Journal of Feline Medicine and Surgery (2000) 2, 317

REVIEW
Current understanding of feline diabetes:
Part 2, treatment
G Martin, J Rand
Companion Animal Sciences,
School of Veterinary Science and
Animal Production, The
University of Queensland,
Australia 4072
Date accepted: 29 October 1999
When treating diabetic cats, the primary aim is to control clinical signs without
causing clinical hypoglycaemia. Secondary goals are to maximise the chances
of attaining diabetic remission and to minimise the risk of complications due to
chronic hyperglycaemia. A treatment plan that is convenient for the owner is
important for compliance. Underweight or overweight diabetic cats should be
fed with the aim of normalising bodyweight. Current evidence suggests that
non-obese diabetic cats can be fed ad libitum. The oral hypoglycaemic drug
glipizide is well established as a treatment for about a third of diabetic cats,
which have residual beta cell function. Preliminary studies on other oral agents
such as vanadium salts, metformin, and troglitazone indicate a potential use in
some diabetic cats. Insulin treatment remains the treatment of choice for the
majority of diabetic cats. Choice of insulin, dose rates and monitoring of
treatment are discussed.
2000 European Society of Feline Medicine
T
his is the second of a two-part review on
diabetes in cats. Part I (Rand 1999) dis-
cussed the pathogenesis and diagnosis of
diabetes in cats. Knowledge of pathogenesis is
important for understanding treatment issues.
Sick ketotic diabetic cats
Diabetic cats that present with diabetic ketosis
or ketoacidosis (DKA) may be severely ill, and
their treatment is a medical emergency. In two
separate studies, each of 104 diabetic cats,
there were 12 cats (11.5%) and 38 cats (36.5%)
diagnosed with DKA on the basis of ketosis
and metabolic acidosis (Crenshaw & Peterson
1996, Goossens et al 1998). In Goossens study,
eight of 12 cats with DKA died or were eutha-
nased in the initial hospitalisation period
(Goossens et al 1998). Acute necrotising pan-
creatitis was a frequent concomitant problem
in these cats. The treatment of DKA involves
addressing underlying disease processes
present, correcting uid, electrolyte, and acid-
base imbalances, and lowering blood glucose
(Macintire 1995).
Depressed, dehydrated, hypothermic, or
pyrexic cats require hospitalisation. In dehy-
drated diabetic cats, uids are as important as
insulin therapy. For most dehydrated diabetic
cats, the type of uid is not as important as the
uid itself, and a balanced electrolyte solution,
preferably with lactate, is a good initial choice.
Generally, uid administration rates of 100 to
150 ml/kg/24 h are appropriate for dehydrated
diabetic cats. For severely hyperglycaemic
(>32 mmol/l) dehydrated cats, half strength
sodium chloride (0.45% NaCl) may be the pre-
ferred choice of uid for the rst few hours,
because these cats are markedly hyperosmotic.
However, it should be used with careful
monitoring of blood glucose and electrolytes.
Bicarbonate supplementation is rarely indicated
because acidosis improves rapidly with uid and
insulin therapy.
Ketoacidotic cats may initially be hyperkalae-
mic. Acidosis causes intracellular potassium to
be exchanged with extracellular hydrogen ions,
which may result in hyperkalaemia. Extracellular
potassium concentration falls quickly as potass-
ium moves intracellularly with insulin and uid
1098-612X/00/010003+15 $35.00/0 2000 European Society of Feline Medicine
therapy, and as acidosis is corrected. Whole body
potassium depletion occurs when glucose and
uid induced diuresis causes renal potassium
loss (Dow et al 1987, Feldman & Nelson 1996).
Hypokalaemia may occur within 1224 h in cats
that were hyperkalaemic on admission. Hypo-
kalaemic myopathy and weakness can occur
with plasma potassium concentrations less than
3.5 mmol/l, and levels below 2 mmol/l should
be considered an emergency because of the
possibility of death from respiratory paralysis
(Dow et al 1987). Potassium therapy should
commence immediately in normokalaemic
acidotic cats, and within 1224 h after com-
mencement of uid therapy in initially hyper-
kalaemic cats. If possible, potassium therapy
should consist of both oral and intravenous
therapy. Potassium chloride should be added to
uids at between 40 and 80 mmol/l, and potass-
ium gluconate given at 23 mmol/cat per os, one
to three times per day. Potassium concen-
trations need to be monitored carefully in the
rst few days of uid therapy to avoid hypo- or
hyperkalaemia.
Often ketoacidotic cats become hypophospho-
taemic within 1224 h after commencement of
insulin therapy (Feldman & Nelson 1996). Meta-
bolic acidosis causes cellular and whole body
loss of phosphorus, similar to potassium (Willard
et al 1987). Signs of hypophosphataemia
(<0.5 mmol/l) in cats are haemolysis, muscle
weakness, as well as neurological problems such
as seizures and ataxia (Forrester & Moreland
1989). Phosphorus can be given subcutaneously
at 0.141.26 ml/kg. Alternatively, potassium and
phosphorus can be supplemented in the intra-
venously administered uid by calculating the
potassium requirement and supplying it as
50% potassium chloride and 50% potassium
dihydrophosphate (Feldman & Nelson 1996).
In dehydrated diabetic cats, insulin is best
given intramuscularly or intravenously, and
blood glucose levels monitored carefully. The
aim of insulin therapy is to decrease blood glu-
cose levels slowly, while decreasing ketoacidosis.
Problems can be encountered when blood glu-
cose levels fall too rapidly, as diabetic cats have
adapted to prolonged hyperosmolality and
hyperglycaemia. Aim for a glucose drop of
34 mmol/l/h and do not exceed 6 mmol/l/h.
