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.
References
1. Prahl A, Guptill L, Glickman NW, et al. Time trends and risk
factors for diabetes mellitus in cats presented to veterinary teaching
hospitals. J Feline Med Surg 2007;9:351358.
2. Baral RM, Rand J.S., Catt M.J., Farrow H.A. Prevalence of
feline diabetes mellitus in a feline private practice. J Vet Intern Med
2003;17:433434.
3. Hoenig M, Thomaseth K, Brandao J, et al. Assessment and
mathematical modeling of glucose turnover and insulin sensitivity
in lean and obese cats. Domest Anim Endocrinol 2006;31:373389.
4. Nelson RW, Griffey SM, Feldman EC, et al. Transient clinical
diabetes mellitus in cats: 10 cases (19891991). J Vet Intern Med
1999;13:2835.
5. Bennett N, Greco DS, Peterson ME, et al. Comparison of a
low carbohydrate-low ber diet and a moderate carbohydrate-high
ber diet in the management of feline diabetes mellitus. J Feline
Med Surg 2006;8:7384.
6. Alt N, Kley S, Tschuor F, et al. Evaluation of IGF-1 levels in
cats with transient and permanent diabetes mellitus. Res Vet Sci
2007;83:331335.
7. Rand J. Current understanding of feline diabetes: Part 1,
pathogenesis. J Feline Med Surg 1999;1:143153.
8. DeFronzo RA, Tobin JD, Andres R. Glucose clamp tech-
nique: A method for quantifying insulin secretion and resistance.
Am J Physiol 1979;237:E214E223.
9. Bardet S, Pasqual C, Maugendre D, et al. Inter and intra in-
dividual variability of acute insulin response during intravenous
glucose tolerance tests. Diabetes Metab 1989;15:224232.
10. Scheen AJ, Castillo MJ, Lefebvre PJ. Assessment of residual
insulin secretion in diabetic patients using the intravenous glucagon
stimulatory test: Methodological aspects and clinical applications.
Diabetes Metab 1996;22:397406.
11. Utzschneider KM, Prigeon RL, Tong J, et al. Within-subject
variability of measures of beta cell function derived from a 2 h
OGTT: Implications for research studies. Diabetologia 2007;50:
25162525.
12. Ward WK, Bolgiano DC, McKnight B, et al. Diminished B
cell secretory capacity in patients with noninsulin-dependent diabe-
tes mellitus. J Clin Invest 1984;74:13181328.
13. Druet C, Tubiana-Ru N, Chevenne D, et al. Characteriza-
tion of insulin secretion and resistance in type 2 diabetes of
adolescents. J Clin Endocrinol Metab 2006;91:401404.
14. Drucker D, Zinman B. Pathophysiology of beta cell failure
after prolonged remission of insulin-dependent diabetes mellitus
(IDDM). Diabetes Care 1984;7:8387.
15. Brandle M, Lehmann R, Maly FE, et al. Diminished insulin
secretory response to glucose but normal insulin and glucagon se-
cretory responses to arginine in a family with maternally inherited
diabetes and deafness caused by mitochondrial tRNA(LEU(UUR))
gene mutation. Diabetes Care 2001;24:12531258.
16. Curry DL, Morris JG, Rogers QR, et al. Dynamics of insulin
and glucagon secretion by the isolated perfused cat pancreas. Comp
Biochem Physiol A 1982;72:333338.
17. Kitamura T, Yasuda J, Hashimoto A. Acute insulin response
to intravenous arginine in nonobese healthy cats. J Vet Intern Med
1999;13:549556.
18. Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6
regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci
USA 2008;105:1316313168.
19. Alt N, Kley S, Haessig M, et al. Day-to-day variability of
blood glucose concentration curves generated at home in cats with
diabetes mellitus. J Am Vet Med Assoc 2007;230:10111017.
20. Sieber-Ruckstuhl NS, Kley S, Tschuor F, et al. Remission of
diabetes mellitus in cats with diabetic ketoacidosis. J Vet Intern Med
2008;22:13261332.
21. Zini E, Osto M, Franchini M, et al. Hyperglycaemia but not
hyperlipidaemia causes beta cell dysfunction and beta cell loss in the
domestic cat. Diabetologia 2009;52:336346.
22. Furrer D, Kaufmann K, Reusch CE, et al. Amylin reduces
plasma glucagon concentration in cats. Vet J 2010;184:236240.
23. Stevenson RW, Steiner KE, Davis MA, et al. Similar dose
responsiveness of hepatic glycogenolysis and gluconeogenesis to
glucagon in vivo. Diabetes 1987;36:382389.
24. Huypens P, Ling Z, Pipeleers D, et al. Glucagon receptors on
human islet cells contribute to glucose competence of insulin release.
Diabetologia 2000;43:10121019.
25. Srensen H, Winzell MS, Brand CL, et al. Glucagon receptor
knockout mice display increased insulin sensitivity and impaired
beta-cell function. Diabetes 2006;55:34633469.
26. Gelling RW, Vuguin PM, Du XQ, et al. Pancreatic beta-cell
overexpression of the glucagon receptor gene results in enhanced
beta-cell function and mass. Am J Physiol Endocrinol Metab
2009;297:E695E707.
27. Lutz TA, Rand JS. Detection of amyloid deposition in var-
ious regions of the feline pancreas by different staining techniques.
J Comp Pathol 1997;116:157170.
28. Palmer JP, Walter RM, Ensinck JW. Arginine-stimulated
acute phase of insulin and glucagon secretion in normal man. Dia-
betes 1975;24:735740.
88 Tschuor et al
29. Unger RH. Insulin-glucagon reltationships in the defense
against hypoglycemia. Diabetes 1983;32:575583.
30. Jiang G, Zhang BB. Glucagon and regulation of glucose me-
tabolism. Am J Physiol Endocrinol Metab 2003;284:E671E678.
31. Unger RH. Glucagon physiology and pathophysiology in
the light of new advances. Diabetologia 1985;28:574578.
32. Unger RH. Role of glucagon in the pathogenesis of diabetes:
The status of the controversy. Metabolism 1978;27:16911709.
33. Burcelin R, Katz EB, Charron MJ. Molecular and cellular
aspects of the glucagon receptor: Role in diabetes and metabolism.
Diabetes Metab 1996;22:373396.
34. Marshall RD, Rand JS, Morton JM. Treatment of newly
diagnosed diabetic cats with glargine insulin improves glycaemic
control and results in higher probability of remission than
protamine zinc and lente insulins. J Feline Med Surg 2009;11:
683691.
89 Diabetic Remission in Cats