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Management of Canine Diabetes
Abstract
The majority of diabetic dogs appear to have a form of type 1 diabetes analogous to the latent autoimmune diabetes of adults (LADA) in humans. Evidence of acute or chronic pancreatitis occurs in about 40% of diabetic dogs. Blindness caused by cataract formation eventually occurs in the majority of diabetic dogs and is not dependent on glycemic control. Insulin is the mainstay of therapy for diabetic dogs, and a conservative approach to insulin therapy is crucial. Most diabetic dogs require twice-daily dosing with lente or NPH insulin to adequately control their clinical signs. The diet fed should primarily be palatable and nutritionally balanced. Improved glycemic control may be achieved in some dogs if the diet contains increased insoluble fiber.
... The ALIVE project of the European Society of Veterinary Endocrinology defines diabetes mellitus as a heterogeneous group of diseases with multiple etiologies characterized by hyperglycemia resulting from inadequate insulin secretion, inadequate insulin action, or both [19]. The global prevalence of CDM from published literature ranges from 0.15 to 1.33% while sex and gonadal status (entire or desexed) predisposition to CDM varies according to the population studied [6,[20][21][22][23][24][25][26][27]. However, it is generally accepted that entire females are at increased risk for CDM development due to the influence of diestrus [3][4][5][6][7][8][9]11,26]. ...
... However, it is generally accepted that entire females are at increased risk for CDM development due to the influence of diestrus [3][4][5][6][7][8][9]11,26]. Female dogs have a two-fold higher CDM incidence compared to males, and nearly 75% of the diagnosed dogs with DM are females [5][6][7][8]26,27]; however, this distribution can show a vast range. The reduction in synthetic progestin use as a contraceptive and systematic neutering of non-breeding dogs can make CDM incidence similar between males and females [28]. ...
... Eventually, a dog undergoing diabetic remission after spaying can be presented due to a hypoglycemic crisis [14]. When diabetic remission is suspected due to the above-mentioned factors, progressive insulin dose reduction can be tested (e.g., 25-50% reduction every 3-5 days) while glycemic values and clinical score are being monitored [27,29,124]. In this scenario, maintenance of a long-acting "peakless" basal insulin analog once daily (e.g., glargine 300 U) before complete insulin withdrawal would be safer to reduce hypoglycemic risk while insulin resistance is reducing, and endogenous insulin secretion is recovering [148]. ...
Simple Summary
Canine diabetes mellitus (CDM) is a multifactorial condition caused by insufficient insulin secretion, inadequate insulin action on peripheric tissues, or both. This scenario leads to increased blood glucose levels, which causes excessive urine output and thirst as the main clinical signs. Life-long insulin treatment is mandatory to control clinical signs and avoid life-threatening CDM complications. However, some female dogs may have a transient form of CDM associated with peripheral insulin resistance due to physiologically hormonal fluctuations’ impacts during their reproductive cycle. The resolution of antagonisms on insulin action may induce diabetes remission and allow insulin therapy interruption. This work aims to review the impacts of the reproductive physiology of the bitch on CDM risk and to discuss helpful steps to better manage entire diabetic bitches and eventually improve remission rates. Preventive measures are also discussed, as well as the role of pyometra, a common eventually life-threatening purulent infection of the uterus in entire females. Despite spaying being the best way to complimentarily treat diabetic female dogs, and to avoid reproductive-cycle-related CDM cases, the benefits and eventual harms should be considered before a decision individually.
Abstract
Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. This narrative review aims to provide relevant detailed information on (1) the canine estrus cycle and its impact on canine diabetes mellitus (CDM) etiology and management, (2) the role of pyometra as a further cause of insulin resistance, and (3) useful individual therapeutic and preventive strategies. PRDM is recognized due to diestrus, exogenous progestogen exposure, pregnancy, and P4-production ovarian dysfunction. Pyometra represents additional inflammatory and septic negative influence on insulin sensitivity, and its diagnosis associated with CDM is therapeutically challenging. The estrus cycle’s hormone fluctuations seem to modulate peripheric insulin sensibility by influencing insulin receptor (IR) affinity and its binding capacity, as well as modulating tyrosine kinase activity. Pyometra was shown to negatively influence IR compensatory mechanisms to insulin resistance causing glucose intolerance. Spaying and pregnancy termination may cause diabetes remission in PRDM cases in a median time of 10 days (1–51). Pharmacological annulment of progesterone effects may benefit patients unable to undergo surgery; however, remission chances are virtually null. The ALIVE (Agreeing Language in Veterinary Endocrinology) project proposed new criteria for CDM diagnoses and subclinical diabetes recognition. These new concepts may increase the frequency of a PRDM diagnosis and, even more, its relevance. Spaying represents a preventive measure against pyometra and PRDM that should be individually assessed in light of its recognized benefits and harms.
... The ALIVE project of the European Society of Veterinary Endocrinology defines diabetes mellitus as a heterogeneous group of diseases with multiple etiologies characterized by hyperglycemia resulting from inadequate insulin secretion, inadequate insulin action, or both [36]. The global prevalence of CDM from published literature ranges from 0.15 to 1.33% while sex and gonadal status (entire or desexed) predisposition to CDM varies according to the population studied [6,[37][38][39][40][41][42][43][44]. However, is generally accepted that entire females are at increased risk for CDM development due to the influence of diestrus [3][4][5][6][7][8][9]11,43]. ...
... However, is generally accepted that entire females are at increased risk for CDM development due to the influence of diestrus [3][4][5][6][7][8][9]11,43]. Female dogs have a two-fold higher CDM incidence compared to males, and nearly 75% of the diagnosed dogs with DM are females [5][6][7][8]43,44]; however, this distribution can show a vast range. The reduction in synthetic progestin use as a contraceptive and systematic neutering of non-breeding dogs can make CDM incidence similar between males and females [45]. ...
... Eventually, a dog undergoing diabetic remission after spaying can be presented due to hypoglycemic crise [14]. When diabetic remission is suspected due to the above-mentioned factors, progressive insulin dose reduction can be tested (e.g., 25-50% reduction each 3-5 days) while glycemic values and clinical score are being monitored [44,46,122]. In this scenario, maintenance of a long-acting "peakless" basal insulin analog once daily (e.g., glargine 300U) before complete insulin withdrawal would be safer to reduce hypoglycemic risk while insulin resistance is reducing, and endogenous insulin secretion is recovering [145]. ...
Correlations among estrus cycle, pyometra, and canine diabetes mellitus (CDM) have been described since the late 1950s, and substantial progress in understanding mechanisms beyond was achieved nowadays. Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. Thus, a deep understanding of the physiopathological aspects involved is crucial to postulate treatment guidelines to improve the PRDM remission rate, as well as to inform preventive measures. This narrative review aims to provide relevant detailed information on 1) canine estrus cycle and its impact on CDM etiology and management, 2) the role of pyometra as a further cause of insulin resistance, and 3) useful individual therapeutic and preventive strategies. Pharmacological annulment of progesterone effects, as well as inflammatory and progesterone-related conditions resolution in association with adequate exogenous insulin therapy, and residual beta cell function, are key aspects to achieve remission, or at least to improve diabetic clinical control. In this way, spaying should be considered mandatory in most PRDM cases. Preventive measures against CDM can include spaying recommendations; however, individual-based recommendations should be considered since castration may be associated with some long-term health issues.
... 16 A ativação das enzimas pancreáticas dentro dos ácinos e do sistema de ductos pancreáticos inicia a pancreatite, podendo o envolvimento das ilhotas ocorrer por extensão da necrose e inflamação pelos tecidos ao redor. 2,3 Entretanto, a discussão sobre quem surge primeiro nos casos onde DMC e pancreatites parecem correlacionadas é um tema polêmico e repleto de incertezas, uma vez que o quadro diabético por si também pode desencadear pancreatite, e apesar do diagnóstico de diabetes ser relativamente simples, o diagnóstico de pancreatite é muito mais convoluto. 17 ...
... 12 Eventualmente, algumas pacientes não castradas podem sofrer remissão espontânea ao término do diestro, porém com grande probabilidade de desenvolver DMID na próxima fase progesterônica do ciclo estral, uma vez que a quantidade de células beta funcionais é bastante reduzida nesses pacientes (diabetes subclínico). 6,13 Por esses motivos, recomenda-se a ovariohisterectomia logo após o diagnóstico de DM. 2,6,13 Essa forma de diabetes no cão remete ao diabetes mellitus gestacional em humanos, no qual diversos fatores nutricionais, raciais, genéticos e imunológicos podem aumentar o risco de diabetes durante o predomínio da progesterona. 19 Uma possibilidade menos comum de diabetes transitório é secundária ao uso de glicocorticoides ou início de síndrome de Cushing em cães. ...
