Remi ssi on of Di abet es Mel l i t us i n Cat s Cannot be Predi ct ed by t he

Argi ni ne Sti mul ati on Test

F. Tschuor, E. Zini, S. Schellenberg, M. Wenger, K. Kaufmann, D. Furrer, T.A. Lutz, and C.E. Reusch
Background: Cats with diabetes mellitus frequently achieve clinical remission, suggesting residual b-cell function. Respon-
siveness of b-cells to arginine persists the longest during diabetes progression, making the intravenous arginine stimulation test
(IVAST) a useful tool to assess residual insulin and glucagon secretion.
Hypothesis: Diabetic cats with and without remission will have different arginine-induced insulin or glucagon response.
Animals: Seventeen cats with diabetes, 7 healthy cats.
Methods: Blood samples collected on admission and during subsequent IVAST. Glucose, insulin, and glucagon were mea-
sured. Response to IVAST was assessed by calculating the insulin and glucagon area under the curve (AUC) and the AUC
glucagon-to-insulin ratio. Diabetic cats were treated with insulin and were followed for 18 weeks. Remission was dened as
normoglycemia and disappearance of clinical signs of diabetes for 4 weeks, without requiring insulin.
Results: Seven diabetic cats (41%) achieved remission. On admission, blood glucose concentration was signicantly lower
in cats with remission (median, 389 mg/dL; range, 342536 mg/dL) than in those without remission (median, 506 mg/dL; range,
266738 mg/dL). After IVAST, diabetic cats with remission had higher AUC glucagon-to-insulin ratios (median, 61; range, 34
852) than did cats without remission (median, 26; range, 20498); glucose, insulin, and glucagon AUCs were not different.
Diabetic cats had lower insulin AUC than did healthy cats but comparable glucagon AUC.
Conclusions and Clinical Importance: Diabetic cats with and without remission have similar arginine-stimulated insulin
secretion on admission. Although cats with remission had lower blood glucose concentrations and higher AUC glucagon-
to-insulin ratios, large overlap between groups prevents use of these parameters in clinical practice.
Key words: Feline; Glucagon; Insulin; Normoglycemia.
D
iabetes mellitus (DM) is one of the most common
endocrinopathies in cats, and its incidence is in-
creasing because of a rise in predisposing factors, such as
obesity and physical inactivity.
1,2
Most cats seem to
suffer from a Type 2-like form of DM that is character-
ized by decreased insulin secretion and insulin resistance.
In up to 50% of diabetic cats, insulin therapy can be
withdrawn within 4 months after beginning treatment.
36
This phenomenon, called diabetic remission, is thought
to be because of recovery from glucose toxicity.
7
Several insulin secretagogue tests have been evaluated
for measurement of insulin secretion capacity in humans,
including the hyperglycaemic clamp, the intravenous
(IV) and by mouth (per os, PO) glucose tolerance tests,
the IV glucagon stimulation test, and the intravenous ar-
ginine stimulation test (IVAST).
812
In Type 1 or 2
diabetic humans, b-cells show progressive deterioration
in their responsiveness to various secretagogues (eg, glu-
cose, glucagon, amino acids).
13,14
Responsiveness to
amino acids has been shown to outlast other stimuli,
thus suggesting that the IVAST may be used to detect re-
sidual b-cell secretory capacity later during the
progression of DM.
15
L-Arginine is known to be the most
potent insulin secretagogue of all amino acids. It increases
b-cell secretion by membrane depolarization and a subse-
quent increase in intracellular calcium.
16
Apart from
b-cells, L-arginine also stimulates glucagon from pancre-
atic a-cells by a similar mechanism.
12
Only 1 study has investigated residual insulin secretory
capacity in cats with DM,
4
but the glucagon stimulation
test failed to show signicant differences in insulin re-
sponse between cats that achieved diabetic remission and
those that did not.
4
The IVAST so far has been investigated in healthy cats
and was shown to be a valuable tool for evaluating insu-
lin secretory capacity.
a,17
The test also was used for
simultaneous stimulation of a-cells, thus yielding infor-
mation about glucagon secretion. Until now, the IVAST
has not been used in diabetic cats, and it is therefore un-
known whether it can help differentiate between cats that
achieve diabetic remission and those that do not during
the course of treatment. Therefore, the objectives of this
study were to assess insulin and glucagon response in an
IVAST in healthy and diabetic cats and to evaluate if
differences in a- and b-cell response to arginine exist in
cats with DM that will achieve remission as compared
with those that will not.
