www.caninsulin.com
Successful
diabetes
management
made possible
with Caninsulin
Veterinary Technical Brochure
1
Incidence
and Etiology
Diabetes
Diabetes mellitus due to pancreatic disease
Introduction
Diabetes mellitus is a common endocrine disorder of
dogs and cats that results from an absolute or relative
insulin deficiency. In general, the prognosis is good,
provided that the diagnosis is made at an early stage and
treatment is adequate.
Insulin treatment is the cornerstone of successful
management, but appropriate diet and a regular lifestyle
are also important. First-rate communication between
you, the veterinarian and the pet owner is of major
importance. Your attitude to diabetes mellitus will largely
determine the owner’s motivation and compliance with treatment.
Vacuolar degeneration
of islets of Langerhans in
a dog, Hemaxtoxylin and
eosin (HE) stain, 10x.
Amyloidosis of islets of
Langerhans in a cat, HE
stain, 25x.
Amyloidosis of islets of
Langerhans in a cat,
polarized light (left) and
Congo red stain (right).
Photographs courtesy of Pathology Department, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands.
Incidence
Estimates of the incidence of diabetes mellitus in dogs and cats range from 1:100
to 1:500.1 Diabetes occurs most commonly in middle aged and older dogs and
cats. In dogs, there is a genetic predisposition in Keeshonds and Samoyeds and a
higher incidence in intact females. A higher incidence is seen in Burmese cats and
in neutered male cats.
Diabetes mellitus due to disease not primarily of
pancreatic origin
Overproduction of counteracting hormones and insulin resistance
Growth hormone excess
Etiology
Diabetes mellitus can originate from either pancreatic or non-pancreatic disease.
Endocrine
Destruction of endocrine pancreatic tissue can lead to diabetes mellitus. In dogs,
there is some evidence that autoimmune destruction of the islets of Langerhans
plays a role in the pathogenesis of diabetes. In cats, amyloid deposition may
contribute to the destruction of the islets of Langerhans.
Exocrine
Severe inflammation or neoplasia of the exocrine pancreas can
also lead to loss of islet function. In these cases, diabetes is
complicated by exocrine pancreatic insufficiency.
Progesterone-induced
Progesterone produced during the luteal phase induces
the production of growth hormone by the mammary
gland. This counteracts the action of insulin.
Pituitary origin - acromegaly
Acromegaly (hypersomatotropism) is caused by growth
hormone excess. This is not uncommon in cats where it
is due to a growth hormone-secreting pituitary tumor.
Cushing’s syndrome
Corticosteroids stimulate gluconeogenesis, leading to
an increase in the blood glucose concentration. This stimulates insulin synthesis,
which can eventually result in exhaustion of the islets of Langerhans.
www.caninsulin.com
2
Reference: 1. Panciera DL et al. (1990) J Am Vet Med Assoc 197, 1504-1505.
3
pathogenesis
and clinical signs
Diabetes
Figure 1: intercellular energy shortage
Figure 2: extracellular hyperglycemia
extracellular hyperglycemia
Glucose toxicity
hyperosmotic plasma
Glucose toxicity occurs when insulin secretion is reduced
by prolonged hyperglycemia. Prolonged hyperglycemia
can be due to a number of causes including the ones
listed below.
dehydration of cells
intracellular energy shortage
blood glucose > renal threshold
glucosuria
high urine
specific gravity
osmotic diuresis
hyperglycemic coma
polyuria
polydipsia
The therapeutic use of corticosteroids can induce
diabetes mellitus.
Progestogens
The use of exogenous progestogens can lead to growth hormone excess.
Progestogens also have an affinity for glucocorticoid receptors.
gluconeogenesis increases
increase of fatty acid
concentrations in plasma
protein synthesis decreases
– cachexia/lethargy
– polyphagia
–decreased gamma globulin concentrations
– increased susceptibility to infections
– impaired wound healing
ketosis
hypokalemia
hyponatremia
ketoacidosis; ketonuria
Iatrogenic
Corticosteroids
fat metabolism
acidotic coma
Clinical signs
There are three clinical scenarios in diabetes mellitus
•uncomplicated
• complicated by ketoacidosis
• hyperosmolar hyperglycemic non-ketotic syndrome
Obesity
In obesity, tissue receptors have decreased insulin sensitivity. This leads to a
greater demand for insulin, which can result in exhaustion of the islets of
Langerhans.
