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


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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
, T.S. Mottin
, F.H.D. González
Programa de Pós-Graduação em Ciências Veterinárias, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9090, Agronomia, Porto Alegre,
Hospital de Clínicas Veterinárias, Faculdade de Veterinária, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9090, Agronomia, Porto Alegre, Brazil
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
Insulin resistance
Gestational diabetes
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
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.
Corresponding author. Tel.: +55 51 33088033; fax: +55 51 33086112.
E-mail address: (A.G. Pöppl).
Research in Veterinary Science 94 (2013) 471–473
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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
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-
, 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.
This study was supported by CNPq (Brazilian National Research
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... 3,4 Reportedly, transient diabetes and IR have been described in a dog with ORS being resolved after ovariohysterectomy. 5 Hyperlipidemia refers to an increased serum triglyceride and/or cholesterol concentrations and can be developed by primary and secondary causes. Primary hyperlipidemia in dogs is less common and is most often reported in certain breeds. ...
... Dyslipidemia as hypertriglyceridemia is a relatively common biochemical finding in dogs which can be caused as either primary (idiopathic) or secondary to other diseases such as hypothyroidism, DM or hyperadrenocorticism. 6 However, hypercholesterolemia especially severe hypercholesterolemia without hypertriglyceridemia is less common. 5,13 Primary hypercholesterolemia without hypertriglyceridemia has been described in a family of rough Collies and in 15 Briards from the United Kingdom. 5 Common causes of secondary hypercholesterolemia without hypertriglyceridemia in dogs are nephrotic syndrome, hypothyroidism and cholestasis. ...
... 5,13 Primary hypercholesterolemia without hypertriglyceridemia has been described in a family of rough Collies and in 15 Briards from the United Kingdom. 5 Common causes of secondary hypercholesterolemia without hypertriglyceridemia in dogs are nephrotic syndrome, hypothyroidism and cholestasis. Furthermore, hypercholesterolemia can be caused by DM in dogs. ...
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A 9-year-old spayed female Terrier dog was evaluated for lethargy, anorexia, polyuria, polydipsia and dysuria. The dog had been diagnosed with diabetes mellitus about 6 months ago and received subcutaneous doses of insulin. The patient showed insulin resistance and severe persistent fasting hyperglycemia in the face of high-dose insulin treatment, hyper-cholesterolemia and urinary tract infection. After a complete evaluation, the dog was diagnosed with a polycystic ovary and a cystic uterine remnant during an exploratory celiotomy. The polycystic ovary and cystic uterine remnant were removed and submitted for histopathological evaluation. Two weeks after surgery the blood glucose level and one month later serum cholesterol level were controlled, using a low level of insulin therapy (0.25 IU kg-1 Neutral Protamine Hagedorn (NPH) insulin, every 12 hr). In the present study, the clinical and laboratory results showed that ovarian remnant syndrome as an infrequently encountered condition in dog was related to some metabolic disorders such as insulin resistance, uncontrolled hyperglycemia, dyslipidemia and also recurrence urinary tract infection. To the best of authors' knowledge, no reports of hypercholesterolemia in dog have been made before as a complication of ovarian remnant syndrome.
... Desde a década de 1950, o desenvolvimento de diabetes em cadelas, logo após o estro, tem sido bem reconhecido e a ovariohisterectomia, a terapia recomendada (PÖPPL et al., 2009;MOTTIN;GONZÁLEZ, 2013;JERICÓ;ANDRADE NETO;KOGIKA, 2015). Em 2010, foi relatada uma prevalência de 17% de diagnósticos de piometra em cadelas com diabetes mellitus concomitante durante o diestro (FALL et al., 2010). ...