From the Clinic for Small Animal Internal Medicine (Tschuor,
Zini, Schellenberg, Wenger, Kaufmann, Reusch), and the Institute of
Veterinary Physiology (Furrer, Lutz), Vetsuisse Faculty, University
of Zurich, Winterthurerstrasse, Zurich, Switzerland. The study was
done at the Clinic for Small Animal Internal Medicine and Institute of
Veterinary Physiology, Vetsuisse Faculty, University of Zurich,
Zurich, Switzerland.
Corresponding author: Prof C.E. Reusch, Clinic for Small Animal
Internal Medicine, Vetsuisse Faculty, University of Zurich, Winter-
thurerstrasse 260, 8057 Zurich, Switzerland; e-mail: creusch@
vetclinics.uzh.ch.
Submitted April 15, 2010; Revised September 30, 2010; Accepted
October 15, 2010.
Copyright r 2010 by the American College of Veterinary Internal
Medicine
10.1111/j.1939-1676.2010.0649.x
Abbreviations:
AUC area under the curve
DM diabetes mellitus
G
0
, I
0
, and Gl
0
glucose, insulin, and glucagon concentrations before
arginine stimulation, respectively
IPR and GlPR insulin and glucagon peak response, respectively
IVAST intravenous arginine stimulation test
J Vet Intern Med 2011;25:8389
Materials and Methods
Cats
Seven healthy control and 17 diabetic cats were included in the
study. Seven neutered male, healthy domestic shorthair cats
b
were
used following principles of laboratory animal care (permission No.
213/2003, Veterinary Ofce of Zurich, Switzerland). The median
age of control cats was 15 months (range, 1624 months), and they
were healthy based on physical examination and routine clinical
clinicopathologic data; cats had a body condition score of 5 (ie, lean
cats) and their median body weight was 4.8 kg (range, 4.55.2 kg).
Cats had free access to water and were fed twice daily with a com-
mercial diet
c
given at maintenance. The diet was given for 4
consecutive weeks before testing.
Cats admitted to the Clinic for Small Animal Internal Medicine,
Vetsuisse Faculty, University of Zurich between September 2004
and May 2008 were considered for the study if DM was diagnosed.
A diagnosis of DM was based on clinical signs (eg, polyuria, poly-
dipsia, weight loss), hyperglycemia (fasting blood glucose 4180 mg/
dL), glucosuria, and increased serum fructosamine concentration
(4340 mmol/L; reference range, 200340 mmol/L). Diabetic cats
were included if they had not received insulin before admission and
if diabetic ketoacidosis, acromegaly, heart failure, kidney failure,
urinary tract infection, and hyperthyroidism were absent based on
clinical ndings, plasma IGF-1 measurement, serum biochemistry,
urinalysis, urine culture, and diagnostic imaging. Cats that had
received corticosteroids or progestagens within 6 months before ad-
mission and those with suspected pancreatitis based on clinical
ndings and abdominal ultrasound examination also were excluded.
To be included in the study, all cats must have had follow-up of at
least 18 weeks.
Study Design
In healthy cats, a central venous catheter was implanted in the
jugular vein on the day before IVAST. The procedure was carried
out under general anesthesia. In diabetic cats, after routine diag-
nostic evaluation, a central venous catheter
d
was placed in the
saphenous vein under general anesthesia.
The IVAST was performed on the day after implantation of the
central venous catheter in cats that had been fasted overnight and
not treated with insulin. Diabetic cats received IVuids (0.9%NaCl
at 1 mL/kg/h supplemented with 20 mEq of KCl/L of NaCl) to min-
imize the risk of development of ketoacidosis. A baseline blood
sample was collected and thereafter arginine
e
was infused slowly
(over 1 minute) via a cephalic vein at a dosage of 0.2 g/kg body
weight.