In dehydrated, depressed ketoacidotic cats, regu-
lar insulin can be administered intramuscularly
at an initial dose of 0.2 iu/kg, and continued
hourly at 0.1 iu/kg. To achieve blood glucose
decreases of between 3 and 4 mmol/l/h, insulin
doses may have to be increased to 0.2 iu/kg/h
or decreased to 0.05 iu/kg/h (Feldman &
Nelson 1996). Hourly injections should be con-
tinued until blood glucose reaches 16 mmol/l,
when injections of 0.10.4 iu/kg should be given
every 46 h to achieve a nal blood glucose of
between 11 and 14 mmol/l. If blood glucose
levels fall below 8 mmol/l in the rst 36 h, a 50%
dextrose (glucose) solution should be added to
the intravenous uids to produce a 5% dextrose
solution. Alternatively, regular insulin can be
given intravenously at 0.050.1 iu/kg/h and
adjusted to achieve a glucose decrease of
34 mmol/l/h. If the cat is very dehydrated and
ketotic and regular insulin is not available for
several hours, then other longer-acting forms can
be given intramuscularly. Lower the dosing fre-
quency to every 46 h if using either lente or
ultralente forms (0.30.5 iu/kg), and monitor
glucose very carefully, especially after the second
injection. Subcutaneous injection of maintenance
insulin, such as lente, PZI or ultralente, can
commence when the cat is well hydrated.
For further details on treating DKA, and other
severe forms of diabetes mellitus in cats, the
reader is referred to reviews on this specic
disorder and its clinical management (Macintire
1995, Nicholls & Crenshaw 1995a, 1995b,
Bruskiewicz et al 1997).
Therapeutic goals for otherwise
healthy diabetic cats
The principal goals of treating diabetes in cats
are to correct the major clinical signs of diabetes
(weight loss, polydipsia/polyuria, and poly-
phagia or inappetence), and to prevent diabetic
ketoacidosis. Additional goals are to minimise
the risk of hypoglycaemia by appropriate dose
adjustment of insulin or oral hypoglycaemic
agents. Appropriate therapy of cats may also
lead to diabetic remission (Nelson et al 1992a),
although currently it is not possible at diagnosis
to predict which cats are more likely to go into
remission. Treatment that is most effective in
correcting hyperglycaemia is more likely to lead
to remission by facilitating the recovery of the
pancreatic beta-cells from glucose toxicity.
The long-term complications of diabetes in cats
are of less concern than with other species, and
hindlimb neuropathy is the most signicant
problem (Munana 1995). Tight glycaemic control
is pursued in human diabetics to avoid the long
term complications associated with chronic
4 G Martin and J Rand
hyperglycaemia such as retinopathy, but this
leads to an increase in the frequency of
clinical hypoglycaemic episodes (Reichard 1994).
Because of the risk of hypoglycaemia in insulin-
treated diabetic cats (Whitley et al 1997) and the
lack of life-threatening complications associated
with moderate hyperglycaemia, pursuing tight
glycaemic control is not advised.
Treatment modalities
Diet
General considerations. Unlike humans and dogs,
normal cats fed ad libitum will eat 12-20 meals
spread throughout the day and night, and tra-
ditionally the major energy source is protein
rather than carbohydrate (Morris & Rogers 1983,
Houpt 1991). Another important species differ-
ence is that post-prandial hyperglycaemia does
not occur in cats fed typical cat foods (Kienzle
1994, Martin & Rand 1997). Therefore there does
not seem any need to match the timing of the
insulin dose to meals, which is important in the
control of blood glucose in human diabetics
(Eaton et al 1978). Diabetic cats can be fed ad
libitum and allowed to follow a normal feeding
pattern of multiple small meals (Kane 1989,
Martin & Rand 1997). Feeding multiple kilojoule-
restricted meals may also be advantageous for
weight loss in obese diabetic cats (Hand et al
1989).
Diabetics have energy loss via glucose in
the urine, and may have maldigestion/
malabsorption due to previous pancreatitis or
diabetic enteropathy (Diehl 1995), therefore
maintenance energy requirements may be higher
than in normal cats. Polyphagic diabetic cats
should not have their food intake restricted
unless as part of a planned weight loss program
for obesity.
High bre diets are recommended in diabetic
humans to blunt post-prandial hyperglycaemia
and increase peripheral insulin sensitivity
(Anderson & Akanji 1991). Ahigh bre diet (12%
insoluble bre) was found to be benecial in
some diabetic cats, in comparison to a very low
bre diet (1%) (Nelson et al 1994). However,
varying carbohydrate contents of the diets con-
founded the results of this study, as the low bre
diet had substantially more carbohydrate. There
are no studies in diabetic cats showing an advan-
tage of a high-bre diet over a good quality
commercial cat food with a moderate bre
content (eg, 5%). The benet of increased bre,
isolated from changes in dietary carbohydrate,
may be less in cats than in humans because of
the absence of post-prandial hyperglycaemia in
cats.
Although only foods containing substantial
amounts (36.1% w/w) of glucose (and not other
carbohydrates) led to post-prandial hyperglycae-
mia in a study of normal cats (Kienzle 1994), for
diabetic cats it is probably advisable to avoid
diets that are unusually high in carbohydrate,
and to avoid glucose-containing treats.
Feeding recommendations for diabetic cats. Dia-
betic cats, particularly soon after diagnosis, may
have reduced or no appetite. This may require
the initiation of assisted feeding, such as hand
feeding of highly aromatic, palatable food
(Laamme et al 1993). Once eating normally,
diabetic cats with a normal bodyweight should
be fed a good quality feline diet ad libitum,
and have their bodyweight monitored. As the
diabetes is stabilised with therapy, bodyweight
often increases. If the cat starts to become over-
weight, it should be changed to a moderately
calorie-restricted diet, such as a geriatric diet, or
a diet for less active cats. Most high bre diets
are calorie-restricted, and these diets may be
unsatisfactory for some non-obese diabetic cats.
Some normal weight diabetic cats lose weight,
and underweight cats may fail to achieve normal
bodyweight, despite polyphagia when fed this
type of diet. The increased stool volume may
also be unacceptable to the owner.
When diabetic cats are underweight, energy
dense foods such as conditioning or growth diets
should be used. As weight approaches normal,
cats can be switched to maintenance cat foods.
The best combination of protein, fat, and carbo-
hydrate for diabetic cats is currently unknown.
