia. Histologically they have fewer, smaller pancreatic islets. Hyperadrenocorticism, diestrus and pregnancy might cause transient diabetes in dogs but almost all dogs require insulin and will require insulin life long.

Cats more commonly develop non-insulin dependent, or type II, diabetes but they can become type I. Cats often deposit amyloid in their pancreas that leads to progressive destruction of acinar cells. Chronic pancreatitis can lead to diabetes in the cat as well. Their pancreas can often produce insulin but either they don't produce enough to maintain euglycemia or they are resistant to insulin's effects. Transient diabetes is more common in this species because of waxing and waning insulin requirements. Obesity contributes to insulin resistance in both species.

Treatment - Diet

Currently, dietary recommendations for cats are for high protein and low carbohydrates. Cats can not convert dietary glucose for storage and energy as well as dogs. Cats primarily use amino acids and fat in the diet for energy so carbohydrates are left over to contribute to hyperglycemia. Currently Hills md® and Purina DM® are diets that fit into this category of low carbohydrate, high protein. These diets help reduce postprandial glucose and insulin concentrations, decrease insulin requirements, result in better control of diabetes and can produce remission in some cats. Cats are fed the majority of their caloric intake twice daily prior to insulin administration but because they often eat throughout the day, the remainder of their daily calories is left for free feeding. This regimen might be necessary in some dogs that are grazers. Correction of obesity should also be a goal of dietary therapy and can decrease insulin resistance.

The dog is an omnivore by nature and is more capable of utilizing carbohydrates for energy and storage than the cat. For this reason, dietary recommendations for dogs focus on minimizing dramatic post-prandial increases in glucose as well as weight control. Diets higher in fiber, particularly soluble fiber, are used and there are many that fit into this category. Dogs are usually fed twice daily prior to insulin administration. Again, correction of obesity is also a goal in the dog.

It is important to remember that there is not an ideal diet or feeding schedule for all patients. Dogs and cats that are underweight will not tolerate a diet that promotes weight loss so other diets may be necessary.

Oral Hypoglycemics

The majority of the oral hypoglycemics previously used to treat diabetes have fallen out of favor. The sulfonylureas (glipizide, glyburide) were used in cats because their primary mechanism of action is stimulation of insulin production by the pancreas which means they must have some capacity to make insulin on their own. Unfortunately it is now believed that increased stimulation of the pancreatic islets also leads to burn out of the beta cells which can actually result in a decrease of insulin production and progression of diabetes so these drugs are not used.

Biguanides, like metformin, do not stimulate insulin production by the pancreas. Instead they enhance sensitivity of the liver and peripheral tissues to insulin. There has been a high incidence of intestinal side effects with this medication and the results in cats are inconsistent but metformin does appear to work better with some residual insulin production. Again, because it requires insulin production, it is not particularly useful in the dog.

Acarbose is an alpha-glucosidase inhibitor that affects brush border enzymes in the small intestine decreasing glucose absorption. There has been some success with its use in diabetic cats and dogs.

Chromium and vanadium are trace elements thought to increase tissue sensitivity to insulin. Chromium may have some effect in cats with diabetes and vanadium may be beneficial in diabetic cats and dogs.

Insulin Therapy

Insulin is the cornerstone of therapy for diabetes in the dog and cat. Even though many cats are non-insulin dependent, early administration of insulin has been shown to decrease beta cell loss and, when administered with a low carbohydrate diet, result in clinical remission in many cats. There are basically three types of insulin; short, intermediate and long-acting. Regular insulin is available in a human recombinant formulation and is the only short-acting preparation used in small animals. This insulin should be used in diabetic dogs and cats that can not be on maintenance insulin, in essence, dogs and cats that are not eating reliably enough to be on their maintenance insulin (i.e. diabetic ketoacidosis). It can be given IV, IM and SC. IV administration is limited to treatment of life-threatening hyperkalemia and as a low dose CRI for treatment of sick diabetics. IM followed by SC administration is recommended in most settings during treatment of diabetic ketoacidosis (or in other instances in which a diabetic is not eating). Regular is a U-100 insulin.