... 24 Classicamente as fêmeas são afetadas pelo menos duas vezes mais que os machos, especialmente devido as não castradas estarem diretamente expostas a quadros de diabetes secundária à progesterona. 2,24,25 Machos castrados apresentam risco maior de desenvolverem DM que machos inteiros, assim como cães com menos de 22 kg. 20,24 O surgimento de DMC em filhotes é extremamente raro, sendo incomum o aparecimento da doença em pacientes com menos de 1 ano, por exemplo. ...
... (Catchpole et al., 2005). Outro grande impasse na DM é seu diagnóstico, muitas vezes tardio, elevando a mortalidade da doença para 50% (Denyer et al., 2021;Fleeman & Rand, 2001). ...
... Como citado anteriormente, a diabetes não tem cura, portanto, é imprescindível que o paciente diagnosticado siga um tratamento, e dessa maneira, aumente sua expectativa e qualidade de vida. A DM mais presente em cães é a DM tipo I (Fleeman & Rand, 2001), aquela onde o paciente é insulino dependente. ...
... Como terapia para contornar os sintomas e reflexos da doença, o paciente diabético precisa de um tratamento baseado em três protocolos, sendo eles, administração de insulina, alimentação equilibrada e prática regular de exercícios (Fleeman & Rand, 2001). ...
O objetivo deste estudo é agregar informações úteis sobre o tema, buscar mais clareza sobre as definições da Diabetes Mellitus (DM) em cães e explorar o que já se tem de concreto em relação ao diagnóstico e tratamento. A DM é uma enfermidade endócrina associada ao hormônio insulina, responsável por controlar os níveis de glicose no sangue. Sua incidência em cachorros pode chegar à 1 em cada 100 animais da população, onde fêmeas representam até 70% dos casos. O diagnóstico tardio eleva a mortalidade da doença para 50%. Sua etiologia ainda precisa ser definida, mas é irrefutável que sua origem é multifatorial. Há o mesmo consenso sinalizando que os genes que envolvem o sistema imune são fortemente associados com a predisposição de DM. A insulina é um hormônio pancreático secretado pelas células ß, que são ativadas após os níveis séricos de glicose estarem altos. Sua ação reduz os níveis de glicose sérica fazendo-a penetrar na célula. A perda da homeostase glicêmica acarreta um desequilíbrio nas funções orgânicas que ao ultrapassar certos limites será perceptível através de manifestações clínicas. Os principais sinais percebidos são poliúria, polidipsia compensatória, polifagia, emaciação e cetoacidose diabética, dentre outros. A avaliação de exames laboratoriais quando há a suspeita de DM deve incluir a mensuração da glicemia e exame de urina tipo I. A enfermidade não tem cura, portanto, é imprescindível que o paciente diagnosticado siga um tratamento e dessa maneira aumente sua expectativa e qualidade de vida. As fontes de insulina derivam de uma combinação bovina e suína purificada e até de uma recombinação com a insulina humana. A discussão sobre o número de doses diárias, uma ou duas, não está encerrada; porém, estudos revelam melhores resultados no controle glicêmico com dosagem de insulina duas vezes ao dia, enquanto episódios de hipoglicemia aparecem mais vezes nos pacientes que receberam apenas uma dose por dia.
... Sin embargo, se ha reportado que algunos perros pueden tener hiperglucemia posprandial cuando se los trata con esta insulina. [32][33][34][35] La insulina lenta es una formulación purificada de origen porcino cuyo rango de acción es intermedio. Entre sus características fisicoquímicas se ha descrito que no contiene proteínas extrañas y el retraso en su absorción se basa en el contenido de zinc y el tamaño de cristales zinc-insulina que posee. ...
... La duración del efecto oscila entre 10 y 16 h, por lo que tiende a producir hipoglucemias en perros recién diagnosticados, aunque se puede utilizar en aquellos caninos mal controlados. [33][34][35][36] La insulina Glargine es un producto recombinante análogo de la insulina humana que se cataloga como de acción prolongada y que se ha usado principalmente en gatos. Este fármaco presenta una sustitución de asparagina por glicina en su cadena y un agregado de dos argininas en su extremo terminal, lo que provoca que sea más soluble en pH ácido y menos en pH fisiológico, con lo cual se retrasa su absorción. ...
... 39,40 Dado su mecanismo de acción, su uso no se recomienda en pacientes con diabetes tipo 1 que no poseen tejido pancreático donde estos medicamentos puedan realizar su efecto, y deben administrarse junto con la comida. 35,38 • Inhibidores de la -glucosidasa. Se utilizan para inhibir la absorción de glucosa intestinal y reducir la hiperglucemia posprandial. ...
Diabetes is defined as a group of metabolic diseases characterized by hyperglycemia,
caused by a defect in the secretion or action of insulin. This pathology is recognized
both in humans and animals, reporting an incidence of 0.4-1.2% in companion
animals. The pathogenesis of this disease tends to vary between these species,
being more common in dogs in entire adult females and in geronts, while in cats
it is observed with a higher incidence in castrated males. The diagnosis is based
on the correlation of clinical signs with laboratory findings, mainly the presence of
hyperglycemia; however, to observe signs such as polyuria and polydipsia, it is
necessary to exceed the renal glucose threshold. On the other hand, the treatment
and clinical management for diabetes in dogs and cats is based on the use of insulin,
of which there are different active principles such as regular insulin and insulin lispro,
where the use will depend on the characteristics of the molecule and its half-life, for
example, insulin lispro can be administered as a continuous infusion during states of
ketoacidosis. Likewise, to establish an effective therapy, it is recommended to monitoring
blood glucose levels directly, or else to indirectly evaluate proteins associated
with glycosylated hemoglobin. This to categorize if the patient can be considered in
remission. Therefore, the aim of this work is to carry out a bibliographic review of
the diagnosis, monitoring, management of the patient and criteria for its remission
on diabetes that serves as a guide for the dog and cat clinician.
... Independente dos fatores etiológicos envolvidos no desenvolvimento da diabetes mellitus canina [10], muitos dos quais são similares à etiologia da diabetes mellitus tipo II humana [4], no momento do diagnóstico os pacientes apresentam necessidade de insulinoterapia para controlar os sinais clínicos, retomar a qualidade de vida e evitar a cetoacidose diabética [5,9]. ...
... Existem diversas apresentações de insulina para tratamento de pacientes diabéticos com variações tanto na espécie de origem da insulina como na duração do efeito e na potência (na ordem de menor potência e maior duração do efeito a maior potência e menor duração do efeito: Glardine, ultralenta, zinco protamina, lenta, NPH, mistas de NPH e regular cristalina, regular cristalina, Lispro, Aspart) [4,18,31]. Para tratamento de cães diabéticos preconiza-se a utilização de insulina humana NPH ou lenta (a cada 12 horas) por sua fácil obtenção no mercado, reduzida antigenicidade e adequada farmacodinâmica, com início do efeito de 30 a 120 minutos após a aplicação e duração média do efeito de 12 horas [5,31]. ...
... Fatores como estresse, estro/diestro, corticoidoterapia, alimentação inadequada e doenças intercorrentes como hipotireoidismo, cistite, neoplasias, pancreatite, gengivite/periodontite, uveíte e infecções de pele influenciaram negativamente a terapia com Caninsulin na população avaliada. Qualquer desordem inflamatória, infecciosa ou neoplásica concomitante à diabetes mellitus apresenta enorme potencial para reduzir a eficácia da terapia insulínica [4,5]. ...
... 1 Apesar do crescente aumento na incidência de obesidade e diabetes mellitus em cães nos últimos 40 anos, diversos fatores genéticos, inflamatórios, hormonais e imunológicos podem estar associados ao surgimento da doen-ça em cães. 2 Essa tendência parece estar associada a maior contato com fatores ambientais adversos perante complexos fatores genéticos em segundo plano. 3 ...
... A glicose, além de servir como fonte de energia por sua total oxidação no processo de glicólise, serve como precursora de uma série de moléculas não menos importantes, como diversos aminoá-cidos, ácidos nucleicos, lipídios e carboidratos complexos como o glicogênio. 2 O principal efetor do controle da glicemia é o fígado, tecido primário envolvido no metabolismo da glicose, uma vez que ele pode secretar glicose para a corrente sanguí-nea por dois mecanismos distintos: a glicogenólise e a gliconeogênese. ...
