Diabetes mellitus remission after resolution of inflammatory and progesterone-related conditions in bitches

Abstract

Canine diabetes mellitus (CDM) remission is a rare event that is possible after the resolution of insulin resistance conditions, especially those related to the estrus cycle. A retrospective study was carried out at the Division of Veterinary Endocrinology from 2006 to 2011 to assess CDM remission rates after the resolution of problems associated with ovarian activity. Out of 117 female dogs diagnosed with CDM, six diabetes remission cases were identified and described after resolution of diestrus (1), or after ovariohysterectomy for pregnancy (1), ovarian remnant syndrome (1), and pyometra (3), even after initial presentation in severe diabetic ketosis or long after diagnosis (ovariohysterectomy was performed from 3 to 81days after diagnosis, and diabetes resolution was achieved within 4-39days after gonadectomy). Several factors may lead to diabetes remission. However, in these cases, ovariohysterectomy was crucial for the restoration of normal blood glucose levels, suggesting that diabetic bitches be spayed independently of the length of time after diagnosis.

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Diabetes mellitus remission after resolution of inflammatory
and progesterone-related conditions in bitches
A.G. Pöppl
a,
⇑
, T.S. Mottin
b
, F.H.D. González
c
a
Programa de Pós-Graduação em Ciências Veterinárias, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9090, Agronomia, Porto Alegre,
Brazil
b
Hospital de Clínicas Veterinárias, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9090, Agronomia, Porto Alegre, Brazil
c
Departamento de Patologia Clínica Veterinária, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9090, Agronomia, Porto Alegre, Brazil
article info
Article history:
Received 8 February 2012
Accepted 15 October 2012
Keywords:
Insulin resistance
Diestrus
Gestational diabetes
Pyometra
abstract
Canine diabetes mellitus (CDM) remission is a rare event that is possible after the resolution of insulin
resistance conditions, especially those related to the estrus cycle. A retrospective study was carried out
at the Division of Veterinary Endocrinology from 2006 to 2011 to assess CDM remission rates after the
resolution of problems associated with ovarian activity. Out of 117 female dogs diagnosed with CDM,
six diabetes remission cases were identified and described after resolution of diestrus (1), or after ovar-
iohysterectomy for pregnancy (1), ovarian remnant syndrome (1), and pyometra (3), even after initial
presentation in severe diabetic ketosis or long after diagnosis (ovariohysterectomy was performed from
3 to 81 days after diagnosis, and diabetes resolution was achieved within 4–39 days after gonadectomy).
Several factors may lead to diabetes remission. However, in these cases, ovariohysterectomy was crucial
for the restoration of normal blood glucose levels, suggesting that diabetic bitches be spayed indepen-
dently of the length of time after diagnosis.
Ó2012 Elsevier Ltd. All rights reserved.
One of the subtypes of canine diabetes mellitus (CDM) in
bitches can be compared to gestational diabetes mellitus (GDM)
in humans, characterizing a subtype of insulin-resistant diabetes
mellitus (IRD) (Catchpole et al., 2005; Fall et al., 2007). Since the
1950s, development of diabetes shortly after estrus has been well
recognized in bitches and ovariohysterectomy (OHE) has been rec-
ommended as radical treatment of CDM (Campbell, 1958; Wilkin-
son, 1960). In the 1960s, Krook et al. (1960) first correlated CDM
with pyometra, another typical condition associated with diestrus
(Noakes et al., 2001) characterized by purulent fluid collection
within the uterus with variable amounts of inflammatory cells in
the uterine wall, that may or may not be preceded by cystic
endometrial hyperplasia (Feldman and Nelson, 2004). Although
insulin resistance mediated by progesterone is well characterized
(Scaramal et al., 1997; Connolly et al., 2004; Batista et al., 2005),
there is a paucity of case reports correlating CDM with diestrus,
and mainly on its remission after spaying (Fall et al., 2008, 2010).