17
Blood samples were obtained after 2, 4, 7, 9, 15, 25, and 30
minutes via the central venous catheter. Baseline samples and sam-
ples collected after arginine injection were immediately placed in ice-
cold EDTA tubes containing aprotinine
f
and centrifuged within 5
minutes after the test. Plasma was stored at 801C until further use.
At baseline, glucose (G
0
), fructosamine, insulin (I
0
), and glucagon
(Gl
0
) were measured, and the Gl
0
-to-I
0
ratio was calculated. Insulin
and glucagon responses to IVAST were assessed by determining the
insulin and glucagon peak response (IPR and GlPR, respectively)
above baseline by calculating the insulin and glucagon area under
the curve (AUC) during the initial 9 minutes (AUC
9
) and the entire
30 minutes (AUC
30
) of stimulation, and by calculating the AUC
9
and AUC
30
glucagon-to-insulin ratio. The reason for calculating the
AUC
9
, in addition to AUC
30
, is that the highest response to arginine
has been demonstrated during the 1st 9 minutes after injection in
cats.
17
Insulin-to-glucagon ratios were calculated because it has
been shown that a close interplay exists between a- and b-cells in
mice and rats, with glucagon being 1 possible a-cell product neces-
sary for normal b-cell secretion.
18
Treatment of Cats with DM
After recovery from the IVAST, diabetic cats were discharged
and prescribed routine SC treatment with insulin, either porcine in-
sulin zinc suspension
g
or insulin glargine,
h
based on ease of
availability, and according to the following scheme: the starting
dose in cats 4 kg was 1 Uq12h and in cats 44 kg 1.52 Uq12h. In
addition, a specic commercial diet
c
was recommended. Follow-up
examinations were performed 1, 3, 6, 10, and 18 weeks after admis-
sion and included assessment of clinical signs and body weight,
measurement of a serum biochemical prole with serum fructosa-
mine concentration, and generation of a blood glucose curve. The
latter was performed by measuring capillary blood glucose every 2
hours over 1012 hours, as previously described.
19
The insulin dose
was adjusted to improve glycemic control if necessary. Because the
ideal glucose nadir should fall between 90 and 160 mg/dL, if the na-
dir was below 90 mg/dL the insulin dose was decreased by 0.51 U
per injection; if the nadir was above 160 mg/dL, the insulin dose was
increased by 0.51 U per injection. The diet was changed if the cat
developed renal failure, diarrhea, or food aversion.
Cats with and without Remission of DM
To achieve remission, cats needed to have no clinical signs of
diabetes (eg, polyphagia, polyuria, polydipsia), as well as norm-
oglycemia and normal serum fructosamine concentrations for at
least 4 weeks, without insulin administration.
20
Cats that required
insulin throughout the study were dened as not being in remission.
Analytical Procedures
CBCs, serum biochemical proles, and urinalyses were per-
formed by standard laboratory methods. Plasma glucose and
serum fructosamine concentrations were measured by an automatic
analyzer
i
with commercial reagents.
j
Insulin and glucagon were
measured by commercial radioimmunoassay
k,l
previously validated
in our laboratory.
21,22
Insulin interassay and intra-assay coefcients
of variation were 7.0 and 6.5%, respectively; the sensitivity of the
assay was 2 mU/mL. To validate the glucagon assay, plasma from 5
healthy cats was assayed 7 times with 2 different kits. To determine
sensitivity, the 95% probability of the zero standard and the lowest
standard concentration that was signicantly different from zero
were measured, and the average value was calculated. Parallelism
was determined measuring a sample with a concentration of 510 pg/
mL, serially diluted (ie, 100, 80, 60, 40, and 20%). Glucagon inter-
assay and intra-assay coefcients of variation were 8.2 and 7.5%,
respectively; the sensitivity of the assay was 50 pg/mL. With the
above dilutions assay linearity was 108%.
Statistical Analysis
Results are expressed as median and range. Characteristics of di-
abetic cats, including body weight, blood glucose, and fructosamine
concentrations on admission, and prescribed dosage of insulin at
discharge were compared between cats that achieved remission and
those that did not by the Mann-Whitney U-test. The same test was
used to compare results of the IVAST in healthy and diabetic cats
and in diabetic cats with and without remission. Specically, base-
line concentrations of G
0
, I
0
, and Gl
0
, and the Gl
0
-to-I
0
ratio, and,
after arginine stimulation, the IPR, GlPR, AUC
9
, and AUC
30
of glucose, insulin, and glucagon, and the AUC
9
and AUC
30
of
glucagon-to-insulin ratios were determined.