Obese diabetics. Weight loss and attainment of
normal bodyweight is a treatment goal of over-
weight diabetic cats, as obesity in cats reversibly
decreases glucose tolerance (Nelson et al 1990,
Biourge et al 1997). Calorie restriction should be
conservative, and matched to the individual cat
by ongoing monitoring of food intake and body-
weight (Sloth 1992). Cats should be fed approxi-
mately 70% of their maintenance energy
requirements for their target weights (Sloth
1992). Severe calorie restriction or starvation
should not be used for weight loss because
diabetic cats have an increased risk of hepatic
lipidosis (Bruskiewicz et al 1997). It is important
Current understanding of feline diabetes: treatment 5
to ensure that the cat will eat the diet when
a change is made to a weight reducing diet.
To avoid excessively rapid weight loss, slow
introduction of a diet over 2 weeks may be more
successful in getting the cat to eat a new diet than
abrupt dietary changes. Once the estimated
target weight is reached, re-evaluation of the
cats body condition should be made.
Oral hypoglycaemics
Approximately one-third of diabetic cats achieve
good clinical control with oral hypoglycaemic
drugs. However, in the majority of cats, the
control of diabetes is not as good with oral
hypoglycaemics as with insulin, and in some cats
it may be more difficult for the owners to admin-
ister oral medication than insulin injections.
When owners are unwilling to use insulin, oral
agents may be lifesaving for a cat that would
otherwise be euthanased. Insulin treatment can
be started if oral treatment is unsuccessful, which
is usually evident within 46 weeks. By this time,
owners may be more amenable to the use of
insulin (Feldman et al 1997). Oral hypoglycaemic
agents are generally not recommended in sick
ketotic or anorexic diabetic cats, which should be
treated with insulin (Nelson et al 1993). Treat-
ment for these cats may be subsequently at-
tempted using oral drugs, once their condition
has improved with insulin and supportive care.
The oral sulphonylurea hypoglycaemic drug
glipizide has been used successfully in the treat-
ment of diabetic cats (Miller et al 1992, Nelson et
al 1993, Feldman et al 1997). The usual dose of
glipizide is 5 mg bid, regardless of the body-
weight of the cat, though lower doses (1.25
2.5 mg bid) may initially be used to acclimatise
the cat to the drug and reduce side-effects (Miller
et al 1992, Nelson et al 1993, Feldman et al 1997).
Glipizide requires less intensive clinical monitor-
ing than insulin treatment, due to a lower risk of
clinical hypoglycaemia, and may create sufficient
glycaemic control to lead to diabetic remission
(Nelson et al 1993, Feldman et al 1997). Hypogly-
caemia may still occur in cats given glipizide,
particularly in those cats whose hyperglycaemia
is mild (1215 mmol/l), or those which are
attaining diabetic remission (Nelson et al 1993,
Feldman et al 1997).
Glipizide stimulates beta cells to produce
insulin and is only effective in diabetics which
have functional beta cells (Zimmerman 1997),
which were about 40% of diabetic cats reported
in a recent study (Feldman et al 1997). Good
control has been reported in about 3540% of
diabetic cats treated with glipizide (Feldman et al
1997), although the success rate depends on the
population of cats studied and criteria for good
control. As glipizide may cause transient elev-
ation of liver enzymes and in some cases icterus,
monitoring hepatic enzymes is recommended
during glipizide treatment, which adds to treat-
ment costs (Miller et al 1992, Nelson et al 1993,
Feldman et al 1997). Oral hypoglycaemic drugs
fail to function adequately in some human
patients over time, as the number of functional
beta cells decreases (Chow et al 1995), and this
may also occur in some cats on glipizide treat-
ment (Feldman et al 1997). Of concern with
drugs which stimulate insulin and amylin secre-
tion, such as glipizide, is that amyloid deposition
may be accelerated and lead to further loss of
beta cells (Hoenig & OBrien 1998, Rachman et al
1998). This may lead to insulin-dependence and
poorer control of blood glucose than if other
types of drugs, including insulin, had been used
initially.
There are a variety of other oral agents that are
used in humans for the treatment of diabetes.
Preliminary studies in cats have been performed
with vanadium, which increases insulin receptor
sensitivity. However, as a sole agent it was only
useful early in the pathogenesis of diabetes when
blood glucose was relatively low (Greco 1997).
By the time a diagnosis of diabetes is made,
vanadium is unlikely to be effective by itself. A
further preliminary report of a comparative
study using PZI insulin with and without con-
current vanadium administration (45 mg orally
once daily), showed that vanadium may reduce
the required dosage of insulin (Fondacaro et al
1999). However, the biologically available forms
of vanadium, such as di- and tripicolinate or
bismaltolatooxo, may not be readily obtainable
by practitioners.
Chromium, a compound next to vanadium on
the periodic table and with similar properties,
has been shown to have small but signicant
effects on blood glucose in some normal cats,
although there are no reports of its efficacy in
diabetic cats (Appleton et al 1999). It has a wide
safety margin and if useful, it could be used as
an adjunctive dietary additive for diabetic cats.
The biologically available tripicolinate form is
usually used.
There are anecdotal reports of the use in dia-
betic cats of acarbose, an agent which blocks
glucose absorption from the gastrointestinal tract
(Greco 1999), but there are no studies document-
6 G Martin and J Rand
ing its effectiveness. The lack of post-prandial
hypoglycaemia in cats may reduce the usefulness
of acarbose in diabetic cats, but it may have a role
in combination with other agents (Greco 1999).
One drug which has potential to be useful
in the treatment of feline diabetes is met-
formin, which enhances peripheral insulin
sensitivity and reduces hepatic glucose output
(Schernthaner 1985). To date, the only study
reported describes the pharmacokinetics of
metformin in normal cats (Michels et al
1999). Studies on metformin in diabetic cats are
currently in progress.
The pharmacokinetics of the insulin-resistance
reducing drug troglitazone have been reported
for normal cats in a recent study (Boudinot et al
1999). An anecdotal report of its use in diabetic
cats at a dose of 200 mg once daily suggests its
efficacy may be limited (Greco 1999).