Potential diabetes mellitus
Potential diabetes mellitus, defined as impaired insulin synthesis and/or decreased
sensitivity of tissue receptors to the effects of insulin, results in an increased blood
glucose concentration that does not yet exceed the renal threshold. This is seen
in intact female dogs during metoestrus. At this stage, the problem may still be
reversible by spaying (elimination of the progesterone source).
Mild hyperglycemia may also be encountered in Cushing’s syndrome (hyperadrenocorticism) and reversal of the cortisol excess may prevent the development of diabetes
mellitus.
4
Uncomplicated diabetes mellitus
The classical signs are
•polyuria/polydipsia
•polyphagia
•cachexia
•increased susceptibility to infections
(e.g. urinary tract infections)
Complications, due to protein glycosylation, include
• cataracts (mainly in dogs)
• peripheral neuropathy (mainly in cats)
Fructosamine and glycated hemoglobin concentrations also increase due to
protein glycosylation.
Complicated by ketoacidosis
Pathogenesis
Animals may become comatose if the ketoacidosis is severe.
Diabetes mellitus is a paradox: simultaneous extracellular hyperglycemia and
intracellular glucose deficiency. The consequences of this paradox are shown in
Figs. 1 and 2.2a
Hyperosmolar hyperglycemic non-ketotic syndrome
Reference: 2a. Rijnberk A. (1996) Clinical Endocrinology of Dogs and Cats, Kluwer Academic Publishers, The Netherlands; 95-117.
When resistance of target tissues to insulin plays a role in the disease, insulin
levels can be elevated. In these cases, ketosis is suppressed and blood glucose
concentrations can become very high. These animals are usually comatose.
5
Diabetes
Management
Successful
Diagnosis
Diabetes mellitus is not the only cause of polyuria, polydipsia and weight loss.
Cases should be investigated fully to rule out other causes before starting insulin
treatment.2b A preliminary diagnosis of diabetes mellitus based on clinical signs
must be confirmed by urine and blood tests.
Reference intervals for blood glucose in non-diabetic, healthy animals are
approximately 3.5-6.1 mmol/L (63-110 mg/dL) in dogs and 2.6-8.4 mmol/L
(47-151 mg/dL) in cats. The renal threshold is around 10 mmol/L (180 mg/dL) in
dogs and around 14 mmol/L (252 mg/dL) in cats. If the blood glucose concentration
exceeds this threshold, glucose is excreted in the urine (glucosuria).
Transient hyperglycemia can occur particularly in cats in stress situations, usually
where struggling is involved. Fructosamine concentrations are correlated with the
average blood glucose concentration over the previous 1-2 weeks. Fructosamine
measurement is a valuable tool in confirming a diagnosis of diabetes mellitus
particularly in cats.
Diet and feeding schedule
The volume and composition of meals should be
identical from day to day to avoid changes in
insulin requirements. As this is difficult to accomplish
with home-prepared meals, commercial pet food
is preferable.
General considerations
Commercial diets with a high quality, highly digestible
protein source and a low fat content provide a more
gradual intestinal uptake of glucose. In animals that
are over- or underweight, the ideal body weight
should be reached by gradual weight loss or gain.
Very calorie-dense diets, especially those high in
soluble carbohydrates, should be avoided in animals
that are underweight.
Treatment of diabetes mellitus is likely to succeed only if the pet owner
understands all aspects of its management, including the importance of diet
and regular exercise. Investment of time in a careful explanation of all aspects
of diabetes management is strongly recommended.
For dogs the daily food intake is usually divided into two
meals. The timing and quantity of these meals varies,
based in part on whether insulin is administered once or
twice daily.