... 6 É provável que ocorram infiltrados leucocitários nas ilhotas pancreá-ticas no início do processo autoimune, porém não estejam mais presentes no momento da morte da maioria dos cães diabéticos. A identificação de que muitos cães diabéticos apresentam anticorpos anti-insulina e anticomponentes das células b suporta a existência de autoimunidade humoral 2,13 O DMC compartilha algumas características do DM tipo 1 em humanos, mais precisamente com o diabetes autoimune latente do adulto (LADA), em que ocorre infiltração linfocitária de ilhotas pancreá-ticas no in-di-ví-duo adulto. 3 Contudo, existem raros relatos de filhotes diabéticos com infiltrados linfocitários nas ilhotas. ...
... The diagnosis of diabetes mellitus in the dog is relatively easy and based on three findings: typical clinical signs (polyuria, polydipsia, weight loss, polyphagia), and persistent fasting hyperglycemia and glycosuria (Plotnick and Greco, 1995a;Fleeman and Rand, 2001). The combination of persisting fasting hyperglycemia and glycosuria is essential for the diag nosis of diabetes mellitus. ...
... An essential part of the therapy is maintaining or achieving an ideal body weight. The goal is to eliminate the owner-observed clinical signs, provide a good quality of life and prevent complications such as hypoglycemia (Miller, 1995;Fleeman and Rand, 2001;Feldman and Nelson, 2004). The severity and duration of hyperglycemia are directly correlated with the clinical signs and the development of complications. ...
... This type of insulin must be administered with a 40 international units (I.U.) syringe. The recommended starting dosage is 0.25-0.5 I.U./kg of the optimal body weight twice daily, although most dogs are safely started on 0.5 I.U./kg twice daily (Fleeman and Rand, 2001;Behrend, 2006). The risk of hypoglycemic episodes is higher when insulin is administered once daily, and most dogs need a twice-daily administration for an adequate glycemic control (Hess and Ward, 2000;Fleeman and Rand, 2001;Davison et al., 2005;Monroe et al., 2005;Behrend, 2006). ...
Diabetes mellitus is one of the most common endocrine disorders in the dog. Although diagnostics are relatively straightforward, treatment and especially adequate long-term monitoring are challenging. To avoid complications, such as hypoglycemia, weight loss, diabetes ketoacidosis and urinary tract infections, adequate monitoring is indispensable. In this review different monitoring tools, such as history and clinical signs, single and serial blood glucose measurements, glycated blood products, continuous glucose measurements and urine glucose will be evaluated. Because each monitoring technique has its limitations, the challenge for the veterinarian is to use an adequate combination of these tools to obtain a good image of the patient's glycemic status.
... Diabetes mellitus (DM) is a complex, multifactorial disease characterized by the absolute or relative lack of insulin (Beam et al. 1999) most frequently in elderly and middle-aged dogs (Fleeman & Rand 2001, Feldman & Nelson 2004. A cataract is described as one of the first symptoms of diabetes in dogs and usually results in visual impairment; diabetic retinopathy (DR) is the most common cause of vision loss among people (Landry et al. 2004). ...
... DM is an endocrine disorder frequent in dogs which mainly affects the elderly and middle aged individuals (Beam et al. 1999, Fleeman & Rand 2001, Guptill et al. 2003, Feldman & Nelson 2004, like those of our study, which the mean age was 10.3 years. ...
Diabetes mellitus is one of the most common endocrine disorders characterized by relative or absolute lack of insulin; this can lead to several ocular manifestations, among them diabetic retinopathy and cataracts. Diabetic retinopathy (DR) is a microangiopathy that involves retinal precapillary arterioles, postcapillary venules, and large vessels, causing them to be functionally and anatomically incompetent. Hyperglycemia seems to be the most probable cause of damage to the retina due to interference in cellular metabolism and transduction processes. The aim of this study was to evaluate retinal thickness in eight diabetic dogs, four females and four males of different breeds and ages ranging from 6 to 15 years, by optical coherence tomography (OCT) and to compare them with non-diabetic dogs. Assessment provided by OCT in diabetic dogs showed retinal layers thinning and loss of stratification when compared to non-diabetic dogs (198μm versus 219μm respectively), with statistical significance (p=0.008). OCT images may suggest that diabetes mellitus causes retinal neuropathy in dogs, as also seen in diabetic humans.
... A glicemia pré-insulina é útil na verificação da sobreposição do efeito de duas doses de insulina. O Quadro 5 apresenta um resumo dos ajustes propostos com base nas glicemias documentadas durante curvas glicêmicas.31 Outra consideração importante é que curvas glicêmicas seriadas e medidas isoladas de glicose não são confiáveis em animais agitados, nervosos ou agressivos em decorrência de hiperglicemia por estresse.3 ...
... Usualmente, recomenda-se uma redução de 25 a 50% na dose de insulina, com ajustes subsequentes, de acordo com a resposta clínica e as mensurações de glicose. Caso o veterinário não tenha sido contatado até o horário da próxima aplicação de insulina, a dose não deve ser aplicada.3,4,31 Somente cerca de 30% dos pacientes hipoglicêmicos manifestam algum sinal clínico. ...
Ao final da leitura deste artigo, o leitor será capaz de
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identificar os principais mecanismos diabetogênicos;
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reconhecer um paciente diabético na rotina clínica;
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diferenciar um paciente que necessita de internamento em decorrência de cetoacidose diabética de um paciente que pode iniciar o tratamento em casa;
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indicar a insulinoterapia mais adequada para cada paciente;
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orientar os tutores sobre o adequado manejo de insulinoterapia e controle domiciliar;
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reconhecer a necessidade de pequenos ajustes na terapia;
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identificar as principais complicações do tratamento do DM e sua resolução
... Multifaktöriyel olduğu düşünülen bu hastalıktan pankreatitis önemli derecede sorumlu olup, travma, yangı, enfeksiyon, neoplazi ve otoimmunite pankreas hastalıklarına yol açan başlıca nedenlerdir (9,17,18,38). Langerhans adacıklarındaki hücrelerin köpeklerde şiddetli pankreatitis, kedilerde ise amiloidosis sonucu yıkımlanmaları nedeniyle yeteri miktarda insülin üretilemez. Kronik nüksedici pankreatitiste hem endokrin, hem de ekzokrin hücrelerinin kaybı ve bunların yerini fibröz bağdokunun alması Diabetes mellitusa yol açar (6,9,24). ...
... Klinik Bulgular: Diabet sinsi olarak başlar ve kronik seyreder (9,28). Polidipsi, poliüri, polifaji ile birlikte kilo kaybı, güçsüzlük (10, 14,23,25,34,44,47) ve katarakt (kedilerde nadir) (17,23,38,44,48,49) hastalığın yaygın klinik bulgularıdır. Ancak obez hayvanlarda kilo kaybı gizlidir (9,17,48). ...
... One of the dogs was found to have a ketone body level of 7.4 mmol/L and was diagnosed as diabetic ketoacidosis (DKA) ( Table 1) showed vomiting, cachexia and recumbency. Ketosis and metabolic acidosis can lead to systemic signs like vomiting and anorexia in dogs with DM (Fleeman and Rand, 2001). The dog succumbed to death due to severe ketosis and metabolic acidosis fourth day post treatment. ...
Diabetes mellitus is an endocrinopathy associated with insulin insufficiency or insulin resistance. Three female middle-aged Dachshund dogs presented with clinical signs of polyuria, polydipsia, cataract and emaciation were diagnosed with diabetes mellitus using portable blood glucose monitor. One of the dogs succumbed with diabetic ketoacidosis (ketone bodies of 7.4 mmol/L) with concomitant diabetic nephropathy and hypercalcemia. Leukocytosis, elevated liver enzymes, cholesterol and glycosuria were evident in all the dogs. Blood glucose level was effectively managed with human recombinant DNA protamine zinc insulin administration twice daily for a period of six months.
... Cadelas com DM transitória causadas por fases de diestro e/ou quadros infecciosos uterinos, apresentam grandes chances de apresentar novamente um quadro redicivante de DM em um próximo ciclo, por conta disso sugere-se a gonadectomia como método preventivo e eficaz após o diagnóstico do DM (Fleeman & Rand, 2001;Rand et al., 2004). No presente estudo, após a resolução do quadro a paciente reverteu o quadro para um estado euglicêmico após 3 dias de alta médica, retirou-se insulinoterapia por completo e não apresentou mais manifestações clínicas, evidenciando que quanto mais rápida for a correção, maior a chance da remissão do DM. ...