Intermediate-acting insulins are human recombinant NPH and pork lente (Vetsulin®). They are intermediate because their duration is 6 to 22 hours with SC administration. NPH is used in dogs exclusively because it is typically too potent and short-acting for cats. NPH must be administered twice daily. NPH is a U-100 insulin. Lente is also an intermediate insulin. Because it is pork origin and is most similar to dog insulin it is used primarily, but not exclusively, in this species. About 20% of dogs can be maintained on once daily lente so it is common to try dogs on once daily. Label directions are for once daily dosing and if giving twice daily the dose should be reduced by 50%. Lente is given to cats twice daily. Lente is a U-40 insulin.

The long-acting insulins are insulin glargine and PZI. Insulin glargine is a synthetic insulin that is given to cats. Most cats will have acceptable regulation on once daily but twice daily administration might result in better overall control. Hypoglycemia is common when starting this insulin but clinical hypoglycemia is not. Insulin glargine can be stored refrigerated for up to 6 months. This is a U-100 insulin. PZI is a beef/pork insulin. It is primarily beef so its use is limited to the cat. PZI must be given twice daily. PZI is a U-40 insulin.

In summary, regular insulin is given to sick diabetics or diabetics off feed (anesthesia) to control their blood sugars. Typically it is administered IM or SC for diabetes mellitus. Lente and NPH are intermediate insulins used primarily in the dog. PZI and insulin glargine are long-acting insulins used in the cat. Glargine and, to a lesser extent, PZI have been associated with diabetic remission in recently diagnosed diabetic cats when used with a low carbohydrate diet. Remember to use U-100 syringes for U-100 insulin and U-40 syringes for U-40 insulin. U-100 insulin contains 100 units per ml whereas U-40 contains 40 units per ml. Insulin should be rolled and inverted and not shaken to preserve crystals. Insulin should be refrigerated to avoid contamination. Subcutaneous administration sites are on the lateral thorax and abdomen and should be alternated.

Monitoring - Initial Examination and Follow-up

Diabetic monitoring includes evaluation of historical and physical parameters as well as the blood glucose. History and physical exam findings are very important in monitoring diabetics because glucose curves are relatively unreliable. The initial consultation is paramount to successful management of a diabetic. I recommend that a 1 hour appointment be scheduled with owners of all newly diagnosed diabetics to discuss the disease, sequelae, treatment options, therapeutic plan for their pet, monitoring at home and hospital. Insulin handling, storage, formulation, strength, use of appropriate syringes and sites of administration should be discussed. The client should practice insulin handling and administration in the veterinary hospital utilizing saline or insulin and their pet. Discuss what the owners should expect to see now that they are beginning treatment. Signs of hyperglycemia and hypoglycemia (lethargy, anorexia, seizures) should be reviewed with instructions about what to do if signs of hypoglycemia occur. The diet should be discussed including why we use certain diets and feeding schedules. Stress adherence to strict dietary and exercise regimens. Allow the owner time to ask any questions they might have. The owner should be sent home with a complete written description of diabetes, its pathogenesis, treatment and sequelae so they can review the information discussed.

On follow-up visits standard questions pertaining to diabetes are insulin type, dose, frequency and last time of administration. Questions about diet, water consumption, urination, activity level and appetite should also be asked. A complete physical exam should be performed paying attention to changes in weight, development of cataracts (dogs), hindlimb weakness/diabetic neuropathy (cats) and coat quality. Cats with diabetic neuropathy may or may not regain normal function. Unfortunately cataracts are very common in dogs despite tight regulation of blood glucose.

Monitoring Blood Glucose

Glucose curves can be determined by blood or interstitial glucose concentrations. Glucose curves can be done at home and this allows pets to engage in normal eating and exercise behaviors. Glucose curves in hospital may be less reliable because of changes in appetite and activity level as well as the effects of stress hyperglycemia. Glucose curves at home are considered more reliable in most animals but unfortunately there has also been some variability. The owner can purchase a portable glucose monitor. The ear veins and buccal mucosa are excellent sample sites. A 25 g needle can be used in place of more expensive lancets. If sampling the ear, vasoline can be placed over the venipuncture site so blood will bead up. When performing glucose curves it is important to have a pre-meal/insulin glucose followed by readings every 2 hours. If the pet is receiving twice daily insulin then a 12 hour curve may suffice but a longer curve may be necessary for once daily insulin to get an idea of duration of activity.