Spaying
The first meal is given around the time of the morning
insulin injection and the second meal approximately
8 hours to 12 hours later.
Diabetes management
If diabetes mellitus has been diagnosed in an intact female dog, immediate
spaying (ovari(ohyster)ectomy) is advisable, to prevent further exposure to
endogenous progesterone. In animals fit for surgery, this can be carried out prior
to insulin treatment and intravenous fluid therapy administered.
If the animal’s condition is critical (dehydration, anorexia, uremia, severe
hyperglycemia and glycosuria) and surgery is contraindicated, intravenous fluid
therapy and insulin administration should be started. Spaying can then be
carried out as soon as the dog’s condition has improved sufficiently. On the day of
surgery, pre-operative fasting will necessitate reducing the insulin dose, e.g.
to around 30% and intravenous fluid therapy should be administered.
6
Following surgery, regular monitoring is necessary until the animal’s condition
is stable. The response to insulin will often improve and the insulin demand will
decrease accordingly.
Reference: 2b. Rijnberk A. (1996) Clinical Endocrinology of Dogs and Cats, Kluwer Academic Publishers, The Netherlands; 221-222.
Cats are often very fussy eaters and usually prefer to eat when they choose. Free
access to a measured amount of the food is often the best option. Diabetic cats
can be stabilized on their usual diet if need be, but diets low in carbohydrate are
usually preferred.
Clean drinking water should be available at all times. A reduction in excessive
water consumption indicates successful management of the diabetes mellitus.
7
Management
with caninsulin ®
Diabetes
Due to differences in metabolism, the duration of activity of a particular insulin
will vary from animal to animal. The source of the insulin can be also different.
Caninsulin is an aqueous suspension of 40 IU highly purified porcine insulin per
mL, consisting of 35% amorphous and 65% crystalline zinc insulin. Caninsulin
is available in vials and cartridges. Caninsulin is administered using a U40 insulin
syringe or VetPen®.
Pharmacokinetics of Caninsulin
In cats, the maximum effect is seen
around 4 hours after administration
and the total duration of action is
around 12 hours.5
Figure 3: Schematic representation
of Caninsulin concentration in dogs
showing biphasic activity
amorphous
(30%)
Dogs
The initial dose for dogs is 0.5 IU/kg once daily. Many dogs
need twice daily insulin. The dose per injection is often the
same whether the insulin is administered once or twice
daily. When changing a dog from once daily to twice daily
insulin, a dosage reduction of 25% per injection
is recommended. For example, a dog on 20 IU once daily
would receive an initial daily dose of 15 IU twice daily.
Even after stabilization it is not uncommon for a dog’s insulin
requirements to change suddenly, often after a period of
months or even years.
crystalline
(70%)
activity of Caninsulin
In dogs the amorphous fraction
has peak activity approximately
3 hours after subcutaneous
administration, and its effects last
for about 8 hours. This effect is
maintained by the crystalline fraction,
which has a slower onset of action
and peak effects from 7 to 12 hours
following injection.3,4 The total
duration of effect ranges from 14 to
24 hours depending on the individual
dog (Fig. 3).
Initial regulation
Cats
The initial dose for cats is 1 to 2 IU per injection twice daily, depending on the initial
blood glucose concentration (Table 1). The starting dose should ideally not exceed 2 IU
per cat twice daily in the first 3 weeks of treatment.
0
2
4
6
8
10
12
14
16
18
20
22
24
time in hours
Dogs
The duration of activity of Caninsulin may be sufficient to treat dogs once daily.
However, in many cases, injections have to be given twice daily.
Cats
After several weeks or even months it is not unusual for either insulin to be no longer
required (clinical remission) or a major change in the dose to be required.
