Obstacles to regulation

Food

• High-carb cat/dog food: Many commercial dry foods (especially "Light" foods) are extremely high in cereals and therefore carbohydrates. The extra carbohydrates will keep the cat or dog's blood sugar high, and if you're free-feeding may also make the blood sugar curve over the course of the day unpredictable. In general, canned foods are lower in carbohydrates than dry ones, and canned "kitten" foods lower still. See Low-Carb diet for more information on how to lower your pet's carbs.

• Semi-Moist Pet Foods: sometimes contain a lot of simple carbohydrate sugars which can cause problems with regulation.

Diet changes can help regulate a non-regulated pet; they can also be the reason why a previously-regulated pet is having problems.

Hormones/steroids

• Naturally Occuring Hormones:  All females should be spayed as the hormones released in their menstrual cycles drive blood glucose up. Some revert to non-diabetic status after being spayed. It's very much like a transient diabetes state found in some human females during pregnancy called gestational diabetes, which in most cases resolves after giving birth. Sufferers of either condition have a higher risk of developing permanent diabetes even after full resolution.

• Steroid Use:Steroid use can also produce a temporary, transient diabetes which often disappears after discontinuing use of steroids.

Hormones and steroids can also contribute to non-regulation or loss of regulation. See Steroids for various drug names and uses.

Other medications

• Medications: Certain medications for other conditions (including heartworm and flea medications), may cause dogs' or cats' blood sugar to skyrocket temporarily. Interceptor (Novartis) carries no advisory regarding these possibilities for both dogs and cats, nor do other comparable medications.

See Medication warnings for drugs which can interfere with diabetic regulation.

Infections/Illness

• Infection: Any infection in the body, including dental, Urinary tract infections AKA UTIs, kidney, colds, and even hidden infections, will often cause stubborn high blood glucose levels.

Hypoglycemia is also possible when dealing with infections.

Untreated bladder infections can easily become Kidney infections, which pose more problems for those with diabetes. Some vets have observed lower glucose levels due to infection instead. Ask your vet to check for the possibility of infection if dosage and diet don't seem to be bringing sugar levels down. There is reason to believe that diabetic dogs and cats, like their human counterparts, are more prone to infections of the respiratory system, such as pneumonia and other types of infections.

New information regarding cats with diabetes indicates that they warrant careful attention to the respiratory tract as there is a significant connection between diabetes and various respiratory disorders.

• Illness: Colds, viruses, and other temporary illnesses and infections, even hidden ones , can push blood sugar high for a while. Other medical stresses can lead to insulin resistance too. Illness involving vomiting and/or diarrhea can mean some degree of dehydration as well; this can mean for more variability of insulin doses.

Dehydration can change the way subcutaneous insulin is absorbed, causing either hyperglycemia or hypoglycemia.Those with diabetes are at risk for dehydration as it is triggered by hyperglycemia.

Concurrent medical conditions

• Concurrent Diseases such as hyperadrenocorticism, more commonly known as (Cushing's Disease) and hypothyroidism (low thyroid function) are two common canine disorders which diabetic dogs can suffer from. Hyperthyroidism (overactivity of the thyroid gland) is more common in cats. Acromegaly, which can affect both cats and dogs, is another concurrent condition which can affect regulation.
  A 2000 study identified the most common concurrent diseases in diabetic dogs as hyperadrenocorticism AKA Cushing's Disease, Urinary tract infections, dermatitis (various skin problems), otitis (irritation/infection of the ear), acute pancreatitis, hypothyroidism, and neoplasia (a form of cancer).

• Excess circulating fats (lipids)/tryglycerides in the blood can produce problems with regulation. The fat does not allow the insulin to bind with the cells it acts on to lower blood glucose. At times the excess fats are the result of another disease state (Cushing's disease and hypothyroidism are two with regard to dogs). Treating the medical problem which caused them should remove this regulation obstacle.

• However, some breeds of dogs (miniature schnauzers in particular), tend toward excess circulating fats without other disease states being present. If no medical condition causing this can be found, diet and omega 3 fatty acid supplements can help.