Interstitial glucose monitors require placement of a probe within the subcutaneous space. The probe then attaches to a recording device that reports glucose every 5 minutes. These devices can be worn for several days and the pet can be discharged form the hospital.

Glucose curves are usually done on newly diagnosed diabetics until they are controlled or poorly regulated diabetics. Newly diagnosed diabetics have curves every 1 to 2 weeks until they are regulated. More frequent adjustments are not recommended, except in cases of hypoglycemia, because the body must adjust to the new levels of insulin. Monitoring glucose upon initiation of therapy is debated. With most intermediate and long-acting insulin, monitoring glucose for the first 12 to 24 hours should be adequate if desirable. Insulin glargine commonly causes hypoglycemia for up to 72 hours on initiation of therapy. Cats do not develop clinical signs of hypoglycemia but depending on its severity, adjustments in insulin dose may need to be made.

Let's talk about the ideal world and the ideal glucose curve. It would be ideal if diabetic dogs and cats had a pre-meal/insulin glucose between 200 mg/dl and 300 mg/dl with a drop of only 100 mg/dl and the nadir right in the middle of dosing. So if this was twice daily insulin then a nadir at 6 hours vs. at 12 hours for once daily insulin. This is an unrealistic expectation for almost all diabetics and when you regulate them this tightly they are more susceptible to hypoglycemia.

In general you ask yourself four questions when evaluating a glucose curve. Is the animal responding to insulin? Is this response adequate? Is the dose appropriate? Is the duration of effect adequate? When determining if an animal is responding to insulin you are looking to see if the glucose is lowered. If the glucose decreases then there is a response. To determine if the response is adequate, keep in mind where you want your pre-meal/insulin glucose and how much of a drop you want to see. If your pre insulin glucose was 598 mg/dl and your nadir is 300 mg/dl there is evidence of a response but an inadequate response. When determining if the dose is adequate you should determine the dose the animal is currently getting on a U/kg basis and then ask yourself if this dose would be considered low, adequate or excessive. Then look at the curve. If you have a dog that is not responding to insulin but is on a relatively low dose (<1.0 U/kg) then perhaps a dose increase is in order. If you have a dog that is not responding and he is getting 2.5 U/kg then there may be a problem with the insulin or insulin resistance. Duration is defined as the time it takes to return to baseline or your pre-meal/insulin glucose. If you are giving a cat 2 units of NPH BID and it drops from 398 mg/dl to 225 mg/dl at 3 hours but is back up at 500 mg/dl at 6 hours the duration would be considered too short. If you are giving a dog lente twice daily and you notice the glucose is still dropping at the time for the next dose then perhaps the duration is too long for twice daily administration.

Fructosamine can also be evaluated and eliminates the effects of stress hyperglycemia on the glucose curve. Fructosamine measures glucose bound to albumin and is a reflection of serum glucose over the last two weeks. Occasionally cats have a moderate hyperglycemia and glucosuria with minimal clinical signs. A fructosamine might be helpful in determining if the glucose has been increased more chronically. Fructosamine can be followed and would be expected to decrease as diabetes becomes more controlled. Diabetic dogs and cats should rarely have a normal fructosamine. If this is the case then insulin overdose may be occuring.

There are cat litters that contain color indicators for glucosuria. While these may be helpful in monitoring persistent glucosuria (probably not well regulated) or absence of glucosuria (may be persistently hypoglycemic), changes in insulin should be based on blood glucose measurements and not urine glucose.

Poor Regulation of Diabetes Mellitus

The most common problems observed in uncontrolled diabetics are short duration of insulin effect, Somogyi phenomenon and concurrent insulin-antagonistic disorders. Most dogs and cats take weeks to months for their diabetes to stabilize so control within the first few weeks is unlikely. Short duration is more common with the intermediate-acting insulins, especially NPH, because they are potent insulins that often reach their nadir within a few hours and return to baseline in less than 10 hours. This is typically not a problem with the pork lente formulation when given twice daily in fact it's duration is often greater than 12 hours in dogs. Short duration is often a complication with once daily insulin administration or NPH formulations. Short duration is addressed by switching to a longer-acting formulation or increasing frequency of administration.