In summary, glipizide is the only oral hypo-
glycaemic drug that has well documented ef-
fectiveness in diabetic cats. A preliminary
study suggests vanadium may be a useful ad-
junct to insulin treatment to improve insulin
sensitivity.
Insulin
The mainstay of treatment in diabetic cats is
injectable insulin. The types of insulin available
and the rationale for their use in cats has been
the subject of several papers and reviews (Moise
& Riemers 1983, Schaer 1983, McMillan &
Feldman 1986, Nelson et al 1992b, Bertoy et al
1995, Broussard & Wallace 1995, Dowling 1995,
Goossens et al 1998) (see Table 1). The following
discussion concentrates on some aspects of
insulin treatment, treatment monitoring, and
making insulin dose rate adjustments.
Choice of insulin. The choice of insulin for dia-
betic cats centres around minimising the number
of injections required each day, while still achiev-
ing adequate diabetic control. Insulins used for
maintenance are those classied as either inter-
mediate duration (lente or NPH [Isophane]), or
long acting (ultralente or protamine zinc insulin
[PZI]) (Greco et al 1995). The species of origin of
the insulin effects the duration of insulin action,
with beef insulin being longer acting than pork,
and human insulin the shortest in duration
(Brange et al 1990). Despite the variation in
insulin types used, no correlation was found
between the type of insulin and diabetic control
(Goossens et al 1998).
The antigenicity of an injected insulin is pro-
portional to the difference in its amino acid
sequence to the amino acid sequence of the
animals native insulin (Neubauer & Schone
1978, Schernthaner 1993). Cat insulin is most
similar to beef insulin (one amino acid differ-
ence), less so to pork (three amino acids dif-
ference), and least similar to human (four amino
acids difference) (Hallden et al 1986). Unfortu-
nately in many countries, the withdrawal of
animal insulins for human use, and insulin con-
taining the amino acid protamine (PZI), has
decreased the range of suitable insulins for the
treatment of diabetes in cats.
Human insulin has been found to be effective
in the treatment of feline diabetics (Nelson et al
1992b, Bertoy et al 1995). Although most different
from feline insulin, it has not been found to be
associated with substantial antibody production.
Human insulins are sold as 100 iu/ml concen-
tration or greater in most countries, which may
cause difficulties in dosing cats, as doses of less
than 2 iu cannot be measured accurately in a
U-100 syringe (Casella et al 1993). Dilution of
insulin may signicantly shorten its duration
of action (Binder 1969, Chantelau et al 1985,
Heinemann et al 1992).
The long-acting insulin PZI insulin was
particularly favoured for the treatment of cats
until it became unavailable as a human product,
forcing a change to shorter-acting insulins, which
have subsequently been found to give as good,
and in some cats better glycaemic control. PZI
insulin is now available as a veterinary product
in the USA as a 40 iu/ml 90% beef10% pork
suspension (PZI insulin; Blue Ridge Pharmacy)
and in the UK as a 100 iu/ml beef suspension
(Insuvet Protamine Zinc, Schering-Plough Ani-
mal Health). PZI can be used once daily in 50%
of cats (Moise & Riemers 1983, Goossens et al
1998), but is noted for its unpredictable onset
and duration of action (Moise & Riemers 1983).
Prolonged marked hypoglycaemia may occur
in some cats on PZI and, in some cats, gly-
cemic control is poor, possibly because of in-
adequate absorption. PZI is particularly useful
for cats in which the duration of action of
lente insulin is too short to give adequate gly-
caemic control, and when owners are unwilling
to give twice-daily injections. Many cats have
good to excellent clinical control with PZI, but
cats which do not achieve good control should be
tried on a shorter acting insulin such as lente,
before the poor control is attributed to insulin
resistance.
Current understanding of feline diabetes: treatment 7
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8 G Martin and J Rand
Human ultralente insulin can be used once
daily in many cats, but the majority of cats (92%)
will require twice daily treatment (Goossens et al
1998). It is readily available through human
pharmacies, although not licensed for veterinary
use. Because of this dosing frequency and
100 iu/ml concentration, it does not offer an
advantage over lente or PZI insulin, especially if
either of these are available at 40 iu/ml. Bovine
ultralente insulin may also be used, and because
of its relatively peakless absorption, in some cats
it potentially provides better glycaemic control
than the shorter-acting insulins. However, in
some cats blood glucose may not be signicantly
lowered, apparently because of poor absorption
(Broussard & Peterson 1994). Bovine ultralente is
no longer available as a human product in many
countries, including Australia.
In some cats, blood glucose does not fall sig-
nicantly and control of clinical signs is poor
when using the longer-acting insulins (human or
bovine ultralente, or PZI), even when doses of
1 iu/kg or greater are being used. A change to a
better absorbed, shorter acting insulin (lente or
NPH) may improve diabetic control in these cats
(Bertoy et al 1995).
The lente insulins have a more predictable
onset and duration of effect in cats than ultra-
lente and PZI (Martin & Rand, unpublished
data), and have been recommended as a rst
choice of insulin (Rand 1997) or where ultralente
is failing to achieve adequate control (Bertoy et al
1995). Porcine lente insulin is available in many
countries as a proprietary veterinary product,
Caninsulin (Intervet International BV, The
Netherlands), at a concentration of 40 iu/ml,
which is preferable to 100 iu/ml for use in cats.
Porcine lente insulin needs to be given twice
daily in all diabetic cats (Martin & Rand, un-
published data). Caninsulin provides good to
excellent clinical control in the majority of
cats, although the occasional cat has a very early
peak of action (3 h or less), and has better control
with a longer-acting insulin (Martin & Rand,
unpublished data). NPH insulin has a similar but
slightly shorter duration of action than lente
insulin, and usually is given twice daily (Moise
& Riemers 1983). Human NPH is readily avail-
able through most pharmacies and pro-
vides adequate clinical control in a substantial
proportion of cats. It is less useful in cats
than 40 iu/ml porcine lente (Caninsulin) be-
cause it is only available at 100 iu/ml con-
centration and has a shorter duration of action.