... Desde a década de 1950, o desenvolvimento de diabetes em cadelas, logo após o estro, tem sido bem reconhecido e a ovariohisterectomia, a terapia recomendada (PÖPPL et al., 2009;MOTTIN;GONZÁLEZ, 2013;JERICÓ;ANDRADE NETO;KOGIKA, 2015). Em 2010, foi relatada uma prevalência de 17% de diagnósticos de piometra em cadelas com diabetes mellitus concomitante durante o diestro (FALL et al., 2010). ...
... Uma das formas comuns de diabetes canina é aquela relacionada à progesterona, denominado ainda como diabetes mellitus secundário à endocrinopatia ou DM gestacional, que ocorre por influência da progesterona ou de progestógenos sintéticos, que induzem à secreção de quantidades significativas de GH pela glândula mamária (GILOR et al., 2016;PÖPPL et al., 2017). Este hormônio é um importante fator envolvido na resistência à insulina, apresentada por cadelas durante o diestro, gestação e/ou hiperplasia endometrial cística-piometra (PÖPPL et al., 2007;MOTTIN;GONZÁLEZ, 2013;GILOR et al., 2016). Objetivou-se com este trabalho, relatar o caso clínico de uma cadela atendida no Hospital Veterinário da UFCG, diagnosticada com cetoacidose diabética e piometra. ...
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p class="Corpo2">Uma cadela, SRD, 13 anos de idade, foi atendida na Clínica Médica de Pequenos Animais/Hospital Veterinário/UFCG com histórico de anorexia, apatia, poliúria, polidipsia e secreção vaginal. Na ultrassonografia foram observadas alterações sugestivas de piometra. Hemograma completo, bioquímica sérica e urinálise revelaram anemia normocítica normocrômica e intensa leucocitose com neutrofilia, glicosúria (> 1000 mg/dl), hipostenúria (DU 1,015), cetonúria (+++) e hiperglicemia (463,7 mg/dl). A hemogasometria indicou acidose metabólica (pH 6,68; BE: -30; HCO3: 5 mEq/L). Diagnosticou-se cetoacidose diabética sendo indicado o internamento da paciente. Foram tratados os desequilíbrios hídrico e ácido básico e administrada solução de NaCl 0,9% associada a bicarbonato de sódio 8,4%, devido à gravidade da acidose. Foi iniciada a antibioticoterapia com Ceftriaxona (30 mg/kg/IV) e metronidazol (15 mg/kg/IV) para controle do foco infeccioso. A terapia insulínica foi iniciada com insulina regular (0,2 UI/kg, IM), até a glicemia atingir valores abaixo de 270 mg/dl. No 4º dia de internamento, os valores de hemogasometria e glicemia melhoraram, porém a leucocitose aumentou. No 5º dia a paciente foi encaminhada para o procedimento cirúrgico de OH. No 9º dia de internamento, animal recebeu alta com a prescrição de insulina NPH (0,5 UI/kg, BID, junto com as refeições, até novas recomendações).</p
... İngiltere'de köpeklerde gözlenen diabetes mellitusun epidemiyolojisi üzerine yapılan bir çalışmada kısırlaştırılmış dişi köpeklere uygulanan gonadoektomi uygulaması ile diabetes mellitus arasında bir ilişki bulunmadığını bildirmiştir [25]. Diğer yandan farklı bir çalışmada diabetes mellitus bulunan köpeklerde uygulanan overiohisterektomi sonrasında 4-39 gün içerisinde hastalık etkilerinin azaldığı da bildirilmiştir [26]. ...