The Wilcoxon matched paired test was used to assess whether
initial body weight, blood glucose, and fructosamine concentrations
at the time of admission differed between diabetic cats with and
without remission after 18 weeks of treatment.
84 Tschuor et al
Results were considered signicantly different at P o.05. Statis-
tical analysis was performed by standard software.
m
Results
Cats with DM
Seventeen diabetic cats met the inclusion criteria. Me-
dian age was 12 years (range, 817 years). On admission,
median body weight was 5.7 kg (range, 2.910 kg).
Eleven cats were neutered males and 6 were spayed fe-
males; they were all domestic shorthairs. Median fasting
blood glucose was 437 mg/dL (range, 266738 mg/dL)
and median fructosamine concentration was 666 mmol/L
(range, 580895 mmol/L). All cats had severe glucosuria;
none had ketonuria or positive urine culture results.
Seven cats (41.2%) underwent remission during the
study period, whereas remission did not occur in 10 cats
(58.8%) (Table 1). Insulin in cats with remission could be
discontinued after a median time of 8 weeks (range, 614
weeks). Age in cats with and without remission was sim-
ilar. On admission, body weight was not different
between groups and, within each group, did not change
signicantly after 18 weeks compared with baseline. In-
terestingly, on admission blood glucose concentration
was signicantly lower (approximately 25%) in cats that
achieved remission, whereas fructosamine did not differ
(Table 1). Blood glucose and fructosamine concentra-
tions were signicantly decreased in both groups after 18
weeks compared with admission. In all cats with remis-
sion, blood glucose and fructosamine concentrations
were within normal limits after discontinuation of insu-
lin therapy.
Eight cats (5 with remission, 3 without remission) were
treated with porcine insulin zinc suspension
g
and 9 (2
with remission, 7 without remission) with insulin glar-
gine.
h
The initial insulin dose was not signicantly
different for cats with and without remission.
IVAST in Healthy Cats and Cats with DM
Results of the IVAST in healthy and diabetic cats are
presented in Table 2. Cats with DM had signicantly
higher G
0
(P 5 .004), glucose AUC
9
(P o .001), and
glucose AUC
30
(P o.001) than did healthy cats, whereas
I
0
, IPR, insulin AUC
9
, and insulin AUC
30
were signi-
cantly lower (P 5 .026, P o .001, P o .001, and P o
.001, respectively). Gl
0
, GlPR, glucagon AUC
9
, and gluc-
agon AUC
30
were not different between healthy and
diabetic cats. Of note, the glucagon AUC
9
and glucagon
AUC
30
of 5 diabetic cats (4 with remission and 1 without
remission) were 2 to 4 times higher than those of healthy
cats. The Gl
0
-to-I
0
ratio was not different between
healthy and diabetic cats, whereas the AUC
9
and
AUC
30
glucagon-to-insulin ratios were signicantly
higher in the latter group (P 5 .002 and .011, respec-
tively). Insulin and glucagon responses to arginine in
healthy cats and cats with DM are shown in Figure 1.
IVAST in Cats with and without Remission of DM
Results of the IVAST in diabetic cats that achieved re-
mission and in those that did not are presented in Table
3. Differences were not observed between the 2 groups
for G
0
(ie, just before L-arginine administration), glucose
AUC
9
and AUC
30
, I
0
, IPR, insulin AUC
9
and AUC
30
,
Gl
0
, GlPR, glucagon AUC
9
, and the Gl
0
-to-I
0
ratio. The
AUC
30
glucagon-to-insulin ratio was significantly higher
in cats with remission (P 5 .033). Insulin and glucagon
responses to arginine in diabetic cats with and without
remission are shown in Figure 2.
Discussion
In the present study, the insulin response to arginine
was similar between cats with newly diagnosed DM that
achieved remission to those that did not experience re-
mission. In addition, we observed that baseline glucose
concentrations, measured on admission, and the AUC
30
glucagon-to-insulin ratio after arginine stimulation were
higher in diabetic cats with remission, although a large
overlap with cats that continued to require insulin ex-
isted. We also showed that diabetic cats, as compared
with healthy cats, had decreased insulin but comparable
glucagon secretion after IVAST.