O diabetes mellitus (DM) é uma das endocrinopatias mais comuns em cães. É considerada uma síndrome multifatorial provocada pela deficiência absoluta ou relativa da insulina, podendo estar ligado a fatores diversos como os genéticos, hormonais, inflamatórios, infecciosos ou até mesmo imunológicos. O presente relato tem como objetivo descrever um caso de uma cadela sem raça definida, com 10 anos de idade, que apresentou quadro de diabetes transitória que cursa com a fase de diestro e uma infecção uterina como principais fatores de resistência insulínica. O tratamento foi realizado com ovarioslapingohisterectomia terapêutica e manejo de insulinoterapia junto de manejo nutricional com alimentação coadjuvante para diabetes. Após o início do tratamento, a paciente demonstrou melhora e remissão completa da condição de hiperglicemia persistente.
... In both dogs and humans, diabetes is a multifactorial disease involving genetic [24,25] and environmental factors [22,26,27]. Although the most frequent form in dogs is caused by autoimmunity, that is, by immune-mediated, rapid, and progressive destruction of beta cells [23]. ...
Diabetes mellitus and pancreatitis are common pancreatic diseases in dogs, affecting the endocrine and exocrine portions of the organ. Dogs have a significant role in the history of research related to genetic diseases, being considered potential models for the study of human diseases. This review discusses the importance of using the extracellular matrix of the canine pancreas as a model for the study of diabetes mellitus and pancreatitis, in addition to focusing on the importance of using extracellular matrix in new regenerative techniques, such as decellularization and recellularization. Unlike humans, rabbits, mice, and pigs, there are no reports in the literature characterizing the healthy pancreatic extracellular matrix in dogs, in addition to the absence of studies related to matrix components that are involved in triggering diabetes melittus and pancreatitis. The extracellular matrix plays the role of physical support for the cells and allows the regulation of various cellular processes. In this context, it has already been demonstrated that physiologic and pathologic pancreatic changes lead to ECM remodeling, highlighting the importance of an in-depth study of the changes associated with pancreatic diseases.
... Poor glycemic control as a result of insulin resistance may occur secondary to an increase in insulin antagonistic hormones associated with growth hormone excess in diestrus-associated diabetes, acromegaly, or excess exogenous progestogens; glucocorticoid excess in spontaneous hyperadrenocorticism or excess exogenous glucocorticoids; or inflammation. [10][11][12][13][14][15] Poor glycemic control may occur in some diabetic dogs due to inadequate duration of action of insulin, especially when intermediate-acting insulin is used. In many diabetic dogs, NPH and lente insulin have adequate duration of action (≥ 12 hours), but in some dogs, duration is less than 8 to 10 hours, resulting in daily periods of hyperglycemia despite appropriate nadir glucose concentrations. ...
OBJECTIVE
This study evaluated the use of detemir for treating diabetic dogs with comorbidities that were poorly controlled with intermediate-acting insulins.
ANIMALS
7 insulin-treated diabetic dogs.
PROCEDURES
Retrospective pilot study. Dogs were treated with detemir for at least 3 months, and glycemia was assessed by the owners at home initially 2 to 4 times daily for 6 to 8 weeks and twice daily thereafter. Clinical evaluations occurred on days 7 to 14, day 30, and then every 60 to 90 days, and dosage adjustments of detemir occurred as needed to control glycemia.
RESULTS
The mean, peak, nadir, morning, and evening preinsulin daily blood glucose concentrations were significantly lower after dosing with detemir for 1, 3, or 6 months and during the last month of treatment compared to the final month of treatment with intermediate-acting insulin. Intermediate-acting insulins resulted in significantly worse glycemic control than detemir in all 3 categories of control. The odds of a biochemical hypoglycemic measurement with detemir were not significantly different compared to intermediate-acting insulins. Clinical hypoglycemia did not occur following detemir treatment. When insulin was withheld because of low morning preinsulin blood glucose concentration < 6.7 mmol/L (≤ 120 mg/dL) and dogs were fed, mean blood glucose concentration was significantly higher 1 hour later. Glucose concentrations were also significantly higher 12 hours later on days when insulin was withheld in the morning or evening for either 1 or 12 hours.
CLINICAL RELEVANCE
Detemir is useful in diabetic dogs with other comorbidities and can be considered an alternative treatment in poorly controlled diabetic dogs.
... The most common laboratory abnormalities in DM are hyperglycemia, glycosuria, increased liver enzymes, hypercholesterolemia and hyperproteinemia. Complications usually occur due to chronic hyperglycemia and less commonly due to ketoacidosis (Aytuğ, 1998;Fleeman et al., 2001;Schaer, 2003). While blood glucose level is usually above 200 mg/dl in symptomatic patients, blood glucose level is between 125-180 mg/dl in asymptomatic diabetic patients (Aytuğ, 1998). ...
... The most common laboratory abnormalities in DM are hyperglycemia, glycosuria, increased liver enzymes, hypercholesterolemia and hyperproteinemia. Complications usually occur due to chronic hyperglycemia and less commonly due to ketoacidosis (Aytuğ, 1998;Fleeman et al., 2001;Schaer, 2003). While blood glucose level is usually above 200 mg/dl in symptomatic patients, blood glucose level is between 125-180 mg/dl in asymptomatic diabetic patients (Aytuğ, 1998). ...
... Thus hyperinsulinemia and impaired glucose tolerance is common in obese dogs, not type 2 diabetes. Having said that, chronic intermittent hyperglycemia does have major negative health impacts in dogs (Fleeman and Rand, 2001;Catchpole et al., 2013). ...
... Therefore, the role of the adaptive immune system in canine DM remains uncertain. It has also been proposed that canine DM might be more similar to human latent autoimmune diabetes of adults (LADA) rather than T1D [16]. This is a more slowly progressive immune-mediated destruction of pancreatic beta cells occurring in combination with other nonimmunological risk factors, leading to reduced beta cell mass and insulin deficiency later in life. ...
Background
Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes.
Methods
The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together.
Results
Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM.
Conclusions
Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified.
... Along with insulin therapy, multivitamins supplement (Multistar Pet™) at 1 tsp/10 kg BW, PO, BID and liver protective silymarin (Silybon™) at 1 tsp/10 kg BW, PO, BID for 2 weeks. The dietary management was suggested as per earlier reports [4] . Routine blood glucose level was monitored using automated glucometer so that hypoglycaemia should not develop. ...
A 9-year-old female mongrel dog was presented to the Teaching Veterinary Clinical Complex, College of Veterinary Sciences and Animal Husbandry, Selesih with a history of polyurea, polydipsia, polyphagia, fatigue, weakness, weight loss and diminished eye vision. Detailed physical and clinical examination revealed mild cachexia, rough hair coat, dehydration, congested conjunctival mucous membrane, tachycardia and tachypnoea. Ophthalmological examination revealed mild bilateral cataract. Haematological findings were within the normal range. Serum biochemistry revealed hyperglycaemia (526 mg/dL) and increased liver-specific enzymes (aspartate aminotransferase and alanine aminotransferase). Qualitative urinalysis revealed glucosuria and ketonuria with very high specific gravity. Based on the physical, clinical and laboratory findings, the case was diagnosed as diabetic ketosis. The case was successfully managed with insulin therapy along with strict dietary suggestions. The blood glucose level came to normal range within 7 days and remained stable till 14 days of post therapy.
... The objective of the therapy in diabetic patients is remission of clinical signs and return to a normal life. Even dogs with compensated diabetes have high blood glucose levels compared with healthy animals and are more prone to the formation of ketoacids and metabolic acidosis (Fleeman & Rand 2001). Similarly to previous data, in the present study, diabetic patients also exhibited significantly higher glucose levels compared with the control group in most of the perioperative period. ...
The aim of this paper was to compare the incidence of anesthetic complications in diabetic and nondiabetic dogs subjected to phacoemulsification. In total, 30 male and female dogs of different breeds were used. The dogs were distributed into two groups: diabetic (DG) (n=15) and control (CG) (n=15). The animals were premedicated with acepromazine (0.03mg/kg) and meperidine (4mg/kg), intramuscularly. After 20 minutes, anesthesia was induced with propofol (2 to 5mg/kg) and maintained with isoflurane. The animals were monitored and the heart rate, respiratory rate, peripheral oxyhemoglobin saturation, end tidal carbon dioxide tension, inspired and expired isoflurane fraction, and invasive arterial pressure were recorded at 10 minute intervals during the surgical procedure. Arterial hemogasometry was performed after anesthetic induction (T0) and at the end of the surgical procedure. Diabetic patients (DG 10±2 years) were older than non-diabetic group (CG 6±2 years). The expired isoflurane fraction after induction was 30% higher in the control group (CG 1.3±0.3%, DG 1.0±0.2%) (p<0.01). The most common anesthetic complication was hypotension. In total, 80% of the diabetic animals (n=12) exhibited mean arterial pressure (MAP) lower than 60mmHg (54±9.6mmHg) after anesthetic induction, and 83% of the hypotensive dogs (n=10) required vasoactive drugs to treat hypotension. Regarding hemodynamic changes, diabetic patients subjected to general anesthesia were more likely to exhibit hypotension which may be due to the response of older animals to the drugs used; however, this change deserves further investigation.
