Insulin resistance. No firm rules dictate when to classify a dog as insulin resistant, but it is generally appropriate to consider a patient
to have poor glycemic control when its glucose concentrations are > 300 mg/dl despite insulin doses > 1.5 U/kg/dose.7
Insulin-resistant dogs often show a poor response to intravenous insulin, as the problem is due to impaired interaction with
the insulin receptor or altered post-receptor translational events. We tend to think of insulin as working like a key in a
lock to open up glucose transport into cells, but its action is far more complex than that. Insulin profoundly impacts energy
storage in fat and muscle, as well as simply lowering blood glucose concentrations. Consequently, numerous metabolic events
can impact the action of insulin (Table 2).13 The classic causes of canine insulin resistance are described in the following section. See Table 5 for a suggested approach to these cases.
The impact of obesity on insulin sensitivity is well-understood in human medicine and is becoming recognized in the veterinary
field.14-16 Although many diabetics lose weight as a result of the disease, some are still obese when treatment is initiated. Obesity
may blunt the response to exogenous insulin and make regulation more difficult. An appropriate weight loss program should
be started immediately, with the goal of reaching an optimal body condition score within four months. In most cases, switching
to fixed portions of a low-fat, high-fiber food will be helpful. The new weight loss drug for dogs (dirlotapide; Slentrol—Pfizer
Animal Health) is probably not an appropriate choice for weight loss in diabetic patients because food intake can fluctuate
daily and vomiting is a common side effect.17
Hyperlipidemia is associated with insulin resistance in diabetic people. Experimental studies also support a link in dogs,
but little clinical data addresses this issue in spontaneously diabetic dogs.18 However, a fasting serum triglyceride concentration > 800 mg/dl should be addressed in an insulin-resistant diabetic patient.
Possible causes include inherited lipid disorders and hypothyroidism. Switching to a markedly fat-restricted diet is often
effective. Additional interventions may include omega-3 fatty acid supplementation or lipid-lowering agents such as niacin
Concurrent infection is probably the number one reason for acute insulin resistance. Urinary tract infections are routinely
found in diabetic dogs and should be considered in any poorly controlled patient.20 A urine culture is often the first step in the evaluation of an insulin-resistant diabetic, even if the urinalysis is unremarkable
and clinical signs of infection are not reported. In one study of dogs with diabetes, less than 5% of those with positive
culture results demonstrated stranguria or pollakiuria.21 It is important to remember that glucosuria provides an ideal environment for bacterial colonization, while the diuretic
effect of the glucose dilutes the usual sediment examination findings of white blood cells and bacteria.
The other classic spot for an occult infection is the oral cavity.22 A thorough dental examination should be performed, and any suspicious areas should be investigated further. In some cases,
intraoral radiographs may be the only way to identify a subclinical tooth root abscess.
Other endocrinopathies should be considered in dogs with insulin resistance. Hypothyroidism is a recognized cause of insulin
resistance and was noted in 4% of diabetic dogs in one study.20,23 Patients with insulin resistance due to thyroid disease often slowly gain weight despite persistent hyperglycemia. This
is a useful finding, as most unregulated diabetic dogs become thinner over time. Persistent hypercholesterolemia may also
be noted on routine laboratory tests, although this can be explained by poor diabetic regulation for any reason. A mild nonregenerative
anemia may develop with long-standing hypothyroidism but is not reported in most cases. It is usually necessary to measure
total thyroxine (T4), free T4 by equilibrium dialysis, and thyroid stimulating hormone (TSH) concentrations to confirm the diagnosis. A total T4 concentration is often subnormal due to euthyroid sick syndrome in a poorly controlled diabetic and is, therefore, an unreliable
indicator of thyroid status. The classic picture for spontaneous hypothyroidism is subnormal T4 and free T4 concentrations, along with increased TSH concentrations. However, it is important to note that the TSH concentration may
be normal in a subset of dogs with confirmed primary hypothyroidism.24 If results are equivocal, consultation with an internist may be helpful.