• In a VIN online diabetes seminar last November (2005), Dr. Greco states the three main problems with insulin resistance in diabetic cats are: Hyperthyroidism, Cushing's disease (hyperadrenocorticism), and Acromegaly. Her personal preference is to check for Hyperthyroidism first, then Cushing's, then Acromegaly.

• Dr. Wolf, of Texas A & M University, said before the Minnesota Veterinary Medical Association convention that concurrent diseases (Urinary tract infections, hyperthyroidism, Cushing's Disease AKA hyperadrenocorticism), are the most common causes of insulin resistance in cats.

Rebounds

• Rebound due to single overdose: Sometimes your pet's blood sugar will suddenly seem much higher than usual. This is often not a good time to increase their insulin dosage -- quite the opposite. It may instead be another case of "reduced need". It often indicates that a low blood sugar condition (or rapid sugar drop) was experienced a few hours before, and a Somogyi rebound is in progress.
  To be sure, drop the next dose by 15%-50% and take glucose readings every 4 to 8 hours until the glucose levels out. Then wait a day or two for the Somogyi hormones to decrease in the body, and then you can increase again by 0.5-unit steps every 5-7 days. If you experienced this rebound, chances are that your original dose was too high, or the pets' insulin requirements decreased, so you should try to find an ideal dose at a lower point.

• Chronic overdose masked by Somogyi: A dose that is fractionally too high can easily cause a Somogyi rebound, which causes hyperglycemia and can look like a need for more insulin. This condition can continue for days or weeks, and it's very hard on the pet's metabolism. Especially since you're likely to keep raising the dosage to compensate, making things worse.
  This postgraduate medical guide for treating people with diabetes lists "repetitive rebound hypoglycemia" AKA Somogyi rebound, as a factor contributing to what used to be known as "brittle" (hard to control) diabetes. It also indicates that this factor is very treatable.

Activity/Stress

• Increase/Decrease in Physical Activity can either raise or lower blood glucose levels, depending on the individual's response. We all know how we feel when we've tried to fit too much into one day or just can't seem to move from the chair or sofa. For diabetics, marked changes in their daily activity patterns can mean hypoglycemia or hyperglycemia.
  
  Most with diabetes find increasing their physical activity in a regular and sensible fashion means positive effects on their blood glucose levels. When the activity is part of the lifestyle pattern, it means being able to plan ahead with food and insulin, thus avoiding most unwanted consequences.

• Stress can be applied to many common situations. It can take the form of moving to a different home, even with the same caregivers, the addition of a new family member, human or pet, or other more subtle things we understand the reasons for but are unable to explain to our pets.
  Cats--with or without diabetes--are prone to stress hyperglycemia which temporarily raises blood glucose levels.
  
  Persons and pets with diabetes are likely to experience hyperglycemia from experiences deemed stressful to them. There are also those with diabetes who go in the opposite direction--toward hypoglycemia as a response to what they consider stressful.

Insulin Resistance

• Wrong insulin: Different brands and types of insulin have idiosyncratic effects on different cats and dogs. If you've settled on a dose that seems to keep the pet's blood sugar within range at peak effectiveness, but the sugar readings remain dangerously high at shot times, the insulin may not be lasting long enough for your pet, or may not be the best choice. Switching to a slower-acting or a better-tolerated insulin for that pet, and lowering the dose initially to be safe, may be the next step.

• Insulin resistance from glucose toxicity: after a few days of continually high blood glucose (as often happens when first diagnosed), the animal may have "burnt" some of the body cells due to the oxidizing effects of the glucose the tissues are being bathed with. These damaged cells may at first be unable to effectively absorb even an ideal dose of insulin in their usual way, which leads to more high glucose. Consult a veterinarian about this possibility -- some of the recommended ways to break this cycle are unsafe to try without veterinary supervision.

• Antibodies: Antibodies can be created against the insulin itself or even its suspension. Both NPH/Isophane and PZI insulins use protamine (protein derived from salmon) to do this. So it is then possible for the insulin itself not to be rejected, with the reactivity being to the protamine of the suspension.

In some cases, there can be problems with reactions to either the insulin's suspension or preservative ingredients.

A canine diabetes board case involved a dog who had seemingly similar reactions which were more pronounced on R-DNA human insulin NPH/isophane suspension than on rDNA-human insulin Lente suspension. The resolution for her being treatment with Caninsulin/Vetsulin, a pork Lente insulin.