Moreover, although Fall et al. (2010) described a diagnostic
prevalence of 17% for pyometra in females with concomitant
CDM during diestrus, to our knowledge, there is no case report
on the remission of diabetes after the resolution of the cystic endo-
metrial hyperplasia–pyometra (CEH–P) complex, a condition
associated with more severe insulin resistance due to the hor-
monal profile during diestrus and also to the septic/inflammatory
process (Pöppl et al., 2009). The aim of this study was to investigate
CDM remission after the resolution of clinical conditions associated
with ovarian luteal activity.
A retrospective study was carried out by analyzing medical
records of patients treated at the Division of Veterinary Endocrinol-
ogy between 2006 and 2011, searching for female dogs diagnosed
with remission of CDM after resolution of clinical situations related
to ovarian luteal activity. The criteria used to confirm the diagnosis
of CDM were clinical signs, especially polyuria and polydipsia, as
well as persistent glucosuria and hyperglycemia (>200 mg/dL).
The criteria used to define the remission of CDM were maintenance
of normal blood glucose levels after discontinuation of insulin
therapy, often defined after recurrent hypoglycemia, even after
successive reductions in insulin dose. This study was approved by
the Ethics Committee on Animal Experimentation of our University
(CEUA/18.336).
Out of 117 female dogs diagnosed with CDM (patients with con-
comitant hyperadrenocorticism or hypothyroidism were not in-
cluded), 72 (62%) had not been spayed at diagnosis, and from
those, 35 (30%) were diagnosed during the diestrus phase of the
estrus cycle. From those 72 intact bitches, 57 (79%) were spayed
after CDM diagnosis. Six patients, with mean age of 8.5 years
(range of 6–12 years), met the criteria for remission of CDM, after
0034-5288/$ - see front matter Ó2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.rvsc.2012.10.008
⇑
Corresponding author. Tel.: +55 51 33088033; fax: +55 51 33086112.
E-mail address: gomespoppl@hotmail.com (A.G. Pöppl).
Research in Veterinary Science 94 (2013) 471–473
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Author's personal copy
variable periods on insulin therapy. Only one patient had sponta-
neous remission of the disease at the end of diestrus (11 days after
diagnosis and onset of insulin therapy), whereas the remaining five
patients (9%) showed remission, on average 13.6 days (range of 4–
39 days) after ovariectomy or OHE. Table 1 shows some clinical
and laboratory details of each case.
Progesterone-related clinical conditions whose resolution was
associated with the remission of CDM in these patients were: dies-
trus, gestation, ovarian remnant syndrome (n= 1 each) and CEH–P
(n= 3). Surprisingly, four of these patients were initially diagnosed
with severe diabetic ketosis due to severe apathy, anorexia, vomit-
ing, Kussmaul breathing, severe hyperglycemia (>500 mg/dL) and
severe ketonuria (>80 mg/dL). One patient with initial presentation
in ketosis, had already been spayed, but often showed signs of heat.
The abdominal ultrasound evaluation suggested the presence of
ovarian remnant tissue, with quick remission of diabetes within
4 days after ovariectomy. CEH–P was observed and confirmed by
histopathology in two patients after uterine examination in the
postoperative period, and CEH–P was strongly suggested in an-
other patient by abdominal ultrasound before surgery. As to the
pregnant patient, the owner’s decision to terminate pregnancy
was only made after failure to control blood glucose levels 4 days
after stabilization of diabetic ketosis detected at initial diagnosis.
The patient with spontaneous remission of diabetes at the end of
diestrus had a relapse when the animal came into heat again
4 months after remission, but this time the condition was
permanent.
While dogs diagnosed with CDM are totally dependent upon
insulin therapy for control of their clinical signs (Catchpole et al.,
2005; Feldman and Nelson, 2004), case reports on remission of dia-
betes after control of situations which cause insulin resistance re-
veal that, in some cases, beta cells are not yet completely impaired
at diagnosis and, therefore, they can maintain normal glucose lev-
els, provided that the cause of insulin resistance is identified and
eliminated. It has been demonstrated by Imamura et al. (1988) that
chronic exposure to hyperglycemia may induce severe insulin-
dependent diabetes in dogs (glucotoxicity).
Despite the fact that CDM is often associated with destruction of
beta cells secondary to pancreatitis, or secondary to an autoimmune
attack (Catchpole et al., 2005; Feldman and Nelson, 2004), whose
inheritance (Catchpole et al., 2008) is to be unraveled, Fall et al.