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zet: İnsan nüfusunun artması ile kedi ve köpek popülasyonu da yıllar içerisinde hızla artmıştır. Zamanla bu artış kedi ve köpekler için üremenin kontrolünü zorunlu hale getirmiştir. Üremenin kontrolü amacıyla kedi ve köpeklere birçok medikal veya cerrahi yöntem uygulanmaktadır. Cerrahi yöntemler medikal yöntemlere göre daha az komplikasyon oluşturması, hızlı ve pratik olması, ömür boyu sterilite sağlaması açısından daha fazla tercih edilmektedir. Cerrahi uygulamalar içerisinde ise en çok kullanılan yöntem gonadoektomidir. Dişilerde bu uygulama daha çok ovariohisterektomi (OHE) yöntemi kullanılarak yapılmaktadır. Fakat hayvan sahipleri ve hayvanları arasındaki duygusal bağ kısırlaştırma uygulamaları konusunda hayvan sahiplerini tedirgin etmekte ve kısırlaştırma/kısırlaştırmama konusunda kafa karışıklığı oluşturmaktadır. Ayrıca köpeklerini kısırlaştırmayı düşünen hayvan sahipleri için de uygun kısırlaştırma zamanı konusunda çok zorluk yaşamaktadır. Toplumda bu anlamda bir bilgi kirliliği bulunmaktadır. Köpeklerin en az bir kez kızgınlık geçirmesi, gebelik geçirmesi, çiftleşmesi gibi farklı düşünceler mevcuttur. Bu derlemede daha çok dişi köpekler ile ilgili farklı retrospektif çalışmalar sunulmuştur. Dişi köpeklerde OHE uygulamalarının avantaj ve riskleri, prepubertal (erken dönem) ve postpubertal (geç dönem) OHE uygulamalarının meme neoplazileri, neoplastik olmayan üreme bozuklukları, hipotiroidizm, idrar yolu bozuklukları, diabetes mellitus, osteosarkom, hemangiosarkom, ortopedik problemler, mizaç, yaşam süresi, obezite gibi durumlar üzerine etkisi hakkında bilgi verilmesi amaçlanmıştır. Anahtar Kelimer: gonadoektomi, kısırlaştırma, prepubertal, neoplazi Abstract: With the increase in the human population, the cat and dog population has also increased rapidly over the years. Over time, this increase has made it necessary to reproduction control for cats and dogs. Many medical or surgical methods are applied to cats and dogs to reproduction control. Surgical methods are more preferred than medical methods because create fewer complications, are fast and practical, and provide lifelong sterility. Gonadoectomy is the most used method among surgical applications. In females, it is often performed as ovariohysterectomy (OHE). However, the emotional relationship between pet owners and their pets makes animal owners uneasy about neutering practices and confused about spaying and non-spaying. In addition, choosing the appropriate time for spaying is very difficult for animal owners. There is also a confusion in the society regarding this issue. There are different thoughts such as dogs having heating at least once, having one pregnancy at least, and mating at least once. In this review, different retrospective studies about female dogs are presented. The advantages and risks of OHE and its applications in different periods (prepubertal/postpubertal) in female dogs are discussed. In addition, it is aimed to provide information about the effects of OHE on mammary neoplasms, non-neoplastic reproductive disorders, hypothyroidism, urinary tract disorders, diabetes mellitus, osteosarcoma, hemangiosarcoma, orthopedic problems, temperament, life span, obesity.
... Moreover dioestrus has been identified as a major risk factor in the development of cDM (Pöppl et al., 2017). This reflects the importance of sterilization in females to prevent cDM, and to potentially revert its progression at early stages as previously stated (Pöppl et al., 2013). ...
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Background Canine diabetes mellitus has mostly been studied in northern European, Australian and American populations, whereas other regions have received less attention. Objectives We evaluated the epidemiological, clinical and histopathological features of diabetic dogs in Gran Canaria, Spain. Methods Prevalence and incidence were estimated. Clinical features were analysed, and serum and genomic DNA were obtained. Dogs with presumed idiopathic or immune‐mediated diabetes, were DLA‐typed and antibodies against GAD65 and IA‐2 were assessed. Pancreases from ten diabetic dogs were examined and compared with pancreases from non‐diabetic dogs. Results and conclusions Twenty‐nine diabetic dogs were identified in a population of 5,213 (prevalence: 0.56%; incidence: 0.37%). Most were female (79%) and sexually intact (87% of females, 83% of males). Diabetes secondary to dioestrus (55.2%) and insulin‐deficient diabetes (20.7%) were the most frequent types. Antibodies against GAD65 and IA‐2 were identified in two out of five cases and DLA‐genotyping revealed novel haplotypes. Breed distribution differed between diabetic and non‐diabetic dogs. Reduced number of pancreatic islets and β‐cell mass were observed, with vacuolation of islet cells and ductal epithelium. In this population, where neutering is not standard practice, diabetes secondary to dioestrus is the most frequent diabetes subtype. Genetic susceptibility also differed from previous studies. These results support the heterogeneous pathogenesis of canine diabetes.