In cats with inadequate control with PZI
or ultralente insulin, human or bovine NPH
and lente insulins are useful alternatives
when 40 iu/ml porcine lente insulin is un-
available. The imminent release of new insulin
pens with a 1 iu minimal total dose and incre-
mental doses of 0.5 iu may lead to wider use
of human NPH insulin. Lente, ultralente and
PZI are currently unsuitable for use in insulin
pens.
In summary, good to excellent clinical control
and adequate glycaemic control can be achieved
with NPH, lente, ultralente or PZI insulin in the
majority of diabetic cats. The choice of insulin
needs to be based on what is available, and the
suitability for the individual cat and convenience
for the owner. Concentration is an important
consideration and a 40 iu/ml insulin is more
suitable than 100 iu/ml for administration of the
small doses of insulin that diabetic cats require.
Because of legal implications and product sup-
port, use of a licensed veterinary product rather
than off label use of a human insulin is recom-
mended. In general, the blood glucose response
with NPH or lente insulin is more predictable
than with PZI. Up to one in ve cats on PZI or
ultralente have inadequate control, in part from
poor absorption, and in a few cats, the duration
of action of lente insulin may be too short to
achieve adequate glycaemic control. Inadequate
duration of action is more often a problem
with NPH, but can be overcome with admin-
istration three times a day. Approximately 50% of
cats on PZI can be controlled with once-daily
insulin, whereas up to 90% of cats with ultralente
and all cats on lente insulin need twice-daily
dosing.
Starting dose of insulin. The type of insulin chosen
and the baseline blood glucose of the cat deter-
mine the initial dose of insulin. Insulins which
have a longer duration of action do not tend to
lower the blood glucose as much as the same
dose of a shorter acting insulin (Nelson et al
1992b). Our current regime is to start cats which
have marked hyperglycaemia (blood glucose
>20 mmol/l) on 0.5 iu/kg insulin when using
porcine lente, and to start cats with less
pronounced hyperglycaemia (blood glucose
<20 mmol/l) on 0.25 iu/kg insulin. If the blood
glucose response cannot be measured, then it is
best to start with a minimal total dose of insulin
(12 iu). The evaluation of the response to insulin
using serial blood glucose determinations and
the rationale for insulin dose rate changes is
discussed below.
Current understanding of feline diabetes: treatment 9
Inter-day variability of the insulin response. The
responsiveness of diabetic cats to insulin can be
frustratingly variable, both from day to day and
over longer periods. For example, we have seen
differences in the nadir (lowest) blood glucose of
greater than 5 mmol/l on consecutive days. The
reasons for inter-day variability may come from
variations in the amount of insulin administered,
in the concentration of insulin per batch, in the
absorption of insulin, the availability of insulin
in the plasma to the insulin receptors, and the
magnitude of the responsiveness of the periph-
eral tissues (peripheral insulin sensitivity).
Because of inter-day variation in insulin effects,
the serial blood glucose results should be inter-
preted conservatively for the purpose of making
dose rate adjustments.
The rate of insulin absorption may be affected
by the type of insulin, its species of origin,
concentration, dose, and handling (Galloway
et al 1981, Hildebrandt 1991, Home & Alberti
1992). Practitioners should re-evaluate the blood
glucose response if the insulin type is changed,
the insulin dose is changed, or the insulin con-
centration is changed. Although U-100 and U-40
have a similar time action prole of blood
glucose in humans (Chantelau et al 1985,
Heinemann et al 1992), dilutions of insulin by a
factor of ve or greater may signicantly shorten
insulin absorption and the blood glucose
response (Binder 1969, Chantelau et al 1985,
Heinemann et al 1992). Clients should be advised
carefully on the appropriate methods of storing,
handling, and drawing up of insulin (Greco et al
1995). If U-100 syringes are being used with a
U-40 insulin, it is important to ensure that the
correct dose rate is calculated.
Variability in insulin absorption is suspected to
account for some of the day-to-day variability in
the response to a consistent insulin dose in
humans; factors include: blood ow at the injec-
tion site, anatomical location of the injection site,
circulating epinephrine, ketoacidosis, amount of
fat at the injection site, exercise or local massage,
injection technique (subcutaneous versus intra-
muscular), ambient temperature, scarring and
lipodystrophy at the injection site, and/or anti-
insulin antibodies causing local degradation of
the insulin at the injection site (Galloway et al
1981, Binder et al 1984, Skyler 1988). The varia-
bility in insulin absorption has not been studied
in diabetic cats, but based on the ndings in
humans it is advisable to use a consistent injec-
tion site and to minimise stress at the time of
injection to avoid circulating epinephrine release.
Day-to-day variation in insulin sensitivity
is thought to be a signicant cause of inter-day
variation in normal (Steil et al 1994) and dia-
betic (Ziel et al 1988) humans. Studies in nor-
mal cats have shown inter-day variation in
insulin sensitivity to be marked (Feldhahn et al
1998), and this may also be the case in diabetic
cats.
Longer term variability in insulin response. In
humans, the clinical term brittle diabetes is
used to refer to patients whose blood glucose
responds in an unpredictable fashion to insulin
injections, particularly where hypoglycaemia
occurs (Schade & Burge 1995). One specic cause
of brittle diabetes in humans is the loss of the
normal counter-regulatory glucagon response to
hypoglycaemia, which may lead to hypoglycae-
mia or post-hypoglycaemic hyperglycaemia
through activated counter-regulation (the
Somogyi effect) (Gerich 1988). Cats may exhibit
the features of brittle diabetes, and the Somogyi
phenomenon has been previously reported
in insulin-treated diabetic cats (McMillan &
Feldman 1986). Although the existence of the
Somogyi phenomenon has been subsequently
questioned in human diabetology (Kidson 1993),
a reduction in the insulin dose may improve
control in cats in which either hypoglycaemia
and/or hyperglycaemia is recurrent. Hypo-
glycaemia is more common in dogs when inter-
mediate acting insulin is given once daily, and in
humans, when long-acting insulin is given twice
daily. If glycaemic control is poor in an indi-
vidual cat, especially if insulin seems to have
little effect when previously it caused substantial
lowering of glucose, it is safer to rst try lower-
ing the dose of insulin to 0.30.5 iu/kg (lente
insulin) for 23 weeks and see if blood glucose
or water intake improve. Poor control and
apparent insulin resistance with persistent
hyperglycaemia may result from excessive
insulin dose.