The Somogyi phenomenon is an attempt by the body to regulate glucose in the face of life-threatening hypoglycemia (typically less than 65 mg/dL). When blood glucose is this low epinephrine, cortisol, glucagon and growth hormone are produced in an attempt to bring the blood glucose up. The result is a dramatic increase in glucose often in the 400 to 500 mg/dL range. It can take several days for glucose to return to normal with insulin administration because insulin resistance occurs with hyperglycemia. A curve might suggest the animal is not receiving enough insulin when, in fact, they are receiving too much. An additional complicating factor is that the signs of hyperglycemia (PU/PD, PP, weight loss) can predominate over signs of hypoglycemia (lethargy, anorexia, vomiting). This emphasizes the importance of the glucose curve in animals with poorly regulated diabetes. It is also important to note that this is one instance when spot glucose checks can dramatically affect decision making and not necessarily for the better. Somogyi can occur with intermediate insulins due to potency but can also occur with long-acting insulins due to a wrap around, or 'accumulating', phenomenon. With Somogyi, or hypoglycemia, insulin dose should be reduced by 50% or, if on particularly high doses (> 2 U/kg/dose), you may want to start over with the initial dose recommendations for that particular insulin.

The most common causes of insulin antagonism in the dog are insulin antagonistic medications (e.g. glucocorticoids), obesity, chronic infection (particularly oral, urinary), hyperadrenocorticism and hypothyroidism. The most common disorders in the cat are medications, obesity, hyperthyroidism, pancreatitis and chronic infection (oral disease, urinary tract). Acromegaly and hyperadrenocorticism are rare causes of insulin resistance in the cat. Diseases in other systems can also cause resistance. Insulin resistance should be suspected in cats and dogs that are receiving > 2 U/kg/dose to control signs or those that are not well-controlled on this dose. Insulin antagonism is also suspected in a previously well-regulated diabetic that develops clinical signs and hyperglycemia (once problems with exogenous insulin are ruled out).

Insulin may also be affected by storage, handling and improper administration. Insulin antibodies do not appear to contribute greatly to insulin resistance in the dog and cat. Insulin antibodies were more problematic in beef and beef/pork insulin administered to dogs and this is why PZI is not routinely used in this species

Complications of Insulin Therapy

Persistence of clinical signs is common with insulin therapy. This may be a result of problems with the insulin itself, insulin under dosage, insulin over dosage or insulin resistance.

Insulin may be ineffective if it is stored, handled or administered incorrectly. Unused insulin is typically refrigerated. Once opened, it is often stored at room temperature when used in man. This led to the recommendation that insulin be replaced every 30 days due to potential loss of potency as well as contamination. It is recommended that insulin for animals is stored in the refrigerator once opened. This is thought to prolong potency and prevent contamination. The exact duration of maximum potency for most insulin in dogs and cats is unknown although, as discussed previously, insulin glargine is stable for up to 6 months refrigerated. Most insulin contains crystals that if disturbed can lead to alterations in absorption and potency. For this reason insulin suspensions should not be shaken. It is typically recommended to administer insulin over the lateral thorax and flanks alternating sites. Skin over the neck and back may be thickened and insulin deposited intradermal affecting absorption. Animals can occasionally develop changes in the skin and dermis at the site of repeated injection and this might interfere with absorption. Dilute insulin can have variable potency so dilution should be avoided if possible. If diluting insulin, the diluent recommended by the manufacturer should be used.

Insulin under dosage should be suspected in an animal given < 1.5 U/kg with persistence of signs in conjunction with high serum fructosamine and/or inadequate response on a blood glucose curve. Under dosage is more common in animals on once daily insulin as a result of short duration of effect. In general, if you increase the dose of insulin it will lower the entire glucose curve.

Somogyi phenomenon and insulin resistance were discussed previously.