... Removal of the uterus from the ovaries is also indicated for tumors of the uterus (Bencharif et al., 2010), breast (Murai et al., 2012), vaginal prolapse, pyometra, post-estrus metritis (Nakamura et al., 2012). Ovariohysterectomy also minimizes the symptoms associated with diabetes (Pöppl et al., 2013). ...
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Surgical access for ovariohysterectomy in bitches through the right lateral abdominal wall with an incision in its upper third in the direction from the anterior edge of the macula to the fourth nipple of the corresponding side of the breast is proposed. The article presents the results of studies obtained when used for the purpose of ovariohysterectomy in bitches of operative access through the right lateral and ventral abdominal wall. Research work was conducted on healthy mature bitches. The operations were performed in the area of the right lateral abdominal wall and in the umbilical region. On the lateral abdominal wall, an oblique-vertical incision was used at the border of the inguinal and iliac areas in the direction from the anterior edge of the macula to the fourth nipple of the corresponding side of the breast. The ventral abdominal wall was cut along the white line. It was found that when performing ovariohysterectomy in bitches using the proposed surgical access through the right lateral abdominal wall with a smaller wound size (P < 0.05), the duration of the operation and the healing period correspond to those when using median laparotomy. It is proved that operative access with oblique-vertical incision in the area of the right lateral abdominal wall at the border of the groin and anus during ovariohysterectomy in bitches provides favorable opportunities for surgical reception and closure of the surgical wound. The number of surgical sutures for sutures on the abdominal wall is less than in the case of ventral access (P < 0.01). It is also noted that in ovariohysterectomy in bitches, operative access through the right lateral abdominal wall with an incision in the direction from the anterior edge of the macula to the fourth nipple of the corresponding side of the breast may be recommended as an alternative access through the white line of the abdomen.
The most common causes of insulin resistance in diabetic dogs are Cushing syndrome, diestrus, and obesity. Cushing-associated effects include insulin resistance, excessive postprandial hyperglycemia, perceived short duration of insulin action, and/or substantial within-day and/or day-to-day glycemic variability. Successful strategies to manage excessive glycemic variability include basal insulin monotherapy and combined basal-bolus insulin treatment. Ovariohysterectomy and insulin treatment can achieve diabetic remission in about 10% of cases of diestrus diabetes. Different causes of insulin resistance have an additive effect on insulin requirements and the risk of progression to clinical diabetes in dogs.