Based on the notion that the insulin secretory response
to arginine persists longer than the response to glucose
and glucagon in diabetic humans,
1315
we hypothesized
that the IVAST used at admission may identify cats with
DM that could achieve remission. However, contrary to
our hypothesis, insulin secretion after arginine was sim-
ilar between both groups of diabetic cats, suggesting that
the test is not sensitive enough to identify cats with resid-
ual b-cell function. Arginine-induced glucagon secretion
also was comparable between both groups of diabetic
cats, although it tended to be higher in cats with remis-
sion, as shown by the slightly increased AUC
9
and
AUC
30
(P 5 .089 and .055, respectively). Notably, the
AUC
30
glucagon-to-insulin ratio was signicantly higher
(approximately 2.5-fold) in cats that achieved remission
as compared with cats that continued to receive insulin.
The reason diabetic cats with remission have an
Table 1. Diabetic cats with and without remission, on 1st admission.
Unit
Remission (n 57) No Remission (n 510)
P-Value Parameter Median Range Median Range
Age years 13 1017 11 816 .601
Body weight kg 6.3 4.07.2 5.6 2.910.0 .470
Glucose mg/dL 389 342536 506 266738 .033
Fructosamine mmol/L 649 586688 729 580895 .312
85 Diabetic Remission in Cats
increased secretory reserve of glucagon relative to insulin
is unclear, especially considering that the former hor-
mone is diabetogenic and a potent stimulator of hepatic
glycogenolysis and gluconeogenesis.
23
However, pancre-
atic a-cells and glucagon seem to be required to maintain
b-cell responsiveness to glucose.
24
Indeed, glucagon re-
ceptor knock-out mice have impaired b-cell function.
25
Furthermore, transgenic mice overexpressing the gluc-
agon receptor in b-cells conrmed this concept, as the
model showed improved glucose tolerance and increased
insulin secretion in response to glucose.
26
Whether the
present ndings in cats indicate a direct role for glucagon
in supporting b-cells and insulin secretion remains
unknown.
Compared with diabetic cats that required insulin dur-
ing the study period, we found that the severity of
hyperglycemia on 1st admission was lower in cats under-
going remission. This result suggests that blood glucose
concentrations may be linked to the propensity for clin-
ical recovery from DM in cats. Excessive hyperglycemia
eventually may lead to severe and irreversible toxicity in
feline b-cells,
21
eventually preventing remission. How-
ever, similar concentrations of serum fructosamine were
found in cats with or without remission, implying that
the severity of hyperglycemia during the weeks before di-
agnosis was comparable in the 2 groups. Furthermore,
another study performed at our institution showed that
diabetic cats with and without remission had similar
blood glucose concentrations at 1st diagnosis.
6
The rea-
son the less severe hyperglycemia in the cats of the
present study that later did not need insulin remains
unanswered. Of note, the difference in severity of hyper-
glycemia documented at admission waned after
overnight saline infusion. Indeed, G
0
(just before the
IVAST) was not different between diabetic cats with and
without remission. Saline infusion may have contributed
to increased glucose excretion by the kidneys, thus de-
creasing the severity of hyperglycemia.
As expected, all diabetic cats had lower I
0
than was ob-
served in healthy controls. Arginine-induced insulin
secretion also was decreased, as shown by lower IPR and
insulin AUC
9
and AUC
30
, suggesting b-cell dysfunction.
Impaired insulin secretion may be because of b-cell
exhaustion or decreased insulin gene expression.
21
A
severe decrease of islet cells is consistently observed in
pancreatic tissue sections of diabetic cats,
27
and b-cell loss
also may have partly contributed to decreased insulin
secretion.
Arginine is known to stimulate glucagon release in hu-
mans and rodents, increasing hepatic gluconeogenesis.
28
This mechanismis believed to prevent hypoglycemia caused
by amino acids absorbed through the gastrointestinal
Table 2. Results of IVAST in healthy and diabetic cats.