... ; Fleeman veRand, 2001;Rand ve Marshall, 2005). Hiperadrenokortisizmli köpeklerde ise insüline dirençli sekonder diabetes mellitus gelişebilir. ...
Şeker
hastalığının bilimsel adı olan diabetes mellitus sözcüğü, Yunanca’da geçip
gitmek anlamına gelmektedir ve ilk olarak M.S. 1. Yüzyılda Kapadok’ya da
yaşayan ve Roma’lı bir hekim olan Arateus tarafından kullanılmıştır. Ortaçağ
Avrupası’nda, hastanın idrarındaki şekerden dolayı hastalığa ballı şeker
anlamına gelen mellitus adı verilmiştir. Şeker hastalarının idrarının şeker
içerdiğini tadarak belirleyen Thomas Willis 1764’de bu hastalığa ilk kez
Diabetes Mellitus adını vermiştir. Diabetes mellitus karbonhidrat, protein ve
yağ metabolizması bozukluğu ile karakterize, köpeklerde sıkça karşılaşılan
endokrin bir hastalıktır. Metabolizma bozukluğunun şiddetine bağlı olarak
asemptomatik veya polidipsi, poliüri, polifaji, kilo kaybı ve güçsüzlük gibi
klinik semptomlarla karakterize olan hastalık birçok organ ve sistemi
etkilemektedir. Bu derlemede köpeklerde karşılaşılan diabetes mellitustaki
sınıflandırma, etiyoloji, patogenez, klinik bulgular, laboratuar bulguları,
tanı ve sağaltım aktarılmaktadır.
... Alternatively, some diseasecausing genes hitchhiked (i.e., genetic hitchhiking) in the trait selection process, resulting in the enrichment of genes for risk loci associated with chronic diseases such as cancer, epilepsy, and metabolic diseases (e.g., type 2 diabetes mellitus). 11,14,29 The unique genetic makeup of pet animals is proving valuable for identifying these disease-causing genes. Classical genetic tests that assess the statistical association between one or more markers and a trait in unrelated cases and controls (i.e., association studies 30,31 ) are more powerful in inbred as opposed to outbred populations because of the defined genetic differences between breeds. ...
... Frente à diferença significativa entre idade e peso das pacientes com piometra em comparação às pacientes em diestro, foi determinada a correlação linear de Pearson entre leucograma, idade e peso, contra os índices de sensibilidade à insulina calculados [11,13], sendo que na maioria dos casos observa-se que o início da doença está associado ao período de diestro [35]. Contudo, em uma série de casos norte-americanos, encontrou-se resistência à insulina secundária ao diestro em somente 8% dos casos totais [9,19], provavelmente em decorrência da prática da castração ser mais rotineira naquele país. ...
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.
... No presente estudo, 70% (16/23) dos canídeos eram fêmeas e os restantes 30% (7/23) machos, o que demonstra uma maior predisposição do género feminino, numa relação de 2,3 fêmas para 1 macho. Este predomínio do sexo feminino corrobora o citado por outros autores: fêmeas afectadas duas (Fleeman & Rand, 2001;Foster, 1975) a três vezes mais que os machos (Martin & Crump, 2003;Nelson, 2010). No entanto, vários autores Davison et al., 2005;Monroe, 2009;Reusch et al., 2010) referem um decréscimo na proporção de fêmeas de valores acima de 70% para cerca de 50 a 55%. ...
... Frente à diferença significativa entre idade e peso das pacientes com piometra em comparação às pacientes em diestro, foi determinada a correlação linear de Pearson entre leucograma, idade e peso, contra os índices de sensibilidade à insulina calculados [11,13], sendo que na maioria dos casos observa-se que o início da doença está associado ao período de diestro [35]. Contudo, em uma série de casos norte-americanos, encontrou-se resistência à insulina secundária ao diestro em somente 8% dos casos totais [9,19], provavelmente em decorrência da prática da castração ser mais rotineira naquele país. ...
2009. Índices de sensibilidade à insulina em fêmeas caninas: efeito do ciclo estral e da piometra. Acta Scientiae Veterinariae. 37(4): 361-370. Acta Scientiae Veterinariae. 37(4): 361-370, 2009. Índices de sensibilidade à insulina em fêmeas caninas: efeito do ciclo estral e da piometra Insulin sensitivity indexes in female dogs: effect of estrus cycle and pyometra
... Occasional mistakes in insulin storage, handling or dosage were also taken , but the owner has a large experience with the treatment and no failures were identified[10]. Based on the latest blood work and clinical history[10,22,23], the dog was under perfect diabetes control by means of two injections of NPH insulin (0.5U/kg), associated with two meals of an adequate commercial food every 12 hours, before the development of polyuria, polydipsia and increased glycosuria, indicating that there was something wrong going on[24].Meanwhile, CBC showed a marked inflammatory reaction with important neutrophilia and active monocytes, and after evaluation of the case, the only obvious inflammatory reaction was located in the mouth(Figure 1). Interestingly enough, while bacterial infections are often associated with insulin resistance, periodontitis, one of the most prevalent bacterial conditions in veterinary practice, has not been associated with it[1,10,21,25]. ...
The purpose of this work was to report a clinical case of a spayed, 13-year-old diabetic poodle on insulin therapy with insulin resistance and poor diabetes control secondary to severe periodontitis. Prior to establishing the periodontal surgical approach, the insulin dose needed to be increased to stabilize the patient. Periodontal treatment included the extraction of 19 teeth. After periodontitis treatment, the insulin dose could be reduced to the previous effective dose. To our knowledge, this is the first case report of insulin resistance due to periodontal disease in dogs.
... The aetiology and underlying pathogenesis of canine IDD has not been fully determined, although exocrine pancreatic disease [5,6] and immune-mediated mechanisms [7] are suspected to be underlying causes of pancreatic beta cell destruction. It has been also been suggested that, in many ways, canine diabetes resembles latent autoimmune diabetes of the adult (LADA) in man [8], a more slowly progressive form of autoimmune diabetes. ...
Background:
Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility.
Results:
Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds.
Conclusions:
Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds.
... As pancreatitis appears to be a common cause of diabetes in dogs (Alejandro et al., 1988), this relationship between obesity and pancreatitis in dogs has relevance to the pathogenesis of canine diabetes . The majority of diabetic dogs appear to have a form of type 1 diabetes analogous to the latent auto-immune diabetes of adults (LADA) in humans ( Fleeman and Rand 2001). At least 50% of diabetic dogs would be classified as type 1, because this proportion has been shown to have antibodies against beta cells (Hoenig and Dawe 1992, Elie and Hoenig 1995, Davison et al., 2003 The remainder probably has 'other specific types of diabetes' resulting from pancreatic destruction or chronic insulin resistance, or they have diestrus-induced diabetes . ...
A study was conducted on the dogs with moderate to serious illness coming for treatment
at the Dog Ward of West Bengal University of Animal and Fishery Sciences, West Bengal, India, to
find out possible correlation between fasting blood sugar level with breed, sex and age of dogs. The
study result implicated that the blood sugar level was not having any general tendency to increase
with advancement of age of ailing dogs. The blood sugar level of ailing dogs was higher in small
breeds of dogs, particularly in 0 to <4 year age group. The large breeds showed highest level of sugar
in blood in disease condition at above the age 12 years or more. The blood sugar level of ailing dogs
had a gender bias, as it was found more in females than males in all breeds and age groups.
Background:
Periodontal disease (PD) can adversely affect glycaemic control in humans. However, it is unknown if a similar association exists in dogs.
Methods:
Ten client-owned dogs with poorly regulated diabetes mellitus (DM) and PD were prospectively enrolled. A complete blood count, serum biochemistry, urinalysis and measurement of C-reactive protein, interleukin-6 (IL-6), tumour necrosis factor-α, haemoglobin A1c (HbA1c) and fructosamine concentrations were performed before periodontal treatment (PT) and monthly thereafter for 3 months. A periodontal disease severity score (PDSS) was determined during PT. The effects of time post-PT and PDSS on markers of inflammation and glycaemic control were determined by generalised estimating equation analysis.