The objective of this study was to explore the carbohydrate contents of crop milk, insulin and glucose concentrations in serum and the expression patterns of AMP‐activated protein kinases (AMPKs) and genes related to glucose metabolism in pigeon crops during the breeding period. Crop milk was collected from squabs of rearing Day 1 (R1) to R6. Contents of total sugar and reducing sugar increased to the maximum levels at R6 (p < 0.05). Forty‐two pairs of adult pigeons were allotted to seven groups by different breeding stages, and their crops and serum were sampled. No significant differences were found in either insulin or glucose levels in serum. The glucose transporter 2 gene level was the greatest at R15 in females, whereas it was at R7 in males. However, sodium‐dependent glucose transporters 1 expression in both sexes decreased from incubation Day 17 (I17) to R7. In females, glucokinase expression peaked at R1, and at R1 and R7 in males. Pyruvate kinase mRNA levels peaked at R7 in females and at R15 males. The mRNA abundance of fructose‐1,6‐bisphosphatase 1 in both sexes and glucose‐6‐phosphatase in females decreased after I10. While phosphoenolpyruvate carboxykinase 1 expression decreased after I17 (p < 0.05). Protein levels of AMPKα in crops were minimized at R1 (p < 0.05). In females, expression of AMPKα1 and AMPKα2 was inhibited at I17 and R1 (p < 0.05). In males, AMPKα1 expression was decreased at R7 (p < 0.05) and AMPKα2 was reduced at I10 and R1. pAMPK expression was the lowest at I17 in females, and it was at R7 and R25 in males. Conclusively, glycolysis in pigeon crops was enhanced during chick‐rearing, while gluconeogenesis was significantly inhibited. The stability of the insulin level suggests that it was probably not involved in the regulation of glucose metabolism in crop tissues.
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Remission of diabetes mellitus in dogs is a very rare condition. In our case, the symptoms of diabetes mellitus in the nine‐ year‐old Yorkshire terrier bitch disappeared three months after the therapeutic ovariohysterectomy. The diagnosis of diestrous diabetes mellitus, requiring insulin supplementation, was confirmed on the basis of anamnesis, symptomatology, clinical examination and specific laboratory tests. The chosen therapy and a change in diet led to the stabilization of the patient and its preparation for surgery. Repeated follow‐ups, consisting of control blood samplings for glucose and progesterone levels and urinanalysis, has ensured control of insulin therapy and proper insulin dosing. Three weeks after ovariohysterectomy, normoglycaemia confirmed by control trials, resulted in gradual discontinuation of insulin administration. The stable health status of the patient two months after the performance of therapeutic ovariohysterectomy, confirmed the remission of the disease without the need for further insulin supplementation and regular monitoring.
Diestrus is associated with insulin resistance in bitches and pyometra can further impair insulin sensitivity. The aims of this study were to compare insulin sensitivity, insulin binding, and tyrosine kinase activity in bitches in anestrus, diestrus, or with pyometra. Patients submitted to elective ovariohysterectomy were divided in anestrus (n=11) or diestrus (n=13) according to reproductive history, vaginal cytology, and uterine histology. The group pyometra (n=8) included bitches diagnosed with the disease based in clinical presentation and abdominal ultrasound findings, and further confirmed by uterine histopathology. All patients were submitted to an intravenous glucose tolerance test (IVGTT) before ovariohysterectomy, and rectus abdominis muscle samples were collected during surgery for plasmatic membrane suspension preparation. Muscle-membranes were submitted to cold saturation insulin binding assay for dissociation constant (Kd) and maximum binding capacity (Bmax) determination, as well as exogenous substrate Poly (Glu:Tyr 4:1) phosphorylation assay for basal tyrosine kinase evaluation. Bitches with pyometra showed higher basal insulin (P<0.001) and higher area under the curve (AUC) for insulin (P=0.01) and glucose (p<0.001) response during the IVGTT in comparison with bitches in anestrus or diestrus. Diestrus (P<0.0001) and pyometra (P=0.001) were associated with reduced tyrosine kinase activity in comparison with anestrus. No differences were documented in Kd and Bmax results for the low-affinity/high-capacity insulin receptors; however, high-affinity/low-capacity insulin receptors showed higher Kd and Bmax results in bitches in diestrus or with pyometra (P<0.05) in comparison with anestrus. Despite pyometra group showed highest Kd values (P<0.01), its Bmax results did not differ from diestrus group (P>0.05). Diestrus’ higher Kd values and reduced tyrosine kinase activity in muscle tissue were compensated by increased total insulin binding capacity. Absent differences in IVGTT results between diestrus and anestrus bitches corroborates this finding. However, in bitches with pyometra, highest Kd values were not compensated by increased total insulin binding capacity. This finding was associated with insulin resistance and glucose intolerance in IVGTT results. Moreover, pyometra resolution restored insulin sensitivity and glucose tolerance. These features can play a key role in pyometra-associated CDM, as well as in diabetic remission after pyometra resolution.
