Before investigating potential causes of insulin resistance, make sure of the following:
a)  The owner is storing, mixing and administering the insulin as directed.
     The most common cause for persistently increased blood glucose concentrations is 
     owner error in administering the insulin. 
     Make sure the correct syringes are being used. 
     This is especially important if you are using U100 needles to administer U40 insulin 
     You have to make the proper conversion then.
     Improper administration of insulin. 
     If possible, have your doctor observe you giving the insulin to your pet.
b)  There could be something wrong with the insulin.(wrong type, bad batch, diluted, 
      outdated,overheated, mixed by shaking, etc.) 
      Insulin should be replaced every four weeks even if there is still insulin left in the bottle.
c)  Make sure the owner is following the diet and feeding schedule recommended.
d)  Make sure the dose of insulin is sufficient.
e)  Make sure the animal is not experiencing insulin overdose and glucose counter regulation (Somogyi phenomenon).  If insulin overdose occurs, the body responds by secreting diabetogenic hormones(glucagon,epinephrine, growth hormone, cortisol).  These hormones induce hyperglycemia(morning blood sugar is ususally extremely elevated).  Consequently, the animal goes through a period of hypoglycemia(weakness, lethargy, headtilt, seizure) followed by signs of hyperglycemia(increased PU/PD).  A blood glucose curve is necessary to document this phenomenon.
f)  Make sure low or impaired absorption of the insulin is not occuring.  This is primarily a problem in cats on ultralente insulin.  The blood glucose may not fail until 6-8 hours following the insulin injection.  A blood glucose curve will define this problem(you'll see postprandial hyperglycemia that persists for several hours). OR Rapid insulin metabolism. Insulin wears off quickly in some animals. Your pet may require a different type of insulin or a second injection during the day, most canines require two shots a day and many vets seem to start them at one shot a day.
g)  Make sure insulin is not being rapidly metabolized (transient insulin effect). If the insulin is rapidly absorbed from the injection site, the duration of insulin action is not sufficiently long to achieve adequate control of 
blood glucose.
h)  Make sure the animal is not experiencing transient hyperglycemia following a meal(consider giving an additional low dose or regular insulin at meal-time)

SOME PETS ARE DIFFICULT TO REGULATE
Some pets seem to require re-regulation frequently. There may be an underlying reason to sort out.

Causes of Insulin Resistance

1.  Drugs: glucocorticoids, megesterol acetate (Ovaban).  It is important to obtain a thorough drug history (including any eye or ear medications that could contain steroids).Steroid administration (such as prednisone, prednisolone etc.) will interfere with insulin.

2.  Infections:  particularly of the urinary tract and oral cavity. 
Infections anywhere in the body can induce increased secretion of cortisol, glucagon, and epinephrine, all of which can antagonize the action of insulin.  It is important to perform a complete physical examination and a urine culture in any diabetic when insulin resistance is suspected. Because of the relatively high incidence of bacterial infections in diabetic patients, you may wish to administer a broad-spectrum, bactericidal antibiotic for 10-14 days if no other cause of insulin resistance is found.

3.  Endocrine disorders:
hypothyroidism in dogs
hyperthroidism in cats
hyperadrenocorticsm in dogs and cats (cushing's disease)
acromegaly (hypersecretion of growth hormone) (cats)
diestrous (intact female dogs: improvement in control of diabetes is apparent within a week after ovariohysterectomy)Progesterone also interferes with insulin. Unspayed female diabetics should be spayed once they are sufficiently regulated.

4.  Obesity:  results in internalization of insulin receptors; decrease insulin receptor binding affinity; postreceptor defects
 

5.  Concurrent illness:  with any concurrent problem, counter regulatory hormones (glucagon, glucocorticoids, catecholamines, growth hormone) can be secreted and lead to insulin resistance.
hyperlipidemia
pancreatitis
renal disease
liver disease
cancer (pheochromocytoma, glucagonoma, mast cell tumor, lymphoma)
heart disease
 

6.  Presence of insulin-binding antibodies:

Insulin resistance caused by anti-insulin antibodies is likely rare in small animals and is difficult to diagnose.  In the dog, beef containing insulin products are more likely to be antigenic vs pork insulin or recombinant human insulin.  In the cat, pork insulin and recombinant human insulin are likely to be more antigenic vs beef or beef-pork products.

7. Absorption problems (giving a shot subcutaneously does not guarantee that it will get absorbed. Sometimes giving the insulin in a different spot will make all the difference.

Insulin resistance describes the condition in which the pancreas is capable of producing insulin, but the cells are insensitive to it. If insulin is the “key” which unlocks the “gate” through which glucose must pass to enter cells, then insulin resistance results when there are too few “gates” or the ‘locks’ on the gates are “rusted shut” and are difficult to open despite the presence of insulin. There are many conditions which may predispose to the development of insulin-resistant diabetes or which may unmask a mild, subclinical, or transient diabetes that already exists. These include pregnancy, overproduction or over-administration of steroids like cortisone or prednisone, overproduction of growth hormone (acromegaly), infections, prolonged or severe stress, and many others.

Alternatively, these conditions may increase the dose of insulin required to properly regulate a diabetic already undergoing therapy. A diabetic patient which requires an insulin dose higher than 1-2 units per pound of body weight per injection to maintain normal blood sugar levels is considered to be “insulin-resistant”; every effort should be made to identify possible conditions which may be increasing the insulin requirement. Sometimes, just a prolonged untreated bladder infection may be enough to dysregulate an otherwise well controlled diabetic. If your dog has recently required a significantly increased dose adjustment to re-regulate blood sugar levels, or is difficult to regulate despite high insulin doses, have your pet re-evaluated by your veterinarian. Although there are many reasons why a diabetic may be difficult to regulate, the possibility of insulin resistance must be considered once other potential causes have been investigated and ruled out.

 Auburn University Link