As the hyperglycaemia of diabetes is reduced
by insulin treatment over time, the insulin
requirement of the cat may decrease (Garvey
et al 1985, Link & Rand 1996). This effect requires
2 or more weeks to occur, hence a period of
24 weeks between insulin dose increases is
recommended (Garvey et al 1985, Nijs et al 1989,
Link & Rand 1996). This effect is probably due
to the reversal of one or more of the three
major metabolic lesions of type 2 diabetes:
glucose toxicity, decreased insulin sensitivity,
and increased hepatic glucose output, as
10 G Martin and J Rand
hyper glycaemia is diminished (Garvey et al
1985). The insulin requirement may increase in
some cats after several months of therapy as
further loss of beta cells occurs.
In cats where some functional islet cells
remain, resumption of beta-cell function may
occur after at least 12 weeks of good glycaemic
control, which may lead to cessation of the
diabetes within 13 months (Link & Rand 1996).
If the loss of beta cells is too great for diabetic
remission to occur, the cat may remain insulin-
dependent but with reduced insulin doses being
required. Sudden or gradual reductions of more
than 50% in the required insulin dose may occur
even after several months of insulin therapy in
cats, possibly through this mechanism (Martin &
Rand, unpublished data).
A recent study found that diabetic control was
not correlated with anti-insulin antibody titre in
diabetic cats (Harb-Hauser et al 1998). Further
studies are needed to determine if insulin anti-
bodies affect diabetic control in certain feline
diabetics with, for example, high insulin require-
ments or repeated episodes of hypoglycaemia.
Serial blood glucose curves. Serial blood glucose
curves are essential for establishing and monitor-
ing the blood glucose response to insulin, and for
making insulin dose rate adjustments (Miller
1995, Zerbe 1999). When a low blood glucose
(<3.0 mmol/l) occurs, samples should be taken
every 3060 min until the blood glucose rises, to
determine if glucose should be administered.
Typically, blood glucose is measured every 2 h,
from immediately prior to one insulin dose to
immediately prior to the subsequent insulin
dose. If insulin is given once daily, ideally the
blood glucose should be followed for 24 h, as
nocturnal hypoglycaemia may occur even if the
blood glucose is normal or elevated during the
day. If the insulin is given twice daily, 12 h
should be suitable, although it is uncertain if the
overnight blood glucose curve will exactly match
the daytime curve. When Caninsulin was used,
the median nadir was found to be statistically
higher during the night than during the day
(Martin & Rand, unpublished data).
Pocket glucometers are sufficiently accurate to
use to perform serial blood glucose curves in a
clinical setting (Link et al 1997). The limitations
of such meters, such as the maximum blood
glucose measurable and the tendency to be
falsely low at the lower end of the range, should
be considered when interpreting results (Link
et al 1997).
Stress resulting in struggling can acutely
elevate the blood glucose by up to 10 mmol/l in
normal cats (Kinnaird et al 1998), and possibly
more in diabetic cats. This may lead to the false
impression that the insulin dose is inadequate. If
the insulin dose is increased as a consequence,
hypoglycaemia may occur. If the cat is stressed
or struggles before or during blood collection,
results should be ignored and the pro-
cedure repeated later. Some cats may need to be
hospitalised for 1224 h before a serial blood
glucose curve to allow them to settle into a
foreign environment, however, hospitalisation
may increase stress in other cats.
Blood collection. Blood collection can be per-
formed by direct venepuncture, or peripheral or
central venous catheterisation. Venepuncture is
only suitable for the collection of a limited
number of samples in diabetics cats, as bruising
and intolerance of the procedure cause difficul-
ties after a limited number of samples are taken
in most cats. To provide venous access in a
repeatable and non-stressful manner, placement
of venous catheters may be necessary. Peripheral
catheters can be placed in the cephalic or lateral
saphenous veins, ushed with 20 iu/ml
heparinised saline, and capped. These catheters
can then provide access for small blood samples
suitable for a pocket type glucometer for
repeated sampling of up to 24 h or more in some
cats, although not all cats will tolerate them
(Burrows 1973, Link et al 1997). When blood
glucose needs to be monitored over several days,
or when peripheral vein catheters are poorly
tolerated, jugular catheters are advised (Martin
& Rand 1999b). New vacuum-assisted (Wess &
Reusch 1999) or laser lancing devices may pro-
vide access to capillary blood without the need
to obtain venous samples, and with less risk of
stress to the cat. Non-invasive transdermal
methods for measuring blood glucose are under
development, and would be of great benet in
monitoring feline diabetics (Arnold 1996).
Insulin dose adjustments. From the serial blood
glucose curve, several parameters may be
recorded or calculated, including mean blood
glucose, blood glucose at baseline (immediately
before insulin), nadir (minimum) blood glucose,
and the time to the nadir of blood glucose. Mean
blood glucose gives an indication of overall gly-
caemic control, and the difference between the
baseline and nadir gives an indication of the cats
responsiveness to the insulin. The time to the
Current understanding of feline diabetes: treatment 11
nadir gives an indication of how rapidly the cat
is responding to the insulin injection. The nadir
of blood glucose determines whether the insulin
dose should be increased or decreased.
In practice the most important value to deter-
mine is the nadir blood glucose, as this indicates
the maximum dose of insulin which can be
tolerated by the cat. The dose should not be
increased to the point where hypoglycaemic
episodes are likely (<4 mmol/l). Given the
potential for the response to insulin to be vari-
able from day to day, and the possibility of
a gradually improving insulin response, insu-
lin dose increases should be made conserva-
tively and infrequently (no more than every
2 weeks).