Antibodies can be formed against proteins present in the insulin preparation other than the insulin itself. This type of insulin resistance is defined as loss of 70%+ of injected insulin to antibody binding. It is considered rare but possible.

Reactions are also possible from the preservatives which are necessary to all insulins. They do differ from suspension to suspension, however. Case of a human who was sensitive to the preservatives in NPH/isophane, but not Lente, as they differ.

Two other canine diabetes board cases involved NPH/isophane insulins and sensitivity, one using r-DNA human insulin, the other pork NPH/isophane insulin. Lethargy was a factor in both.

The dog being treated with the r-DNA NPH also had muscle discomfort, but had very fine blood glucose control with this type of insulin. His problems were solved by switching to a 3X daily regimen of r-DNA R/neutral insulin which contains neither protamine as a suspension nor phenol as a preservative.

The dog using the pork NPH/isophane insulin developed neuropathy, had dry skin and a dry, thin hair coat in addition to irritated eyes; all while maintaining the same tightly controlled blood glucose levels he had on pork lente insulin.

Returning to pork lente insulin with Caninsulin/Vetsulin which is zinc, not protamine based, for suspension and contains methylparaben, not phenol, as a preservative, resolved all complications within 2 weeks of resuming its use.

Within this time period, he shed the abnormal fall/winter hair coat; it was replaced by his normal, thick, healthy one for fall/winter. At diagnosis, he had antibodies to both human and beef insulins, able to effectively use only pork.

Reduced insulin need

• Reduced insulin need: Sometimes your pet will suddenly appear to need less insulin than before. If this happens (their blood sugar will go lower than usual one day), drop the dose immediately and call your vet.
  If testing just before an injection, and the reading is much lower than expected, it may be wisest to skip that dose and continue retesting every 2-3 hours. If the drop is dramatic and leads to a hypoglycemic episode (see below), the cat's sensitivity to insulin may increase dramatically. You should consider dropping their dose after consulting your veterinarian, and raise it only by half to one unit per 5-7 days, as before.

Reduced need can happen because of recovery from glucose toxicity, or because a cat is on the way to remission, or for other reasons.
It's rare for a diabetic dog to begin producing insulin again; it is possible from having pancreatitis.

• Improving glucose control can also mean increased insulin sensitivity, therefore reduced insulin needs. Abstract #68 from American College of Veterinary Internal Medicine proves the connection between better glucose control and greater sensitivity to insulin.

The need for less insulin can also signal some potentially serious non-diabetic conditions, renal (kidney)  and hepatic (liver) problems among them. Persons with conditions similar to this and diabetes do not expend or metabolize insulin as quickly as someone with diabetes and no renal or liver-related problems. Their renal or hepatic clearance is reduced, which means that insulin remains in their system longer, as insulin is metabolized mainly in the liver and kidneys. Reduced insulin need in dogs may mean your pet has hypoadrenocorticism, or Addison's disease, which is treatable by replacement therapy. Another disease which may bring about reduced insulin needs is Hypothyroidism, as it may slow down the dog's metabolism, thus the need for less insulin.  Hypothyroidism is also treatable by replacement therapy.  Pancreatic insufficiency is another disease when together with diabetes, can cause reduced insulin needs. A continuing situation of reduced insulin needs should be brought up with your vet promptly.

Insulin problems

• Damaged Insulin: Insulin that is getting too old, or has been dropped or shaken or mishandled, or exposed to a lot of light or heat, will be less effective than before.
  Freezing destroys the molecules of ANY insulin; any that has either been frozen or is suspected of having been frozen should not be used.
  Check for discoloration or floating objects in the insulin -- it may also be contaminated.

It's also possible that the new or newer vial from the pharmacy may be flawed. If you've recently started it and are having problems, this might be the case. Taking down the lot number and getting a new vial that has a different batch/lot number should take care of this.

