Diabetes Mellitus
Antu Radhakrishnan, DVM, DACVIM
Bluegrass Veterinary Specialists
Diabetes mellitus by definition is a disease that results in persistent, fasting hyperglycemia with
glucosuria. There are two forms recognized: insulin-dependent diabetes mellitus (IDDM) and non-insulin
dependent diabetes mellitus (NIDDM). The most common form is IDDM. NIDDM happens more
commonly in cats than in dogs. In IDDM, there is reduction in islet cell number and function within the
pancreas resulting in an absolute decrease in insulin. The main difference between IDDM and NIDDM is
the severity and reversibility of insulin resistance. In NIDDM, there may be less severe islet pathology
and therefore improvement in glycemic control may result in improved beta cell function and secretion of
endogenous insulin. Persistent hyerglycemia suppresses beta cell function (decrease insulin secretion)
and down regulates beta cell receptors (decreased response to insulin) thereby worsening hyperglycemia.
History and physical examination
The most common historical complaints in diabetes mellitus are polyuria, polydipsia, polyphagia,
and weight loss (despite increased appetite or intake). Physical examination findings are typically nonspecific but may include weight loss (not typically emaciated), poor hair coat, hepatomegaly, cataract
formation, and lethargy. Diabetic neuropathy will result in a plantigrade stance or generalized weakness.
With diabetic ketoacidosis, the physical examination abnormalities are much more severe with shock,
vomiting, anorexia, dehydration, and mental depression.
To establish the diagnosis of diabetes mellitus, it is important to establish a persistent, fasting
hyperglycemia with glucosuria and the appropriate historical signs. Transient hyperglycemia can occur
due to stress, particularly in cats. This hyperglycemia can be significant and in typical diabetic range. If
a patient that presents for medical evaluation has a mild hyperglycemia (130-180), another cause should
be sought, even if the patient presents for PU/PD. While euglycemic glucosuria is uncommon, various
renal tubular diseases can result in a primary glucosuria.
Evaluation and diagnostics
The stable, non-ketotic diabetic patient typically should undergo a minimum diagnostic medical
evaluation. CBC, serum chemistry, urinalysis, and urine culture are reasonable baseline database
evaluation for the stable diabetic. This should include a serum T4 level in cats. Since these patients are
older, other abnormalities such as renal disease or liver disease can be concurrently present. Diabetic
patients are susceptible to occult urinary tract infections. Diabetic animals are also at risk for or may have
suffered previously from pancreatitis. Some clinicians or authors may recommend serum pancreatic
lipase immunoreactivity (PLI) or abdominal ultrasound. While informative, a patient that is eating
without any symptoms of pancreatitis may not need a pancreatic evaluation. A healthy diabetic patient
with ketonuria can most likely be managed as a healthy diabetic patient (see below).
The ketoacidotic patient typically presents as a clinical emergency and therefore must be handled
carefully and aggressively. Aside from the standard diabetic work-up described above, further systemic
evaluation with chest radiographs, abdominal ultrasound, clotting times, and regular electrolyte evaluation
is often necessary. These patients require an aggressive therapeutic plan (see treatment below).
Treatment
DKA patient
The sick, ketoacidotic patient requires aggressive treatment. The first step is fluid therapy and
rehydration. Fluid therapy can reduce serum glucose concentrations and restore electrolyte abnormalities.
Most patients are total body potassium depleted despite having on some instances normal serum
potassium therefore potassium supplementation will most likely be needed. Phosphorus supplementation
is also commonly needed. Dilution decreases the concentrations of these electrolytes and then insulin will
create an intracellular shift in potassium and phosphorus.
Insulin therapy is not typically started immediately. It is delayed until the fluid and electrolyte
therapy have begun to have some effect on the patient. The delay is typically on the order of a few hours
and not usually longer 6. Insulin therapy is begun with regular crystalline insulin and there are varying
protocol. I have used 0.2 U/kg IM as needed based on serial blood glucose evaluation. Typically insulin
is required q 6 hours with this method. Other authors recommend an initial dose of 0.2 U/kg IM followed
by 0.1 U/kg every hour. Alternatively, a constant rate infusion can be done. To prepare a CRI, 2.2 U/kg
for dogs or 1/1 U/kg for cats is added to 250 ml 0.9% NaCl. The infusion is then run in a separate line
from the regular fluid therapy and can be run at a rate between 1-10 ml/hr based on the blood glucose.