A suggested regimen is to re-evaluate the
blood glucose response every 24 weeks (or
immediately if clinical hypoglycaemia occurs)
until good control is attained. In the early stages
of treatment, a nadir of 5.09.0 mmol/l is a
suitable target. If the nadir of blood glucose is
above this level, the insulin dose is increased
by 1 iu total dose. If clinical hypoglycaemia
occurs, the insulin dose should immediately be
decreased by 50%, and a serial blood glucose
curve performed for the new dose (Greco et al
1995). Only in cats that show a very consistent
response to insulin, and have good glycaemic
control (mean blood glucose <12 mmol/l) with
no hypoglycaemic episodes, can a nadir of
4.05.0 mmol/l be pursued.
When using a long acting insulin (ie, PZI or
ultralente), the duration of action, as determined
from the serial blood glucose curve, will deter-
mine whether once or twice daily administration
is required. Twice-daily administration is indi-
cated if either: (1) the blood glucose drops to a
nadir and returns to within 6070% of the base-
line and more than 12 mmol/l by 12 h after
injection, or (2) the blood glucose level drops to a
distinct nadir then rises back above 15 mmol/l
by 12 h after injection. When twice daily ad-
ministration is required, lente insulin may be
preferred, as it has been found in human dia-
betics that twice daily ultralente leads to a higher
incidence of hypoglycaemic episodes than twice
daily lente (Tunbridge et al 1989).
If lente or NPH insulin is being used and
diabetic control is poor, two circumstances may
warrant a change to longer acting insulin (ultra-
lente). Firstly, if the insulin is having a rapid peak
of action (within 23 h) and a short duration of
effect (67 h), and/or secondly if a low nadir
blood glucose of (<3.5 mmol/l) is occurring
despite the mean blood glucose remaining high
(above 15 mmol/l).
Once clinical signs are well controlled, and the
insulin dose is unchanged on two consecutive
visits, then re-evaluation can be performed at
longer intervals (every 34 months) unless a
change in clinical status or hypoglycaemia occurs.
Monitoring diabetics. In many cats, good clinical
control can be attained even if there is still
hyperglycaemia (eg, mean blood glucose
>12 mmol/l). Evidence for good clinical control
includes an active cat with a healthy appearance,
a stable, normal bodyweight, and levels of poly-
dipsia and polyuria acceptable to the owner and
veterinarian. Achieving normoglycaemia for
most of the day is unlikely in all but a small
proportion of diabetic cats (Goossens et al 1998).
Water intake can be measured at home or in
hospital, and correlates moderately well with the
mean blood glucose (Martin & Rand 1999a),
providing a useful clinical indicator of diabetic
status. In particular, changes in the water intake
in an individual cat over time can give clues as to
the success (or failure) of treatment. However,
water intake may vary substantially from day to
day, so measurement for more than a single day,
and preferably over a week, should be per-
formed if insulin adjustments are to be based
on water intake. A water intake of less than
20 ml/kg bodyweight/24 h indicates exemplary
diabetic control. Most cats with good clinical
control drink less than 80 ml/kg bodyweight/
24 h. Other clinical signs such as a stable normal
bodyweight and the presence or absence of
lethargy should also be monitored.
The glycated proteins fructosamine and gly-
cated haemoglobin (HbA
1c
) have been advo-
cated as indicators of diabetic control in cats
(Crenshaw et al 1996, Thoresen & Bredal 1996,
Elliott et al 1997). When fructosamine is being
used as an indicator of glycaemic control, it
should be measured when the cat is normally
hydrated to avoid inaccurate results (Link &
Rand, unpublished data). Although the means of
glycated haemoglobin and fructosamine show
signicant differences between cats which were
grouped into normals, well controlled diabetics,
poorly controlled diabetics, and untreated dia-
betics, the results for individual cats may overlap
between the groups (Crenshaw et al 1996, Elliott
et al 1997). This makes the interpretation of
glycaemic control for an individual cat based on
fructosamine alone difficult. Fructosamine levels
may be normal in cats with hyperglycaemia, as it
12 G Martin and J Rand
was found that normal cats infused with glucose
to create hyperglycaemia of around 20 mmol/l
did not have fructosamine levels above the
reference range (Link & Rand 1995).
High fructosamine levels (>500 mol/l) indicate
a problem, but not necessarily whether the insulin
dose needs to be increased or decreased. Making
insulin dose rate changes on the basis of fructos-
amine measurements should be done with caution,
as the fructosamine level does not give an indi-
cation of the nadir blood glucose. However,
fructosamine may be a useful marker where stress
or fractiousness makes an accurate serial blood
glucose curve unobtainable. As with water intake,
fructosamine is probably most useful for monitor-
ing change in an individual diabetic cat over time.
There are no studies that demonstrate convincingly
that glycated proteins are better, or even as useful
as clinical parameters and blood glucose measure-
ment for monitoring diabetic control in cats.
Urine glucose measurements are an inexpen-
sive and simple method for monitoring of dia-
betic status by the owner, and can be measured
from urine soaked cat litter if necessary (Schaer
1994). However, urine glucose also does not give
information about how an insulin dose should be
changed, and is most useful for indicating or
predicting diabetic remission. We get owners to
measure urine glucose once or twice weekly if
possible, particularly in the rst 36 months of
therapy. If the cat becomes aglycosuric, this may
indicate that diabetic remission has occurred,
and the insulin can be discontinued for several
days while the urine glucose is monitored daily.
If glycosuria recurs, it may be necessary to per-
form a serial blood glucose curve to determine
the subsequent insulin dose. Substantial worsen-
ing of glycosuria in a diabetic cat indicates that
the cat should be re-evaluated using blood glu-
cose measurements to determine the direction of
adjustment of insulin dose.
Owner initiated dose rate changes and home moni-
toring. As the blood glucose response to insulin
is so variable, and individual blood glucose
measurements may be easily inuenced by
stress, owner monitoring of blood glucose may
give a better indication of true glycaemic control,
especially if curves are performed frequently, for
example weekly. However, owner-initiated insu-
lin dose rate changes are not recommended and
insulin dose rate adjustments should follow dis-
cussion with the veterinarian managing the case.