Baseline blood glucose
concentration
Initial Caninsulin dose
(round down to nearest
whole unit)
<20 mmol/l
≥20 mmol/l
1 IU twice daily
2 IU twice daily
or
or
<360 mg/dl
≥360 mg/dl
Table 1. Guide to starting twice daily Caninsulin treatment in cats
The duration of action of Caninsulin is shorter in cats than in dogs. As a result, all
cats require twice daily injections. Twice daily injection of Caninsulin can provide
sufficiently good glycemic control that can result in remission of the clinical signs.6
8
References: 3. Graham PA, Nash AS & McKellar QA. (1997) J Small Anim Pract 38, 434-438. 4. Horn B & Mitten RW. (2000) Aus Vet J 78, 831-834.
5. Martin GJ & Rand JS. (2001) J Feline Med Surg 3, 23-30. 6. Michiels L et al. (2008) J Feline Med Surg 10, 439-451.
9
Urine monitoring
In dogs, dose adjustment should be managed in steps of 10%. In cats, the dose
should be adjusted in steps of 0.5 to 1 IU according to an algorithm (Fig. 3).5,6
Following adjustment, full evaluation should not take place before the new dose
has been given for days to weeks, particularly in cats.
Urine monitoring is a quick and easy method
of detecting ketones (ketonuria). Urine
only tests positive for glucose if the blood
glucose concentration remains above the
renal threshold for a substantial period.
Monitoring of urine for glucose can be useful
in diabetic animals that are not yet stable or
in those that have problems with recurrent
hypoglycemia. Here it is used to identify the
absence of glucose.
Maintaining a blood glucose concentration within the reference interval for nondiabetics throughout the entire day is not a treatment goal per se. The aim is to
try to maintain blood glucose concentrations between around 5 and 15 mmol/L
(90 and 270 mg/dL) for a substantial part of the day. This will result in the
disappearance of most of the clinical signs - the goal of therapy.
Are there clinical signs
of hypoglycemia?
No
Yes
Reduce the insulin
dose by at least 1 IU
5–7 days later
Blood glucose nadir of
<54 mg/dl (<3 mmol/l)
No
>162 mg/dl (>9.0 mmol/l)
<90 mg/dl (<5.0 mmol/l)
Yes
Blood glucose 90–162 mg/dl
meal followed by its morning Caninsulin
injection.
Does the cat have a total water
intake of <100 ml/kg/day?
nadir of
(5.0–9.0 mmol/l)
No
Decrease the insulin
dose by 0.5 or 1 IU
•Blood samples should then be taken
approximately every 2 hours throughout
the day (at least 9 to 12 hours). It is
important to record the time that the
samples are taken!
8
12
16
20
24
a stable diabetic dog
20
15
10
Blood glucose curves
•The animal should be given its first
Blood glucose nadir of
4
Figure 3. Blood glucose curve from
5
0
2
4
8
12
16
20
24
Time (hours)
Figure 4. Insulin resistance
(hyperglycemia) (see Fig. 6):
If hyperglycemia persists with dosage
reduction, try increasing the dose
The procedure is:
Biochemical
hypoglycemia
2
Time (hours)
Yes
Blood glucose nadir of
Increase the insulin by
0.5 or 1 IU
0
The most accurate way to assess the response
to treatment is by making a blood glucose
curve (Figs. 3-6). The procedure is as follows:
The first blood sample should ideally be taken
just prior to the insulin administration.
Perform a 12 hour
blood glucose curve
15
5
Blood glucose (mmol/l)
Recheck:
•After 1 week
•Every 3 weeks
•If hypoglycemia is
suspected then:
•Every 2–4 months
Urine monitoring can be used for animals
that are known to have a blood glucose
concentration in an acceptable range. In
this case it is a quick, easy method of
detecting hyperglycemia. This should then
be investigated further by measuring blood
glucose concentrations.
20
10
Blood glucose (mmol/l)
Dose adjustment
Blood glucose (mmol/l)
Diabetes
incidence
Dose Adjustment
and
Etiology
and
monitoring
20
15
10
5
0
2
4
8
12
16
20
24
Time (hours)
10
Figure 5. Short duration of action:
Figure 3. Guide to monitoring stabilization and making dose rate changes in diabetic cats
change to twice daily
11
Diabetes
incidence
Challenges
and
Etiology
in diabetes
management
Somogyi effect
Immediate oral administration of a glucose source (1 g glucose per kg body
weight, approximately one heaped teaspoonful per 5 kg body weight) by
the owner can alleviate these signs. Owners need to keep a glucose source
readily available.