Unit
Healthy Cats (n 57) Diabetic Cats (n 517)
P-Value Parameter Median Range Median Range
G
0
mg/dL 72 5490 306 108486 .004
I
0
mU/mL 8 311 5 28 .026
IPR mU/mL 50 2285 4 115 .001
Gl
0
pg/mL 500 1861361 293 704774 .611
GlPR pg/mL 443 395866 540 4613582 .949
Gl
0
-to-I
0
ratio 64 22257 91 12854 .525
AUC
9
glucose mg/dL/9 min 666 558828 2052 10263474 .001
AUC
30
glucose mg/dL/30 min 2196 18182628 8514 417613950 .001
AUC
9
insulin mU/mL/9 min 255 163494 50 1893 .001
AUC
30
insulin mU/mL/30 min 491 3761320 196 88309 .001
AUC
9
glucagon pg/mL/9 min 4331 267110190 3568 105552570 .899
AUC
30
glucagon pg/mL/30 min 13690 675233600 12670 3839138200 .924
AUC
9
glucagon-to-insulin ratio 15 863 74 251158 .002
AUC
30
glucagon-to-insulin ratio 24 889 90 20852 .011
G
0
, baseline plasma glucose concentration; I
0
, baseline plasma insulin concentration; IPR, insulin peak response; Gl
0
, baseline plasma
glucagon concentration; GlPR, glucagon peak response; AUC area under the curve; IVAST, intravenous arginine stimulation test.
A B
50
60
70
4000
5000
20
30
40
I
n
s
u
l
i
n

(

U
/
m
L
)
2000
3000
0 2 4 7 9 15 25 30
0
10
0 2 4 7 9 15 25 30
0
1000
G
l
u
c
a
g
o
n

(
p
g
/
m
L
)
Minutes Minutes
Fig 1. (A) Insulin and (B) glucagon concentrations after arginine injection in healthy cats (white dots) and cats with diabetes mellitus (DM)
(black dots). Median and interquartile range are shown.
86 Tschuor et al
tract that would otherwise promote insulin secretion.
29
Similar to a previous study we observed a 2-fold increase
in glucagon concentrations 2 minutes after arginine
administration in healthy cats (Fig 1B).
17
In diabetic
cats, glucagon secretion was not different compared with
controls. Although recent studies demonstrated a posi-
tive role for glucagon in b-cells, it has been hypothesized
that glucagon may be detrimental because it is associated
with hyperglycemia in diabetic humans and in rodent
models.
30
Glucagon concentrations often are increased
in various forms of DM in these species.
3133
Five dia-
betic cats had increased glucagon AUC
9
and AUC
30
,
suggesting that in some cases DM is associated with an
increased glucagon response to arginine, as in humans
and rodents. Because 4 of these 5 diabetic cats later
achieved remission, an increased arginine-induced a-cell
response may be associated with a favorable outcome in
DM in cats.
Some limitations of this study should be mentioned.
Diabetic cats were treated with either porcine insulin zinc
suspension
g
or insulin glargine,
h
possibly leading to bias
in the results. In particular, as recently described, cats re-
ceiving insulin glargine may have increased likelihood of
remission.
34
However, in our series, only 2 of the 9
(22.2%) diabetic cats treated with insulin glargine
achieved remission compared with 5 of the 8 (62.5%)
diabetic cats that were treated with porcine insulin zinc
suspension.
g
Thus, the potential benecial effect of insu-
lin glargine likely did not inuence the frequency of
remission in the present series.
Each of the diabetic cats was evaluated for 18 weeks
after diagnosis. Some of the cats may have achieved re-
mission after that period, if they had been followed-up
for a longer time period. However, most diabetic cats
achieving remission have insulin therapy discontinued
within the 1st 4 months of treatment.
36
Thus, the risk of
having included diabetic cats with remission in the group
without remission likely is low.
The group of diabetic cats was compared with healthy
controls that were younger and male. Despite the fact
that the group of diabetic cats included some females,
male cats were chosen for the control group because
diabetes is more commonly diagnosed in male cats. Dia-
betes is also generally diagnosed at an older age, thus it is
possible that interpretation of IVAST results partially
was biased by sex and age. Healthy cats were fed the
same diet before IVAST, whereas diabetic cats received a
variety of diets until diagnosis of diabetes was made and
tests were performed. Thus, we cannot rule out an effect
of diet on test results.