Results:
HbA1c (mean; 95% confidence interval [CI]) decreased 3 months post-PT (32.1 mmol/mol; 21.1-43.1 mmol/mol vs. 44.3 mmol/mol; 36.4-52.0; p = 0.003). PDSS at enrolment was significantly (p = 0.031) positively associated with HbA1c concentration. Due to a significant (p < 0.001) interaction between PDSS and time post-PT in the analysis of fructosamine, dogs with low (1-3) PDSS and high (7-9) PDSS were analysed separately. Fructosamine (mean; 95% CI) significantly decreased 1 month post-PT (570 μmol/L; 457-684 μmol/L vs. 624 μmol/L; 499-748; p = 0.001) in the high PDSS group but not in the low PDSS group. Fructosamine concentration upon enrolment and PDSS were correlated (r = 0.73, p = 0.017). IL-6 concentration significantly decreased 3 months post-PT (9.9 pg/mL; 8.5-11.3 pg/mL vs. 11.2 pg/mL; 9.7-12.7; p = 0.002).
Limitations:
Limitations of the study included the small number of dogs, the lack of a control group and the inability to assess PDSS during follow-ups.
Conclusions:
These findings support a potential detrimental interaction between PD and DM. The apparent beneficial effect of PT on markers of glycaemic control was most conspicuous in dogs with more severe PD.
Insulin induced hypoglycemia (IIH) is common in veterinary patients and limits the clinician's ability to obtain adequate glycemic control with insulin therapy. Not all diabetic dogs and cats with IIH exhibit clinical signs and hypoglycemia might be missed by routine blood glucose curve monitoring. In diabetic patients, counterregulatory responses to hypoglycemia are impaired (lack of decrease in insulin levels, lack of increase in glucagon, and attenuation of the parasympathetic and sympathoadrenal autonomic nervous systems) and have been documented in people and in dogs but not yet in cats. Antecedent hypoglycemic episodes increase the patient's risk for future severe hypoglycemia.
Seekor anjing betina ras Pug berumur empat tahun dengan bobot badan 4,5 kg menunjukkan tanda klinis berupa poliuria, polidipsia, polipagia, dan penurunan bobot badan yang sangat signifikan dalam waktu tiga bulan setelah melahirkan. Pemeriksaan biokimia darah menunjukkan adanya peningkatan kadar glukosa dalam darah hingga 669 mg/dL dan pengujian dipstick urin menunjukkan adanya glukosa di dalam urin dengan hasil ? 2000 mg/dL. Anjing didiagnosis mengalami diabetes mellitus. Hewan kasus diberikan terapi berupa penggantian pakan menggunakan pakan khusus diabetik (Royal Canin Diabetic food ®) dan injeksi insulin glargine dengan dosis 0, 44 IU/kg BB dua kali sehari sebelum makan. Setelah dua minggu terapi, anjing kasus menunjukkan perkembangan yang baik yang ditunjukkan dengan menurunnya kadar glukosa darah menjadi 163 mg/dL dan menurunnya gejala klinis berupa poliuria, polidipsia, dan polipagia, walaupun bobot badan belum berhasil dipulihkan sepenuhnya.
Toxicological Effects of Veterinary Medicinal Products in Humans is the first definitive guide to discuss the adverse effects of veterinary medicinal products in humans. The chapters focus on occupational safety and consumer issues and examine the circumstances under which exposure is likely to occur. To be in context, it reviews this against the background of adverse health effects from other sources in the veterinary and farming professions. The book examines adverse drug effects reported to regulatory agencies (mainly the FDAÆs Center for Veterinary Medicine) and then considers a series of individual drugs, including antibiotics, anaesthetics and organophosphorus compounds. The chapters also discuss the fundamental aspects of regulatory issues relating to safety assessment, and examine the manner in which user safety is assessed prior to authorisation/approval and what measures can be taken after authorisation/approval in the light of findings from pharmacovigilance activities. There is growing concern over the issue of antimicrobial resistance and the contribution made by veterinary medicinal products. This too is addressed along with the significance to human health and measures that can be taken to mitigate the effects (if any) of the use of antibiotics in animals e.g. prudent use measures. The book will be an essential resource for medical practitioners in hospitals and general practice, pharmaceutical industry scientists, analysts, regulators and risk managers.
This two-part article discusses the mechanisms by which genetic variation can influence the risk of complex diseases, with a focus on canine diabetes mellitus. In Part 1, presented here, the importance of accurate methods for classifying different types of diabetes will be discussed, since this underpins the selection of cases and controls for genetic studies. Part 2 will focus on our current understanding of the genes involved in diabetes risk, and the way in which new genome sequencing technologies are poised to reveal new diabetes genes in veterinary species.
In addition to energy production, glucose makes an important contribution to serum osmolarity, influencing fluid distribution throughout the body. Within the pancreatic beta-cells, glycolysis results in ATP production, providing the energy to release insulin into the blood by exocytosis. The majority of glucose uptake in peripheral tissue occurs in muscle, where it is used immediately for energy or stored as glycogen. Discovering fluctuations in blood glucose can afford insight into the metabolic activity of the patient while providing direction for therapeutic intervention and minimizing complications. Continuous glucose monitoring (CGM) is possible with interstitial glucose monitors. The complete blood count (CBC), serum biochemical profile and urinalysis are important to identify disorders known to be associated with alterations in blood glucose. The assessment of plasma insulin concentrations compared to plasma glucose will aid in the diagnosis of insulinoma. Diabetes mellitus is a metabolic disease causing high blood sugar over a prolonged period of time.
This chapter discusses the pathogenesis, classical signs, diagnosis, and treatment for canine diabetes mellitus. In dogs, multiple underlying pathological processes result in diabetes and the most common are type 1, other specific types of diabetes, and diestrual. Evidence is mounting for a genetic basis for canine diabetes mellitus. Diabetes caused by chronic pancreatitis is the result of an absolute insulin deficiency due to extensive inflammatory destruction of pancreatic tissue. Diabetic dogs classically present with polyuria, polydipsia, weight loss, an increased appetite, and lethargy. Diagnosis of diabetes mellitus is based on the presence of hyperglycemia and glucosuria with compatible clinical signs. The majority of diabetic dogs that present with diabetic ketoacidosis have at least one concurrent disease, with acute pancreatitis being the most common. Management of acute pancreatitis is primarily directed at the various clinical sequelae.
Diabetes is among the most frequently diagnosed endocrine disorder in dogs and its prevalence continues to increase. Medical management of this pathology is lifelong and challenging because of the numerous serious complications. A therapy based on the use of autologous viable insulin-producing cells to replace the lost β cell mass would be very advantageous.
A protocol to enable the epigenetic conversion of canine dermal fibroblasts, obtained from a skin biopsy, into insulin-producing cells (EpiCC) is described in the present manuscript. Cells were briefly exposed to the DNA methyltransferase inhibitor 5-azacytidine (5-aza-CR) in order to increase their plasticity. This was followed by a three-step differentiation protocol that directed the cells towards the pancreatic lineage. After 36 days, 38 ± 6.1% of the treated fibroblasts were converted into EpiCC that expressed insulin mRNA and protein. Furthermore, EpiCC were able to release insulin into the medium in response to an increased glucose concentration. This is the first evidence that generating a renewable autologous, functional source of insulin-secreting cells is possible in the dog. This procedure represents a novel and promising potential therapy for diabetes in dogs.
A continuous glucose monitoring system (Seven® Plus Dexcom, DM3, Nintamed GmbH & Co. KG, D) was implanted in twenty cats and eight dogs suffering from diabetes mellitus. Glucose concentration in interstitial fluid was measured every five minutes for at least 24 hours and allowed for assessing insulin response, insulin dose and verification of diagnosis in addition to serum fructosamine levels. In animals with fructosamine levels within physiological range reflecting good diabetes management, continuous glucose monitoring however revealed hyper- and hypoglycaemic phases. Moreover, even animals with increased fructosamine levels showed hypoglycaemic periods over several hours. CGMS (continuous glucose monitoring systems) are important additives for specifying details based solely on fructosamine levels or single blood glucose concentrations. Especially in complicated cases management of diabetic patients can be improved.
Blood glucose curves in the management for diabetic patients have several limitations including intermittent assessment of blood glucose concentration, hospitalization, patient restraint, and repeated phlebotomy. The aim of this study was to apply and evaluate a wireless continuous glucose monitoring system (CGMS) in healthy dogs. Subcutaneous interstitial glucose concentrations in 7 dogs were continuously monitored and recorded by wireless CGMS. During induced hyperglycemia, the interstitial glucose concentrations were compared with whole blood glucose concentrations measured by glucometer and serum glucose concentrations measured by automated chemistry analyzer, respectively. There were no significant differences among interstitial, whole blood and serum glucose concentrations. The interstitial glucose concentrations had a good correlation to serum glucose concentrations. The real-time wireless CGMS is a valuable tool for monitoring system of glucose concentrations in dogs. Use of the CGMS for diabetic patients will provide accurate information over traditional blood glucose curves.