(2010), in a case series of diabetes secondary to diestrus or gestation
in the Norwegian Elkhound breed, showed that none of the patients
had GAD-65 autoantibodies, thus indicating a non-autoimmune eti-
ology. Moreover, some environmental factors such as overweight,
lack of physical activity and an unbalanced diet have been impli-
cated as risk factors for the development of CDM (Klinkenberg
et al., 2006) and overweight was described as a risk factor for diabe-
tes secondary to diestrus in Elkhounds (Wejdmark et al., 2011).
Likewise, in humans, GDM is also associated with advanced age,
family history, ethnicity, and overweight (Phillips, 2006).
Nordic Spitz dogs are usually overrepresented in epidemiologi-
cal studies on diabetes (Guptill et al., 2003; Fall et al., 2007, 2008),
suggesting a probable genetic factor, whereas the Norwegian Elk-
hound breed was proposed as a model for the investigation of dia-
betes secondary to progesterone stimulation (Fall et al., 2010).
However, this phenomenon seems to be frequent in several other
breeds that are apparently also prone to the development of diabe-
tes, such as Poodle, Beagle and Teckel (Guptill et al., 2003; Fall
et al., 2007).
The hormonal profile of diestrus is similar to that of gestation in
bitches and is associated with a plasma progesterone increase from
<1 ng/mL during anestrus to plateau levels greater than 45 ng/mL
during diestrus or gestation (Feldman and Nelson, 2004). At the
end of gestation, the serum levels of prolactin (a diabetogenic hor-
mone) are raised, causing more severe insulin resistance (Connolly
et al., 2004). This greater insulin resistance associated with gesta-
tion may explain why the diabetes remission rate was greater in
the study of Fall et al. (2008) with gestational diabetic bitches than
in this study.
Ryan and Enns (1988) analyzed fat cell cultures and demon-
strated that progesterone inhibits insulin binding to the insulin
receptor (IR) and inhibits the tyrosine kinase activity of the recep-
tor. We have recently shown that estrus cycle phases modulate and
eventually reduce the tyrosine kinase activity in the musculoskel-
etal tissue of bitches (Pöppl et al., 2012). Selman et al. (1994) found
that progesterone stimulates a rise in growth hormone (GH)
secretion by the mammary gland in bitches, and in some cases,
progesterone-induced GH hypersecretion may be conducive to
acromegaly (Eingenmann et al., 1983). There is a lot of evidence
indicating that GH modulates insulin sensitivity by means of sev-
eral intracellular mechanisms due to the influence of the crosstalk
between GH/insulin-like growth factor-1 (IGF-1) and insulin sig-
naling (Dominici et al., 2005). Therefore, bitches exposed to high
progesterone concentrations can develop strong insulin resistance
associated with a higher basal hepatic glucose release, skeletal
muscle insulin resistance and overt diabetes (Scaramal et al.,
1997; Connolly et al., 2004; Batista et al., 2005). This helps explain
why bitches are more prone to CDM than males, and why they are
often in diestrus at the time of diagnosis (Guptill et al., 2003; Batista
et al., 2005).
It should be remarked that an ovarian remnant can behave just
like normal ovarian tissue (Feldman and Nelson, 2004) and it may
trigger strong insulin resistance and lead to diabetes mellitus dur-
ing diestrus, as shown in one case, with quick remission of diabetes
after ovariectomy. Furthermore, female animals that have sponta-
neous remission of diabetes after the end of diestrus, if not spayed,
are at a greater risk for permanent diabetes in their subsequent
heat, as observed in the present case report. Women with transient
GDM have the same increased diabetogenic potential in a subse-
quent pregnancy (Phillips, 2006). Coincidentally, the pregnant
patient was the youngest one, corroborating the finding that
Table 1
Breed distribution, age, body score and body weight identified in the case series at diagnosis, followed by description of the interval between estrus and CDM diagnosis, glucose
values at diagnosis and at remission, interval between CDM diagnosis and gonadectomy, interval between gonadectomy and CDM remission and progesterone-related conditions
for each patient.