In summary, the similar arginine-stimulated insulin
response in diabetic cats with and without remission sug-
Table 3. Results of IVAST in diabetic cats with or without remission.
Unit
Diabetic Cats with Remission (n 57) Diabetic cats without Remission (n 510)
P-Value Parameter Median Range Median Range
G
0
mg/dL 270 144486 360 108414 .363
I
0
mU/mL 5 28 4 27 .161
IPR mU/mL 5 115 4 2.311 .269
Gl
0
pg/mL 1245 904774 284 691415 .314
GlPR pg/mL 2499 16813582 253 464700 .108
Gl
0
-to-I
0
ratio 173 19854 77 12398 .314
AUC
9
glucose mg/dL/9 min 1944 14763006 2322 10263474 .417
AUC
30
glucose mg/dL/30 min 8226 606612078 9270 417613950 .417
AUC
9
insulin mU/ml/9 min 52 3194 50 1881 .740
AUC
30
insulin mU/mL/30 min 198 88309 191 91259 .887
AUC
9
glucagon pg/mL/9 min 19690 117052570 3365 105521330 .089
AUC
30
glucagon pg/mL/30 min 61500 6395138200 10070 383992690 .055
AUC
9
glucagon-to-insulin ratio 301 321158 70 25429 .055
AUC
30
glucagon-to-insulin ratio 61 34852 26 20498 .033
G
0
, baseline plasma glucose concentration; I
0
, baseline plasma insulin concentration; IPR, insulin peak response; Gl
0
, baseline plasma
glucagon concentration; GlPR, glucagon peak response; AUC area under the curve; IVAST, intravenous arginine stimulation test.
A B
12
15
5000
6000
7000
6
9
I
n
s
u
l
i
n

(

U
/
m
L
)
2000
3000
4000
0 2 4 7 9 15 25 30
0
3
Minutes
0 2 4 7 9 15 25 30
0
1000
Minutes
G
l
u
c
a
g
o
n

(
p
g
/
m
L
)
Fig. 2. (A) Insulin and (B) glucagon concentrations after arginine injection in diabetic cats that achieved (white dots) or not (black dots)
remission. Median and interquartile range are shown.
87 Diabetic Remission in Cats
gests that the IVAST cannot be used to predict those cats
with adequate residual b-cell function at diagnosis. The
higher AUC
30
glucagon-to-insulin ratio observed in dia-
betic cats that did not require insulin to maintain
normoglycemia may indicate that a relative increase of
a-cell function is involved in the mechanisms leading to
remission. Less severe hyperglycemia on admission in cats
undergoing remission has not been previously reported
and warrants additional conrmation. Unfortunately, the
large overlap between results of the AUC
30
glucagon-
to-insulin ratio and blood glucose concentrations pre-
vents the use of these parameters to reliably predict
diabetic cats with remission in clinical practice.
Footnotes
a
Link KR, Rand JS. Arginine and phentolamine response test in
cats. J Vet Intern Med 1996;146:185 (abstract)
b
Harlan Sprague Dawley, Indianapolis, IN
c
DM Purina Veterinary diets, Nestle -Purina, Vevey, Switzerland
d
Careow, Becton Dickinson, Basel, Switzerland
e
L-arginin-hydrochlorid 21%, B-Braun, Sempach, Switzerland
f
Trasylol, 500 KIU/ml, Bayer Pharmaceuticals Corporation, Ge-
neva, Switzerland
g
Caninsulin, Intervet International BV, Boxmeer, the Netherlands
h
Lantus, Sano Aventis, Meyrin, Switzerland
i
Cobas Integra, Roche, Basel, Switzerland
j
Glucose and fructosamine, Roche
k
Linco Porcine Insulin RIA Kit, Millipore, Zug, Switzerland
l
Glucagon ICN Biomedicals, MP Biomedicals Europe, Basel, Swit-
zerland
m
GraphPad Prism 4, GraphPad Software Inc, San Diego, CA
Acknowledgment
This study was partially supported by a grant from
Nestle Purina PetCare.
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