Adjustments are made to the CRI based on the blood glucose and dextrose added to the regular fluids if
the serum glucose drops below 250 mg/dL.
Keep in mind with therapy for the sick DKA:
1. you should use regular insulin for the initial therapy, not longer lasting insulins such as NPH,
PZI, Lente.
2. Serial blood glucose measurements are essential, especially when starting insulin therapy.
3. Daily electrolyte measurements, including phosphorus, is essential. Ideally these are
evaluated q 12 hours.
4. Watching for concurrent problems and illness is important. These patients can suffer from
pancreatitis, sepsis, cholangiohepatitis, pyelonephritis, other endocrine disorders, and severe
electrolyte derangements. Serious illness can lead to systemic inflammatory response
syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and disseminated
intravascular coagulopathy (DIC).
The stable, ketotic diabetic can probably be treated as the stable diabetic (see below). Ideally,
these patients should be started on regular crystalline insulin @ 0.1-0.2 U/kg SQ q 8 hrs until ketonuria
resolves. If one chooses to pursue the regular therapy initially, these patients should be hospitalized and
have serial blood glucose measurements to monitor insulin therapy along with serial urine dipsticks to
identify resolution of ketonuria. Once the ketonuria is resolved, or if one wishes to pursue regular
management, the stable diabetic treatment plan can be followed (see below).
Stable diabetic treatment
The goal of therapy for diabetic patients is to minimize the clinical signs associated with
hyperglycemia and to achieve “acceptable” glycemic control. Acceptable glycemic control can vary
between individual clinicians, owners, and pets. .Limiting fluctuations and maintaining blood glucose
concentrations at a level as close to normal for as long as possible will minimize the clinical signs. In
addition, the clinician must avoid hypoglycemic complication and prevent the complications associated
with poor glycemic control. Assessment of these needs requires a 10-12 hour blood glucose curve with
blood glucose measurements taken every 2 hours.
Starting recommendations for insulin are typically between 0.25-0.5 U/kg SQ after eating BID.
Several days are required for equilibration so for the stable patient, I typically do not keep them in the
hospital and measure serial measurements. If the patient was initially ketotic and regular insulin, I will
continue in-hospital blood glucose monitoring when switching them to a longer lasting insulin. However,
I do not make adjustments to the insulin dose unless they are becoming hypoglycemic. This should not
be a problem at the standard starting doses.
Usually both dogs and cats are started at BID insulin treatment, however PZI insulin can have a
longer duration of action in some diabetic cats. This may necessitate once daily insulin or different doses
for the AM and PM insulin needs.
Monitoring and Insulin adjustment
Response to insulin therapy should be determined based on owner perception of symptoms along
with several objective laboratory measures. I prefer to use urinalysis and fructosamine levels for
monitoring only, not insulin adjustment. Blood glucose curves are the preferred way of adjusting insulin
dose and are also used for routine monitoring in the stable patient.
Urinalysis can be performed to assess the amount of glucosuria present and determine if ketonuria
is present. This is something that can be performed at home by the owner however, this is not always
recommended. The most important information gained from the urine dipstick is confirming the presence
or absence of ketones. Persistently elevated or negative glucose readings may suggest a problem with
glycemic control however changes in insulin should not routinely be made on urine dipstick readings. If
urine glucose is of concern, a blood glucose curve should be performed. One must remember that the
diabetic patient will have periods of hyperglycemia. The amount of urine in the glucose is dependent
upon when the animal last voided and what the blood glucose concentration was during the period of
bladder filling prior to the next urination and collection of sample for dipstick measurement. If this
sample was a morning sample prior to feeding and insulin administration, there is a high likelihood of
having elevated glucose readings because the period prior to insulin administration is potentially a
hyperglycemic time. Therefore in my opinion, the most useful information on any given sample is the
presence or absence of ketones.
Serum fructosamine levels can be measured. This value gives an indication of glycemic control
over a several week period and should not be drastically affected by individual isolated fluctuations in
blood glucose (stress hyperglycemia).