Pancreatic islet transplantation is a cell-based therapy that provides a potential cure for type 1 diabetes mellitus. After the introduction of an automated method for islet isolation and steroid-free immunosuppressive protocols, reversal of diabetes by islet transplantation is now performed at major human medical centers around the world. Despite extensive use of animal models in islet transplantation research, practical concerns have slowed the introduction of the technique into clinical veterinary practice and only a small number of studies have reported results of transplantation in dogs with spontaneously occurring diabetes mellitus; however, recent advances in islet isolation and encapsulation may make it possible to perform islet transplantation without immunosuppression in companion animals. This review summarizes experimental and clinical studies of pancreatic islet transplantation in dogs, including future directions for cell therapy in animals with naturally occurring disease.
The objective of this study was to report owner experiences and satisfaction in treating a pet with diabetes mellitus using a descriptive report from an Internet-based survey. Descriptive analysis of results was performed, χ(2) tests were used to detect differences in responses between dog and cat owners, and correlations were assessed using the nonparametric Spearman rank correlation. A total of 834 owners participated in the survey. More diabetic dogs (97%) than cats (82%) were treated with insulin injections. Insulin was administered twice daily in 87% of dogs and 73% of cats. Porcine lente and neutral protamine Hagedorn were the most commonly administered insulins in dogs. In cats, glargine and protamine zinc insulin were the most commonly used insulins. Most pets were not fed a prescribed diabetes diet. More cat (66%) than dog (50%) owners were satisfied with the diabetic control achieved. Cat owners were more likely to use home blood glucose monitoring. Treatment was considered expensive by the majority of owners. Few published reports follow diabetic pets after diagnosis or report owner satisfaction. The results of this study provide useful information that may help veterinarians better educate owners and set expectations regarding diabetes treatment and quality of life for diabetic pets.
Pharmacists can play a valuable role in providing care and preparations for all species of patients with diabetes. Practical knowledge of the differences in diabetes between animals and humans is essential to providing diabetic care to multiple species. Pharmacists should familiarize themselves with the clinical signs of hyperglycemia and hypoglycemia in various species and be prepared to provide appropriate counseling, information, preparations, devices, and referral when signs of inadequate glycemic control arise. Pharmacists also should develop awareness of potential problems associated with the use of human diabetic preparations in animal patients. By maintaining a current knowledge of care for diabetic pets, including the significance of the patient's dietary habits, medical history, and genetics, and species-specific drug reactions, the compounding pharmacist can contribute, through collaboration with veterinarians and pet caregivers, to optimal patient outcomes when providing care for pets with diabetes.
Canine diabetes mellitus has increased in southern Brazil. In the etiology, obesity, sedentary life and stress appear to be the main factors. After diagnosis is recommended to identify concurrent diseases that cause glucose intolerance. For this purpose, serum biochemical profile, urinalysis and complete blood count (CBC) must be determined. The aim of this study was to identify the most common clinical pathological changes in diabetic dogs from an university veterinary hospital in southern Brazil, and to establish fructosamine reference values. Ten diabetic female dogs attended at the veterinary hospital were included in this study to perform CBC, biochemical assays and urinalysis. Creatinine, urea, ALT, AST, GGT, ALP, albumin, total protein, globulins, cholesterol, triglycerides, β-OH-butyrate, pancreatic amylase, glucose and fructosamine were measured in serum. Twenty-five healthy dogs were used as control for values. CBC showed leucocytosis in 30% of diabetic dogs. Glycosuria was observed in all dogs. Proteinuria (50%), ketonuria (40%) and high urine density in 30% of the animals, were the main alterations of urine in diabetic dogs. Serum glucose and cholesterol concentrations were above reference values in all diabetic dogs. Triglycerides were higher than control dogs in 90% of diabetic dogs. High values of total protein (70%), ALP (70%), GGT (50%), ALT and β-OH-butyrate (40%) were observed in diabetic dogs. Control group had a mean fructosamine concentration of 1.53 mmol/L ± 0.27. In diabetic dogs the fructosamine average was 3.24 mmol/L ± 1.16.
Type 1 diabetes mellitus is one of the most frequently diagnosed endocrinopathies in dogs, and prevalence continues to increase. Pancreatic islet transplantation is a noninvasive and potentially curative treatment for type 1 diabetes mellitus. Institution of this treatment in dogs will require a readily available source of canine islets. We hypothesized that clinically acceptable islet yield and purity could be achieved by using deceased canine donors and standard centrifugation equipment. Pancreata were procured from dogs euthanized for reasons unrelated to this study. Initial anatomic studies were performed to evaluate efficacy of pancreatic perfusion. Infusion into the accessory pancreatic duct resulted in perfusion of approximately 75% of the pancreas. Additional cannulation of the distal right limb of the pancreas allowed complete perfusion. Collagenase digestion was performed with a Ricordi chamber and temperature-controlled perfusion circuit. Islets were separated from the exocrine tissue with the use of a discontinuous density gradient and a standard laboratory centrifuge. After isolation, islet yield was calculated and viability was assessed with dual fluorescent staining techniques. Islet isolation was completed in 6 dogs. Median (interquartile range) islet yield was 36,756 (28,527) islet equivalents per pancreas. A high degree of islet purity (percentage of endocrine tissue; 87.5% [10%]) and viability (87.4% [12.4%]) were achieved. The islet yield achieved with this technique would require approximately 1 pancreas per 5 kg body weight of the recipient dog. Purity and viability of the isolated islets were comparable with those achieved in human islet transplantation program. According to initial results, clinically relevant islet yield and quality can be obtained from deceased canine donors with the use of standard laboratory equipment.
Diabetes diets should aim at ensuring an ideal body weight with normoglycemia and normolipidemia. The consensus recommendations of various diabetes associations suggest that these goals are most likely to be achieved by diets high in complex carbohydrates and fiber and low in fat. A typical diabetes diet containing 55-60% energy as carbohydrate (at least 66% complex), less than 30% energy as fat, 0.8 g.kg-1 desirable body wt.day-1 protein, and approximately 40 g fiber/day, improves glycemic control, reduces levels of serum atherogenic lipids, decreases blood pressure in those with hypertension, and reduces body weight in the obese. This diet also reduces insulin requirements in the insulin-treated patient and can promote discontinuation of insulin therapy in those with non-insulin-dependent diabetes mellitus. This article presents our experience with high-fiber high-carbohydrate diets and reviews knowledge on the likely mechanisms of action of fiber, its long-term effectiveness, and the concerns about its long-term safety. We suggest that reports on the risk of hypertriglyceridemia from on the risk of hypertriglyceridemia from high-carbohydrate diets are inconsistent and invalidated if those diets are also high in fiber content. Similarly, we urge some caution in prescribing high-monounsaturated fat diets as an alternative to high-carbohydrate diets, at least until the long-term implications of the former are clearer. We believe that there is no compelling reason to change the current diabetes diets, which should continue to be high in carbohydrate and fiber content.
Erythrocyte insulin receptor binding measurements were evaluated in 8 dogs with spontaneous hyperadrenocorticism. These dogs had normal serum glucose concentration, with normal to high serum insulin concentration (range, 45 to 1,400 pmol/L; normal, 40 to 170 pmol/L). Dogs with hyperadrenocorticism had significant (P less than 0.01) decrease in mean +/- SEM percentage of maximal binding for erythrocyte insulin receptors (2.25 +/- 0.21%), compared with results in 11 clinically normal pet dogs (4.29 +/- 0.42%). The decrease in erythrocyte receptor binding was attributed to significant (P less than 0.01) decrease in high-affinity receptor sites in dogs with hyperadrenocorticism (14.5 +/- 2.8), compared with clinically normal dogs (31.2 +/- 4.3). Significant differences in receptor affinity were not apparent between the 2 groups. Percentage of maximal binding for erythrocyte insulin receptors for dogs with hyperadrenocorticism was inversely correlated with serum insulin concentration (r = -0.85, P less than 0.01). Results indicate that the observed decrease in erythrocyte insulin receptor binding could contribute to insulin resistance and hyperinsulinemia associated with hyperadrenocorticism. Alternatively, decreased binding of insulin receptors in animals with hyperadrenocorticism may result from down-regulation secondary to hyperinsulinemia itself caused by insulin resistance at a postreceptor site (decreased responsiveness).