An insulin dose that is slightly too high may bring about
the Somogyi effect (rebound hyperglycemia) (Fig. 8).
This is a chain of reactions through which the body
attempts to counteract a decline in blood glucose. If the
blood glucose concentration falls rapidly or approaches
hypoglycemia (less than 5 mmol/L or 90 mg/dL), clinical
signs of hypoglycemia may also develop.
Following emergency administration of glucose, food must be given
repeatedly at intervals of 1-2 hours until all the effects of the “extra” insulin
have been counteracted.
In response to a declining glucose concentration in the
brain, adrenaline and subsequently cortisol, glucagon
and growth hormone are released. These hormones
bring about an increase in the blood glucose (through gluconeogenesis, release
of glucose from hepatic glycogen stores and increased peripheral resistance to
insulin). Polyuria and polydipsia are seen and this can easily be misinterpreted.
Hyperglycemia can sometimes persist for days after a single hypoglycemic
episode. If the Somogyi effect is suspected, an alternative approach involves
decreasing the dose by 20% and closely observing the clinical signs. If the
polyuria or polydipsia worsen following dose reduction, it is unlikely that the
Somogyi effect was the problem.
Blood glucose (mmol/l)
If the response to insulin therapy is poor, a blood glucose curve should be made
and every effort made to rule out other concurrent or underlying disorders.
Problems with administration
Caninsulin has been specially developed for use in animals and has a
concentration of 40 IU/mL, making the dose easy to measure and dilution
unnecessary. Caninsulin should be stored upright in a refrigerator and must be
mixed before use. To obtain a homogeneous, uniformly milky suspension, shake
vials thoroughly or invert cartridges, which contain mixing beads, ten times.
Problems with resorption from the injection site
Hypoglycemia
If the insulin dose is too high, clinical signs
of hypoglycemia may be observed. These
include hunger, restlessness, shivering,
ataxia, disorientation, convulsions and
coma. However, some animals just become
very quiet and stop eating. This serious and
potentially fatal condition (which can also be
triggered by anorexia, vomiting or excessive
exercise) may occur at any stage, even after
stabilization has been achieved.
Problems with regulation
This has been reported in cats, especially with ultralente insulin.
Antibodies
25
Antibodies may be directed either against the insulin
or against other foreign proteins in a preparation. The
presence of antibodies is common in diabetic dogs and
does not frequently lead to poor regulation. Insulin
antibodies appear to be less common in diabetic cats.
Antibody production is less likely in dogs if homologous
insulin is given - the porcine insulin in Caninsulin has
exactly the same structure as canine insulin.
20
15
10
5
0
2
4
8
12
16
20
24
Time (hours)
Figure 6. Rebound
hyperglycemia: reduce the dose
12
13
Diabetes
incidence
Diabetic pets
can enjoy Healthy,
and
Etiology lives
Normal
More Information
about Caninsulin online
Get
CLIENT participation
Most clients quickly learn to give daily insulin injections.
It is best to confirm that the animal is eating normally,
before giving the insulin injection.
During therapy the pet owner needs to actively
participate in regularly monitoring their pet’s progress.
Many clients can be successfully instructed to take
capillary blood samples and use a handheld glucometer.
If this is not feasible, an alternative is to have the owner test the urine for the
presence of glucose and ketones. Before dose changes are made, blood glucose
concentrations should be confirmed.
Prognosis in diabetes mellitus
The prognosis for a diabetic animal depends to a large extent on the level
of confidence, knowledge and dedication of its owner. These factors can be
favorably influenced by your attitude and the quality of the information you, the
veterinarian, provide. It should be made clear that treating a diabetic animal is
interesting, rewarding and certainly not as complicated as is sometimes thought.
More information to help you manage diabetes in dogs and cats is available at
www.caninsulin.com.