Serial blood glucose curve is the method by which many people prefer to adjust insulin dose. It
can also be used for monitoring. The curve should ideally be a 10-12 hour curve with readings taken
every 2 hours. This method should allow the clinician to identify the nadir (time and blood glucose
value) and the duration of effect of the insulin. Both are important in determining the efficacy of the
insulin. Problem with either peak effect or duration of effect can lead to poor glycemic control and
require adjustment in dose or type of insulin.
I prefer to have owners feed the pet and give the insulin at home and then present to the hospital
between 7 and 8:30 in the morning. While this does not allow me to obtain a pre-insulin blood glucose
value, I have found it very helpful for identifying problems with insulin administration at home (dated or
ineffective insulin, poor administration).
The 12 hour glucose curve can be inconvenient, especially in a busy practice, however obtaining
the values at the appropriate times can be crucial for appropriate assessment of the efficacy of the insulin
therapy. Prolonged duration of insulin (>10-12 hours), short duration of insulin, hypoglycemia, and
Somogyi effect are complications of insulin therapy that can be missed with only spot glucose readings or
timed serial readings. Spot glucose readings taken at the time of suspected nadir are not helpful for two
reasons: 1) At the time of the reading, one does not know if the blood glucose is decreasing to that level
or if it is increasing to that level, and 2) the nadir’s value and time can change on a daily basis. Similarly,
taking serial reading over a 2-4 hour period to catch a nadir is can result in missing a hypoglycemic
episode if the insulin has a rapid onset of action. Keeping in mind that a recent study showed dramatic
variability in day to day blood glucose curves, it cannot be assumed that the value at any given time is the
same every day.
Insulin therapy complications
Somogyi effect: This complication is the one I worry the most about missing. Somogyi is the response
of the body to a hypoglycemic episode. This phenomenon can occur because of hypoglycemia or because
of a rapid decrease in blood glucose concentration without hypoglycemia. Several counter-regulatory
hormones (cortisol, growth hormone, glucagons, epinephrine) are secreted to counteract the
hypoglycemic or impending hypoglycemic episode. Somogyi effect can last from 24-72 hours.
Therefore, if the effect occurred the day prior to presentation for a blood glucose curve, the serial readings
may be high for the entire day. The interpretation of the curve would be inadequate glycemic control
when in reality the problem is insulin overdose. Diagnosis of Somogyi requires demonstration of
hypoglycemia followed by hyperglycemia. It should also be suspected if there is a rapid decline in blood
glucose followed by hyperglycemia. If you are seeing a persistent hyperglycemia on a blood glucose
curve and the owner has not appreciated any episodes of hypoglycemia, the possibility of Somogyi still
exists, and you must make a recommendation based on your clinical suspicion. If you are early in the
course of treating the disease (ie at the low end of insulin dosage), then most likely what the patient is
experiencing is inadequate diabetic control. If you are at a high dose of insulin (>1.5 U/kg), then insulin
resistance should be suspected for which one differential would be Somogyi phenomonenon.
Short or Prolonged duration of insulin efficacy: Depending on the insulin type and species, some insulin
may work for less than 8 hours while others may have an effect for as long as 16 hours. This should be
identified on the glucose curve and can have significant ramifications. An insulin that is working over 12
hours can eventually result in a hypoglycemic episode if blood glucose values at the time of subsequent
insulin administration continuously decreases. Alternatively, a short duration of insulin may result in
prolonged hyperglycemia and therefore complications associated hypeglycemia (ketosis, cataract
formation, neuropathy, PU/PD, continued weight loss).
For short duration of activity – if the blood glucose nadir is already as low as one can safely go,
increasing the insulin will not be the appropriate adjustment to improving the blood glucose curve. In this
situation, switching to a longer lasting insulin or utilizing TID treatment will be necessary.
For prolonged duration of insulin – switching to a shorter acting insulin or utilizing different AM/PM
doses for insulin administration may be necessary. Another option may be to combine a short acting with
a long acting insulin in order to achieve the desired response.
For any insulin therapy that is not conventional (TID, different AM/PM doses, combination insulin
therapy), the veterinarian must exercise extreme caution with monitoring the glycemic control and
instructing the owner on what to do and how to monitor at home.