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Manual Elaborado pela Associação Brasileira de Endocrinologia Veterinária (ABEV) em parceria com a Nestlé Purina sobe Diabetes Mellitus em Cães e Gatos
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Ocurrence of estrous cycle and pyometra in female dogs are associated to insulin resistance status. Moreover, septic/inflammatory environments such as pyometra may also course with reduced insulin sensitivity. The aim of this study was to check the effect of estrus cycle and pyometra on insulin sensitivity indexes. Based in blood basal glucose levels and serum insulin basal levels from bitches in different estrus cycle phases as well as in bitches with pyometra, different insulin sentivity indexes were calculated (HOMA B, HOMA R, insulinogenic index, amended insulin: glucose ratio, fructosamine and fructosamine: albumin ratio). The insulinogenic index and amended insulin: glucose ratio were more sensible in detecting relative hyperinsulinemic status, specially in pyometra patients. The lack of a cut-off point for HOMA indexes impairs its interpretation, notwithstanding their have been able to shown insulin resistance in female dogs with pyometra. Moreover, this different sensitivity indexes have prove to be really easy, cheap and useful and have some advantages comparing with basal insulin and glucose levels. Fructosamine was not a useful screening test in detecting differences in insulin sensitivity status despite there were a strong influence of hypoalbuminemia on fructosamine levels in bitches with pyometra. Fructosamine: albumina ratio is more reliable than fructosaminemia alone, and future studies are need to determine reference values for this ratio, as well to HOMA B and HOMA R indexes in female dogs.
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Estrus cycle is a well recognized cause of insulin resistance in bitches. The insulin receptor (IR) as well as the insulin-like growth factor-I receptor belong to the same subfamily of tyrosine kinase (TK) receptors. The objective of this study was to evaluate basal TK activity in muscle tissue of bitches during the estrus cycle. Twenty-four bitches were used in the study (7 in anestrus, 7 in estrus, and 10 in diestrus). Muscle samples, taken after spaying surgery to determine TK activity, were immediately frozen in liquid nitrogen and then stored at -80°C until the membranes were prepared by sequential centrifugation after being homogenized. TK activity was determined by Poly (Glu 4:Tyr 1) phosphorylation and expressed in cpm/μg of protein. TK activity was significantly lower (P < 0.001) in the animals in estrus (104.5 ± 11.9 cpm/μg of protein) and diestrus (94.5 ± 16.9 cpm/μg of protein) when compared with bitches in anestrus (183.2 ± 39.2 cpm/μg of protein). These results demonstrate, for the first time, lower basal TK activity in the muscle tissue of female dogs during estrus and diestrus, which may represent lower insulin signaling capacity, opening a new field of investigation into the molecular mechanisms of insulin resistance in dogs.