Concurrent hyperadrenocorticism is commonly reported in dogs with diabetes mellitus and results in severe insulin resistance.20,25 Dogs with untreated hyperadrenocorticism and diabetes mellitus often maintain a blood glucose concentration > 400 mg/dl
despite large doses of insulin. This is probably one of the more difficult disorders to identify in poorly regulated diabetic
dogs, as the clinical signs of hyperadrenocorticism—namely excessive thirst, hunger, and urination—can all be explained by
persistent hyperglycemia. Routine laboratory findings associated with hyperadrenocorticism, such as hypercholesterolemia and
increased alkaline phosphatase activity, are also noted in diabetic patients, so standard laboratory testing is often of little
use. In addition, the stress of poor diabetic regulation can impact adrenal function tests and cause adrenomegaly. Opinions
differ about the best screening test for hyperadrenocorticism in diabetic dogs, as results of both the low-dose dexamethasone
suppression (LDDS) test and the adrenocorticotropic hormone (ACTH) stimulation test are influenced by concurrent disease.26,27 I personally prefer the LDDS test in these cases but am not aware of any definitive data to support its use over the ACTH
stimulation test. A urine cortisol-creatinine ratio would be of little use, as false positive results commonly occur in dogs
with nonadrenal disease.28 Additional clinical evidence of hyperadrenocorticism (e.g. poor hair growth, delayed healing) along with additional diagnostics (e.g. abdominal ultrasonography) should be considered before you initiate treatment for hyperadrenocorticism.
Transient acromegaly can occur in intact females during the diestrus phase of the reproductive cycle and will result in insulin
resistance. In these cases, excess growth hormone is released from mammary tissue, under the influence of progesterone from
Any intact female diabetic dog should undergo prompt ovariohysterectomy when its diabetes is stabilized to prevent the predictable
insulin resistance associated with diestrus. In addition, some dogs may experience diabetes remission after ovariohysterectomy
if enough functional pancreatic beta cells remain. Rare cases of acromegaly secondary to a functional pituitary tumor have
been reported, and this also results in substantial insulin resistance.30 Classic physical examination findings for dogs with pituitary acromegaly include thickened skin, redundant skin folds, and
an enlarged tongue. Respiratory stridor is common because of growth of the pharyngeal soft tissue. This is an uncommon disorder
in dogs compared with cats, and the diagnosis would be based on clinical signs and confirmation of a pituitary mass.
Sterile inflammatory disease can also cause insulin resistance, probably through the release of cortisol. Although any body
organ may be affected, pancreatitis is a common problem in diabetic dogs and may be sustained or severe enough to affect diabetic
regulation.20 Skillful ultrasonography or the measurement of canine pancreas-specific lipase activity (Spec cPL—IDEXX) may be helpful
in cases of suspected pancreatitis.31 No specific therapy exists for this disorder, but pain control and a switch to a strictly low-fat diet are often beneficial.
Another important cause of insulin resistance is concurrent medication. Clearly, any products containing glucocorticoids should
be avoided unless absolutely necessary. This includes topical products, such as ear treatments and skin-soothing sprays. It
is not unusual for clients to purchase these medications for other pets and then use them with the best intentions on their
diabetic animals. Over-the-counter products marketed for people rarely contain enough corticosteroids to cause substantial
insulin resistance, but it is always prudent to check. Synthetic progestins, such as megestrol acetate and medroxyprogesterone
acetate, are potent insulin antagonists and should not be administered to diabetic dogs.32
The difficult-to-control diabetic dog can be frustrating, but most patients can be effectively managed if the cause of poor
regulation is identified and addressed. Once insulin- and client-related problems have been excluded, patient-related issues
should be pursued. The cornerstone of these investigations is reliable serial glucose monitoring, either at home or in the
clinic. A stepwise, logical approach should be followed so that straightforward problems are effectively addressed before
more complex diagnoses are considered.
Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM
Department of Small Animal Clinical Sciences
College of Veterinary Medicine
Texas A&M University
College Station, TX 77843
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