You can also visit the website that provides more information for owners of
diabetic pets at www.pet-diabetes.com.
www.caninsulin.com
14
15
www.caninsulin.com
Product
INFORMATION
PRESENTATION
Caninsulin is an aqueous suspension of insulin containing 40 IU per ml
of highly purified porcine insulin, 30% is amorphous zinc insulin and
70% crystalline zinc insulin.
problems) including its health and urine glucose and ketones record.
Blood glucose is also measured at this time. Adjustments to the insulin
dose are made by the veterinarian based on full analysis of the clinical
data and on blood glucose measurement.
USES
Caninsulin, an intermediate acting insulin containing porcine insulin, is
structurally identical to canine insulin. It is indicated in the treatment of
diabetes mellitus in dogs and cats.
The ability for owners to recognise the signs of hypo- or hyperglycaemia
and respond approprately is important if control is to be achieved
during maintenance therapy. Polyuria, polydipsia and polyphagia in
combination with weight loss, general bad condition, and lethargy
are the most common clinical signs of diabetes mellitus and require
administration of insulin to restore blood glucose concentrations to the
normal range.
DOSAGE AND ADMINISTRATION
Invert the insulin vial a few times to resuspend the Caninsulin.
Caninsulin should be administered by subcutaneous injection.
An insulin syringe with unit markings for a 40 IU/ml insulin should be used.
A once daily injection is sufficient to stabilise the blood glucose level
in many dogs. However, the duration of action may vary, making it
necessary to administer insulin twice daily to some dogs. In cats, it is
necessary to administer Caninsulin twice daily.
The dose depends on the degree of deficit in the animal's own insulin
production and therefore is different in each case. In dogs, the initial
daily dose is 1 IU per kg bodyweight plus a body weight dependent
supplement dose. In cats, the initial daily dose is 0.25-0.5 IU/kg twice daily.
Especially in obese cats, an unduly high starting dose may be dangerous.
Subsequent adjustment to establish the maintenance dose should be
made by increasing or decreasing the daily dose by approximately 10%
per day according to the results of measurement of the blood glucose
concentrations.
Once the maintenance dose has been established and the animal
is stabilised a long term management programme needs to be
implemented. The aim should be to manage the animal in such a
way as to minimise the variations in its insulin requirement. This includes
monitoring to detect under or overdosage of insulin and adjustment of
dose if required. Careful stabilisation and tight monitoring and control
during maintenance will help to limit the chronic problems associated
with diabetes, such as cataracts.
Various approaches to maintenance have been described. The most
clinically rational approach is for the owner to monitor and record the
animal's general health and urine ketones (including well-being, thirst
and appetite) and check urine glucose at least daily. The veterinary
surgeon checks the case every 2-4 months (or more often if there are
CONTRAINDICATIONS, WARNINGS, ETC.
1.Caninsulin is a an intermediate acting insulin and is not intended for
the treatment of animals with severe acute diabetes presenting in
a ketoacidotic state. Caninsulin must not be administered by the
intravenous route.
2.The use of progestogens in patients suffering from diabetes mellitus
should be avoided. Ovari(ohyster)ectomy may have to be considered.
3.Stress and irregular exercise must be avoided. Care must be taken
with the use of corticosteroids.
4.It is important to establish a strict feeding schedule with minimal
fluctuations and changes in consultation with the owner.
5.Administration of Caninsulin must be carried out by an adult
responsible for the welfare of the animal.
For animal treatment only. Keep out of the reach of children.
STORAGE
Store refrigerated at 2-8ºC. Do not freeze. Protect from light. Store in an
upright position. Following withdrawal of the first dose use the product
within 20 days. Discard unused material.
PACKAGING
Vials containing 10 ml or 2.5 ml in single and multiple packs.
Intervet International BV - P.O. Box 31, 5830 AA Boxmeer - The Netherlands
Phone: +31 (0)485 587600 - Fax: +31 (0)485 577333 www.msd-animal-health.com
© 2013 Intervet International B.V., a subsidiary of Merck & Co., Inc.,
Whitehouse Station, NJ, USA. All rights reserved.
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