Don't be in a hurry to discard the "old" vial of insulin you were using. If your insulin is one that needs to be ordered, the old vial is all you have until the order comes in. It can be potent enough to see you through until you get your new one; undamaged insulin loses potency gradually.  If there's nothing wrong with the old vial except that it's begun to lose potency, don't be afraid to go back to it if something seems not right about your new vial. Keeping your old vial until you're certain all's going well with using the new one is a good idea.

Insulin that is not properly rolled before shooting can become weaker or stronger over a period of time, leading either to high blood sugar or overdosing and possible Somogyi rebound.

In general, the newer analog insulins are more fragile, thus more subject to damage by mishandling, than their older beef, pork and R-DNA/GE/GM non-analog counterparts.

• Bad/Weak Insulin: In the United States, no insulin has been required to undergo batch testing since 1998. As per US Federal Register: "With the repeal of section 506 of the act, and the elimination of the insulin batch certification program, the agency is eliminating these subparts." This means that none of them--whether they are genetically produced or the newer analog insulins, need to do this to be sold. Older or newer, any vial of them CAN be substandard.

Getting a different vial from a different lot/batch number can tell you quite a bit about whether there's a problem with the insulin or the pet.

According to US law, the potency of any insulin is allowed to vary by 5%. Therefore, it is possible for a batch or lot of insulin to have only 95% potency and still be legally sold by its manufacturer. If you suspect this is the problem, changing vials and batch/lot numbers should solve it.

Before each use, take a moment to inspect the insulin prior to drawing it into the syringe; clear insulins should appear not discolored and clear; suspended insulins should be uniform in their cloudiness.

Do NOT use the insulin if: The bottle appears frosted. Clear insulin that looks discolored or has turned cloudy, contains particles or haze. Cloudy insulin that appears yellowish or remains lumpy or clotted after mixing.

Injection problems

• Placement of Insulin Injections can make a big difference. Absorption problems can occur possibly causing hypoglycemia or hyperglycemia if the insulin injection sites are not varied.

The area needn't be very far from where the last shot was given--the distance of the width of 2 fingers will do fine as a measure.

When shots are given again & again into an area of skin, the tissue becomes thicker at that point; a fairly good analogy would be the calluses people get on hands and feet. The callus skin is thicker and harder; injection areas become similar to this too from repeated shots. This thicker, harder skin doesn't let the body absorb the injected insulin as well as thinner, non-hardened areas.

Most of us dealing with pet diabetes vary the side we give the injections in--right side mornings and left side evenings, for example. This is another help in avoiding giving shots in the same areas.

• Many people give insulin shots in the scruff of the pet's neck, which is now considered to be a less than optimum choice. The neck area provides poor insulin Absorption, due to it not having many capillaries, veins. etc. (vascularization).

Other sites suggested by Dr. Greco include the flank and armpit.

Intervet recommends giving injections from just back of the shoulder blades to just in front of the hipbone on either side, from 1 to 2 inches from the middle of the back.

• Syringe Needle Length Some caregivers report difference in insulin absorption with different length needles. BD Diabetes explains that you should consult with your health care professional before using a short needle, and carefully monitor blood glucose when changing to a shorter needle.

Some people have found their blood glucose not well-controlled when switching to the shorter needles; this also has been the case with some dogs. Switching back to a longer needle solved the problem. You should consider experimenting with the different length needles as insulin absorption may vary.

Further Reading

• Wiki cases--Feline Difficult Regulation

• Why previously-regulated cats lose control, by Richard Nelson, DVM
• Regulation section of the FDMB FAQ
• Regulation Problems Unique To Cats
• University of Queensland-Managing Problem Cats-ACVIM 2008
• Difficult to Regulate Diabetic Cats-ACVIM 2008/DVM360 News

• Wiki cases--Canine Difficult Regulation
• Temporary immune-related canine diabetes case abstract.

• The Difficult Diabetic
• Treating the Complicated Diabetic Patient
• The Hard to Regulate Diabetic Pet
• Dr. Richard Nelson's NAVC 2001 presentation re: ineffectiveness of insulin.
• Unstable Diabetics: Solving the Problems
• Mechanisms of diabetic deterioration
• Standards of Care-2001-Persistent Hyperglycemia in Diabetic Dogs & Cats-Pages 6-14
• Troubleshooting Persistent Hyperglycemia in Treated Diabetics--WSAVA 2008