Breed, age, BS (1–5) and BW (kg) E–DM (weeks) FGD (mg/dL) DM–OHE (days) OHE–NG (days) FGR (mg/dL) P4-related condition
(1) Teckel, 12y, 2, 5.2 4 493 46 39 78 CEH–P
(2) Beagle, 8y, 3, 11.7 5 513 37 20 109 CEH–P
(3) Brittany, 6y, 3, 10 2 542 5 4 96 Pregnancy
(4) Poodle, 8y, 2, 4 2 >600 81 10 95 CEH–P
(5) Mongrel, 7y, 2, 36 2 >600 3 4 89 ORS
(6) Mongrel, 10y, 2, 29.8 3 305 – – 76 Diestrus
BS, body score; BW, body weight; E–DM, interval between the end of estrus and diabetes diagnosis; FGD, fasting glucose at diagnosis; DM–OHE, interval between diabetes
diagnosis and gonadectomy; OHE–NG, interval between gonadectomy and normoglycemia; FGR, fasting glucose at diabetes remission; P4, progesterone; CEH–P, cystic
endometrial hyperplasia–pyometra; ORS, ovarian remnant syndrome.
472 A.G. Pöppl et al. /Research in Veterinary Science 94 (2013) 471–473

Author's personal copy
gestational diabetes occurs at younger ages than diabetes second-
ary to diestrus (Fall et al., 2008).
While progesterone-induced GH secretion plays a major role in
CDM development during diestrus, the magnitude of GH response
to progesterone as well as tissue response to GH and the glycemic/
insulinemic responses to this phenomenon is quite variable from
dog to dog (Eingenmann et al., 1983; Selman et al., 1994), due to
many unclear variables such as genetics, nutrition, and environ-
ment (Guptill et al., 2003; Klinkenberg et al., 2006; Wejdmark
et al., 2011). In this scenario, the role played by inflammatory
cytokines in inducing insulin resistance cannot be ruled out as in
the case of CEH–P (Pöppl et al., 2009). The largest concentration
of inflammatory cytokines (TNF-
a
, IL-1, IL-6) under sepsis, or
chronic inflammation conditions, inhibits the intracellular signal-
ing of insulin through different mechanisms (Tilg and Moschen,
2008), explaining the severe insulin resistance observed in bitches
with pyometra (Pöppl et al., 2009). Nonetheless, studies that corre-
late insulin sensitivity with septic/inflammatory processes in dogs
are rare (Pöppl et al., 2009; Fall et al., 2010) and ever since Krook
et al. (1960) correlated diabetes with pyometra, no other study
linking these diseases frequently seen in routine practice has been
published. The remission of CDM after resolution of CEH–P
strengthens this association. Moreover, remission of progesterone-
related diabetes in dogs is expected to occur only if progesterone
withdrawal occurs few weeks after CDM diagnosis (Eingenmann
et al., 1983; Fall et al., 2008, 2010). The unexpected long interval
(37, 46 and 81 days) between diabetes diagnosis and OHE in three
bitches reinforces this possible role of insulin resistance due to
CEH–P when compared with the other bitches that were neutered
quickly after CDM diagnosis.
Although there is agreement that the chance of remission is
higher when OHE is performed as soon as possible after the devel-
opment of diabetes mellitus (Feldman and Nelson, 2004), we con-
clude that remission is possible even after some weeks between
diagnosis and therapeutic OHE in some specific cases, even when
severe ketosis is observed at presentation. It is assumed that main-
tenance of insulin therapy played a crucial role for protection
against severe glucotoxicity in this case series. Different aspects
led to the remission of CDM in these cases, but OHE played a key
role, being therefore recommended for bitches with DM, not only
as a way to prevent treatment complications, but also as a way
to induce remission of the disease by allowing a new hormonal
balance after the removal of the progesterone source, or elimina-
tion of inflammatory cytokines in case of pyometra.
Conflict of interest
None of the authors of this paper has a financial or personal
relationship with other people or organizations that could inappro-
priately influence or bias the content of the paper.
Acknowledgment
This study was supported by CNPq (Brazilian National Research
Council).
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