The influence of spontaneous "sex seasons" on blood sugar (BS) and serum insulin levels was studied in bitches with natural diabetes mellitus (DM) and normal controls, in the basal condition and during glucose and insulin tests, was studied. DM increased basal BS, reduced glucose tolerance, distribution space (DS) and clearance from blood, and induced resistance to insulin hypoglycemic action. In normals occurrence of "seasons", inconsistently modified basal BS, increased glucose tolerance and DS; during estrogenic phase (EP), these variables were above those during luteal phase (LP). In diabetics at LP, BS found in lasting condition and during glucose test were higher than in diabetic bitches at EP (respective values at anestrous (A) in between) and glucose DS was smaller. Rate of glucose clearance from blood remained unaffected by "seasons" in both dog groups. Basal serum IRI was not modified by DM or "seasons". In normals, serum IRI response to glucose load was nonsignificant during A and increased during the "seasons"; either insulin DS or the rate of insulin clearance from blood stream remained unchanged under the circumstances, the increase being mediated by insulin secretion. During EP, the increase was particularly intense and mean insulinogenic index (MII) rose. During LP, MII returned to A value, whereby diabetic states might be manifest. Serum IRI profiles during insulin test were not modified by "seasons" in normal bitches; such response in diabetic bitches was intense during A, then decreased (EP) or was later abolished (LP). Either in normal or diabetic bitches, the sensitivity to exogenous insulin hypoglycemic action remained unchanged in spite of "seasons". In diabetic bitches at A, serum IRI after glucose challenge peaked higher than in respective normal controls (insulin clearance and insulin DS were similar): they exhibited relative insulin shortage and resistance to insulin hypoglycemic action partly compensated by promoted insulin secretion. Along with "season", abolished serum IRI response to glucose load in diabetics was observed. During EP, extrapancreatic factors regulating serum IRI concentration and MII did not change in respect to A, whereby abolishment appears mediated by depressed insulin secretion. During LP, insulin antagonism in conjunction with 1) absolute insulin deficiency and 2) intense decrease in MII appears as a powerful factor exposing diabetic bitches to a severe or fatal derangement in diabetic disease.
This study aims to investigate lifestyle risk factors for the development of progesterone-related diabetes mellitus in female elkhounds. Owners of 48 diabetic elkhounds and 58 healthy elkhounds were interviewed by phone concerning lifetime diet and exercise routines. A logistic model was developed to assess the impact of diet and exercise on diabetes diagnosis. The agreement between lifetime owner-perceived body condition score (BCS) and veterinary-perceived BCS at inclusion was estimated in healthy control dogs using the Kappa statistic. The model showed that diabetic dogs had increased odds for having been overweight (before diagnosis) compared with controls (OR=2·8, 95% confidence interval 1·1-7·5, P=0·034). Although feeding other food than commercial dog feed was associated with diabetes case status, the effect was not significant after BCS was entered into the model. The overall agreement between lifetime owner- and veterinary-perceived BCS at inclusion in the study was 75% and had a Kappa statistic of 0·16 (P=0·12). This study indicates that a high owner-perceived lifetime BCS is associated with progesterone-related diabetes in elkhounds.
Female Elkhounds are shown to be at increased risk for diabetes mellitus, and occurrence of diabetes during pregnancy has been described in several cases. Onset of diabetes mellitus in Elkhounds is associated with diestrus. Sixty-three Elkhounds with diabetes mellitus and 26 healthy controls. Medical records from 63 Elkhounds with diabetes were reviewed and owners were contacted for follow-up information. Blood samples from the day of diagnosis were available for 26 dogs. Glucose, fructosamine, C-peptide, growth hormone (GH), insulin-like growth factor-1, progesterone, and glutamate decarboxylase isoform 65-autoantibodies were analyzed and compared with 26 healthy dogs. Logistic models were used to evaluate the association of clinical variables with the probability of diabetes and with permanent diabetes mellitus after ovariohysterectomy (OHE). All dogs in the study were intact females and 7 dogs (11%) were pregnant at diagnosis. The 1st clinical signs of diabetes mellitus occurred at a median of 30 days (interquartile range [IQR], 3-45) after estrus, and diagnosis was made at a median of 46 days (IQR, 27-62) after estrus. Diabetes was associated with higher concentrations of GH and lower concentrations of progesterone compared with controls matched for time after estrus. Forty-six percent of dogs that underwent OHE recovered from diabetes with a lower probability of remission in dogs with higher glucose concentrations (odds ratio [OR], 1.2; P=.03) at diagnosis and longer time (weeks) from diagnosis to surgery (OR, 1.5; P=.05). Diabetes mellitus in Elkhounds develops mainly during diestrus and pregnancy. Immediate OHE improves the prognosis for remission of diabetes.