We advise owners to monitor urine glucose,
bodyweight, and the cats food and water intake
as a measure of diabetic control. If signicant
changes occur, or if markedly abnormal values
persist, a serial blood glucose curve should be
performed before insulin dose rate changes are
made. Cats may have marked polydipsia and
glycosuria while having a low blood glucose
nadir, so increasing the insulin dose without
performing serial blood glucose measurements
risks a hypoglycaemic episode. If blood glucose
is only measured in the afternoon when using
twice daily insulin, especially lente or NPH insu-
lin, the nadir glucose may be missed. This may
lead to inappropriate dose increases and a risk of
hypoglycaemia. If only a few blood glucose
measurements are performed for cost reasons,
the best information is gained from glucose
measurements around the time of, and including
the glucose nadir. With lente insulin, the nadir
occurs approximately 4 h after insulin admin-
istration. With PZI insulin, the time of nadir
glucose is very variable. For lente insulin, glu-
cose measurements at 2, 4, and 6 h may be
sufficient to make an informed adjustment of
insulin dose, but measurements every 2 h from 0
to 8 or 12 h after insulin administration gives
better information. For PZI, glucose should be
measured for at least 6, 8, 12, and 14 h after
administration. However, better information is
gained by including 0, 2 and 4 h measurements.
Concomitant disease
Several diseases which cause insulin resistance
may underlie or complicate the treatment of
diabetes; in particular hyperthyroidism, hyper-
adrenocorticism, acromegaly, infections, pancrea-
titis, and uraemia from renal failure (Ihle &
Nelson 1991, Peterson 1995). Bacterial cystitis,
which occurs with a high incidence in diabetic cats
especially if polyuria is present (Crenshaw &
Peterson 1996, Kirsch 1998), should be treated with
appropriate antibiotics. Although there have been
no detailed studies, anecdotal reports indicate that
diabetic cats commonly have dental disease and
chronic gingivitis (Diehl 1995). The authors have
encountered insulin-treated diabetic cats in which
diabetic control improved markedly when the
dental disease was treated. It has been recorded in
other species that chronic inammatory disease
may lead to a chronic hypercortisolaemia (Ley et al
1994), which may reduce insulin sensitivity and
therefore in diabetics decrease insulin responsive-
ness. Although treatment of concurrent disease
will not improve glycaemic control in some cats
(Goossens et al 1998), it is recommended that
Current understanding of feline diabetes: treatment 13
chronic disorders of this type are addressed as part
of the diabetes treatment regime.
Survival
In one study of 92 diabetic cats, average survival
time was 17 months (Goossens et al 1998). The
survival of diabetic cats is affected by old age
and concurrent disease, as the diabetic cats in
this study had a mean age of 12 years (Goossens
et al 1998). A signicant proportion of cats diag-
nosed with diabetes survive less than 12 months
(Kraus et al 1997, Goossens et al 1998). Factors
reducing survival time included diabetic keto-
acidosis at diagnosis, poor glycaemic control,
and the presence of concurrent disease (princi-
pally renal failure) (Kraus et al 1997, Goossens
et al 1998).
Concluding remarks
Through an understanding of the pathophysiol-
ogy of feline diabetes, cats can be treated more
easily and successfully. Studies demonstrating
the lack of post-prandial hypoglycaemia in cats
have highlighted an important species difference,
that shows ad libitum feeding is suitable for
diabetic cats. Glipizide remains the only oral
agent that has been studied in detail in diabetic
cats. Preliminary studies have been performed
on other agents, but further clinical studies in
diabetic cats are necessary to determine the
efficiency of these drugs. Currently, insulin pro-
vides the most successful clinical and glycaemic
control for the majority of diabetic cats. Success-
ful treatment requires an understanding of the
advantages and limitations of different treatment
modalities, and the rationale for clinical decision
making and therapeutic monitoring.
Summary: blood glucose curves
and changing the insulin dose
Measuring
v Ensure that stress and struggling are mini-
mised.
v Use venous catheters or vacuum assisted
lances to obtain multiple samples atraumati-
cally.
v Pocket blood glucose meters are suitable for
performing blood glucose curves in a clinic or
home setting.
v Feed as usual.
v Measure blood glucose immediately before
insulin is given, then every 2 h.
v Preferably follow the blood glucose through to
the next insulin dose (12 or 24 h later).
v If this is not possible, follow the blood glucose
until it comes back close to baseline.
v If the blood glucose drops below 3.0 mmol/l,
take more frequent samples to ensure hypo-
glycaemia is avoided. Administer oral or
parenteral glucose as needed.
Interpreting
v Parameters that can be determined from the
serial blood glucose curve include baseline
blood glucose concentration, blood glucose
concentration at nadir, time to reach nadir of
blood glucose, and the mean blood glucose.
The difference between baseline and nadir
may be measured, as well as the time taken
for the blood glucose to return to baseline
concentration.
v The nadir of blood glucose concentration is the
most important parameter for determining
insulin dose rate changes, as it determines
whether the dose can be safely increased, or if
the dose needs to be reduced.
v The time taken to reach blood glucose nadir
and the time taken to return to baseline blood
glucose concentration are used to determine
the dose frequency and the insulin type.
v The difference between baseline and nadir of
blood glucose concentration can be used to
determine how responsive the cat is to given
doses of insulin.
v The mean blood glucose gives a measure of the
overall diabetic control.
Insulin and dose changes
v Twice-daily administration is indicated if
either: (1) the blood glucose drops to a nadir
and returns to within 6070% of the baseline
and more than 12 mmol/l by 12 h after injec-
tion, or (2) the blood glucose level drops to a
distinct nadir then rises back above 15 mmol/l
by 12 h after injection
v If the nadir of blood glucose is occurring
within 2 or 3 h of injection, a longer acting
insulin should be considered.
v Insulin dose rate changes should be made
conservatively. Where indicated, dose increases
should be made at 24 week intervals and
1 unit at a time.
14 G Martin and J Rand
v The target for treatment is to achieve a blood
glucose concentration of 5.09.0 mmol/l at
nadir. If the nadir blood glucose is greater
than 9.0 mmol/l, the insulin dose should be
increased by 1 iu.
v Daily changes in insulin dose based on food
intake are not recommended. If the cat shows a
reduced or lack of appetite for more than
1224 h at home, the veterinarian should
examine the cat.
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