Recurrence of clinical signs – probably the most common problem and occurs over time. Typically all
that is needed is a blood glucose curve followed by adjustment of the insulin dose. I typically recommend
routine 4 month glucose curves regardless of the perceived glycemic control based on clinical signs. If
the dose is adjusted, I recommend a repeat blood glucose curve in 1 week. This continues until the dose
is satisfactory and then we switch back to the maintenance schedule.
Reversal of glucose toxicity – persistent hyperglycemia results in “glucose toxicity”. There is down
regulation of insulin receptors and impaired beta cell function. Improvement of glycemic control can
result in improved endogenous insulin secretion and response to insulin. The patient may subsequently
present to the clinic for hypoglycemia and insulin overdose due to the improved control. A decrease in
the dose of insulin is necessary in these cases. For dogs, eventually the insulin requirements increase.
Insulin resistance – should be suspected if the dose of insulin is > 1.5U/kg. Causes of insulin resistance
include infection, diestrus, estrogen therapy, pancreatitis, Cushing’s disease, and Somogyi phenomenon.
Keep in mind that a dog with Cushing’s disease that becomes diabetic is easier to identify than a dog with
diabetes mellitus that develops Cushing’s disease. Poor glycemic control can result in non-adrenal illness
and false positive Cushing’s evaluation.
Transient diabetes mellitus
Cats more commonly than dogs can exhibit transient diabetes. This is typically due to NIDDM
and improved glycemic regulation resulting in improved beta cell function and insulin receptor
upregulation. These cats should be monitored closely and urine dipsticks performed during periods of no
insulin therapy is ideal to identify glucosuria early.
Owner education
When starting insulin therapy, the owners must be warned of several things. First, diabetes is a treatable
but not curable disease. Accomplishing adequate glycemic control requires persistence and patience and
can take as long as 4-6 weeks. Cats are notoriously more difficult to regulate in dogs and can exhibit
transient diabetes mellitus. There are day to day differences in blood glucose values at fixed times despite
consistency in diet, environment, and insulin dose so fluctuations should be expected. They should also
be educated about the complications associated with insulin therapy and chronic complications associated
with diabetes (cataract formation, neuropathy, nephropathy, ketosis, urinary tract infection). Patients
should have routine urine cultures performed with maintenance blood glucose curves. Concurrent
diseases or natural progression of diabetes can affect glycemic control and this could create a situation
similar to a newly diagnosed diabetic (i.e. one must be prepared to commit several weeks to re-achieving
regulation).
Type of
insulin
Concentration Brand name(s) Manufacturer
Insulin zinc
suspension
(Lente)
40 U/mL
Vetsulin
Intervet
ScheringPlough
Protamine
zinc insulin
(PZI)
40 U/mL
ProZinc
Boehringer
Ingelheim
Regular
insulin
100 (& 500)
U/mL
Humulin R
Eli Lilly
Regular
insulin
100 U/mL
ActRapid
Novo Nordisk
Humulin N
Eli Lilly
Isophane
100 U/mL
(NPH) insulin
Isophane
100 U/mL
(NPH) insulin
Protophane
50% Regular
& 50%
isophane
(NPH)
100 U/mL
Mixtard 50/50 Novo Nordisk
30% Regular
& 70%
isophane
(NPH)
100 U/mL
Mixtard 30/70 Novo Nordisk
30% Regular
& 70%
isophane
(NPH)
100 U/mL
Humulin
70/30
Eli Lilly
Insulin lispro
100 U/mL
Humalog
Eli Lilly
Insulin aspart
100 U/mL
NovoLog;
NovoRapid
Novo Nordisk
Insulin
glulisine
100 U/mL
Apidra
Sanofi Aventis
50% Lispro & 100 U/mL
50% lispro
protamine
Humalog Mix
50/50
Eli Lilly
30% Aspart & 100 U/mL
70% aspart
protamine
NovoLog Mix Novo Nordisk
70/30;
NovoMix 30
25% Lispro & 100 U/mL
75% lispro
protamine
Humalog Mix
75/25
Eli Lilly
Insulin
glargine
100 U/mL
Lantus
Sanofi Aventis
Insulin
detemir
100 U/mL
Levemir
Novo Nordisk
Fleeman, L. ACVIM 2010
Novo Nordisk