A case-control study of spontaneous diabetes mellitus in dogs was undertaken, using 2 veterinary data bases. The Veterinary Medical Data Program (VMDP) contained records of 1,019 cases of canine diabetes from 14 university-affiliated veterinary hospitals. The Animal Medical Center (AMC), a private veterinary hospital which has not participated in the VMDP, contained records of 449 diabetes cases. Each data base was analyzed separately, control groups being chosen from all admissions, excluding diabetic animals. Summary odds ratios by sex adjusted for age and breed indicated significantly (P less than 0.05) elevated risks for entire females and neutered females compared with that for entire males. The VMDP data indicated a significantly elevated risk for castrated males, whereas the risk derived from AMC data was not significantly different from 1. Analysis of risks by breed adjusting for age and sex identified Poodles as being at significantly excess risk, and German Shepherd Dogs, Cocker Spaniels, Collies, and Boxers at significantly decreased risk in both data sets. The male-female risk ratio changed with age from 1 at less than 1 year of age to a predominance of females at older ages. In the AMC data base, diabetes was significantly associated with cataracts in dogs of both sexes combined. Diabetes was also significantly associated with benign mammary tumors in female dogs.
To assess the characteristics of patients with hypoglycemia unawareness (development of neuroglycopenia without appropriate prior autonomic warning symptoms) and its predisposing factors.
We studied 43 insulin-dependent diabetes mellitus patients who were objectively categorized as having or not having hypoglycemia using the stepped hypoglycemic clamp technique in which plasma glucose was clamped at plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l and a statistical criterion (onset of autonomic warning symptoms at a plasma glucose concentration 2 SD below normal) and examined their clinical characteristics and hormonal, symptomatic, and cognitive responses.
Eleven (26%) of the patients were classified as having hypoglycemia unawareness. Compared with the other patients, unaware patients had a lower HbA1c level (P < 0.01), a longer duration of diabetes (P < 0.01), and a history of more severe hypoglycemia (P < 0.003). During experimental hypoglycemia, counterregulatory hormone responses, neuroglycopenic symptoms, and cognitive dysfunction all began at lower plasma glucose concentrations in unaware patients (P < 0.01, 0.03, and 0.01, respectively). Moreover, although the magnitudes of their plasma catecholamine responses and autonomic symptoms were reduced (both, P < 0.01), the plasma catecholamine levels at which autonomic symptoms began was not altered. Finally, as seen from glucose infusion rates necessary to maintain identical plasma glucose levels, patients with hypoglycemia unawareness had increased sensitivity to insulin (P < 0.001).
Our results confirm an association between hypoglycemia unawareness and duration of diabetes, glycemic control, and occurrence of severe hypoglycemia, and in addition provide evidence that both autonomic and neuroglycopenic symptoms are affected and that insulin sensitivity is increased, but beta-adrenergic sensitivity is not diminished.
Proinsulin is converted to insulin and C-peptide in the pancreatic beta cells: the latter two peptides are secreted in equimolar concentrations. Thus, measurements of serum C-peptide provide a means of assessing pancreatic beta cell function in addition to that of insulin. This technique has proved particularly useful in insulin treated diabetic patients in whom the development of circulating insulin antibodies interferes with the radioimmunoassay of the hormone. The C-peptide assay has also been used to facilitate the diagnosis of various hypoglycemic conditions, including islet cell tumors and factitious injection of insulin. The extraction of C-peptide in the urine reflects average serum values over a period of time and urine C-peptide measurements are especially useful in children or individuals in whom repeated blood sampling is difficult.
(Arch Intern Med 137:625-632, 1977)
While there is no single diagnostic approach, other than direct examination of the pancreas, that is completely reliable for the diagnosis of pancreatitis, a presumptive diagnosis of acute pancreatitis can be made with a good degree of confidence by careful evaluation of the entire clinical picture - history and clinical signs, results of physical examination, abdominal imaging and laboratory testing. The approach to treatment is to rest the pancreas, by withholding food, while providing general supportive care by fluid therapy including, in severe cases, plasma transfusion to replace plasma protease inhibitors and albumin. Additional specific interventions in an effort to halt the progression of spontaneous pancreatitis have not yet been shown to be effective, but control of obesity and avoidance of high fat diets may help prevent pancreatitis or lessen its severity when it occurs. Pancreatitis is an unpredictable disease of widely varying severity. While many patients with uncomplicated pancreatitis recover spontaneously following several days of supportive care, other patients die in spite of prolonged intensive care.
Cardiovascular and metabolic parameters were evaluated in 15 female spayed dogs before and after they became obese on either a saturated fat (LD, lard, n=8) or unsaturated fat (CO, corn oil, n=7) diet. Body weight and body fat increased significantly in both groups, although no differences occurred between diet groups. Dogs receiving the LD diet exhibited a greater increase in mean arterial pressure than those receiving the CO diet (p<0.01; 15.9 +/- 2.1 vs. 9.8 +/- 3.3 mm Hg increase). The CO diet stimulated a greater increase in heart rate than the LD diet (p<0.05; 32.8 +/- 7.8 vs. 14.1 +/- 5.8 bpm increase). Ganglionic blockade with chlorisondamine caused an increase in HR in both lean groups and in the obese CO group, but not the obese LD group, consistent with a decrease in parasympathetic tone to the heart in the dogs overfed saturated fat. Obesity enhanced the heart rate response to beta-adrenergic stimulation by isoproterenol in the LD, but not CO group. The LD diet increased circulating insulin and decreased insulin sensitivity, whereas the CO diet had no effect on either parameter. These findings suggest that the composition of dietary fat can modulate the autonomic and metabolic adaptations induced by dietary obesity.
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.
Intermittent low-dose heparinised saline flushes were found to be efficacious for maintaining patency of indwelling peripheral and central intravenous catheters in diabetic dogs. The catheters were flushed with 1 mL of 1 U/mL heparinised saline every two hours immediately following blood sample collection, or every 12 hours when not being used for sampling. Central catheters were flushed with saline solution first to clear the line before instillation of the heparinised saline. Patency of 54/57 (95%) of the peripheral catheters and 30/32 (94%) of the central catheters was achieved for up to 36 hours and five days, respectively. No phlebitis, or local or systemic infections were observed and, in each case, catheter failure was attributable to obstruction or extravasation. It is unlikely that there will be any contraindications to this flushing technique and its introduction may improve intravenous catheter survival and reduce catheter-associated complications in hospitalised dogs.
Proinsulin is converted to insulin and C-peptide in the pancreatic in the pancreatic beta cells: the latter two peptides are secreted in equimolar concentrations. Thus, measurements of serum C-peptide provide a means of assessing pancreatic beta cell function in addition to that of insulin. This technique has proved particularly useful in insulin treated diabetic patients in whom the development of circulating insulin antibodies interferes with the radioimmunoassay of the hormone. The C-peptide assay has also been used to facilitate the diagnosis of various hypoglycemic conditions, including islet cell tumors and factitious injection of insulin. The extraction of C-peptide in the urine reflects average serum values over a period of time and urine C-peptide measurements are especially useful in children or individuals in whom repeated blood sampling is difficult.
The immunologie properties of homologous and heterologous insulins have been investigated. Pigs, dogs, cows, sheep, goats, rabbits, guinea pigs, and rats were immunized with different hormone preparations alone or in combination with complete Freund adjuvant. The results obtained provide convincing evidence that in pigs homologous insulin cannot produce specific antibodies, whereas heterologous insulin can. Because the insulins of dogs and pigs have identical amino acid sequences, no antigenicity of porcine insulin in dogs could be observed either.
In cattle, sheep, and goats, not only heterologous but also homologous insulins stimulated antibody production. Sheep and goats proved to be excellent reactor animals.
Most of the small laboratory animals developed specific antibodies against insulin after hyperimmunization. In rabbits, not only the groups injected with nonchromatographed bovine insulin but also those hyperimmunized with single-component bovine insulin responded with a high serum level of specific antibodies. The data suggest that highly purified insulin preparations have not less antigenic activity than nonchromatographed insulin. Immunologically, des-Phe-B1-insulin acted exactly like the original hormone.
Histologie examination of the pancreases of 45 pigs, 22 of which had high antibody titers, did not reveal insulitis. The results of the present paper point out that the production of specific antibodies is essentially a question of species specificity.
A 10-year-old male Miniature Poodle was found to have clinical diabetes mellitus. The patient's dam had died from diabetes. Two 4-year-old dogs, produced from a mating between the patient and its dam, were examined and an oral glucose tolerance test was performed on each. One dog had striking glucose intolerance and was considered to be prediabetic.
Long-term euglycemia by intraperitoneal transplantation of microencapsulated islets has not been described in the diabetic large animal model. In this study, we report the successful long-term reversal of diabetes by this method in spontaneous diabetic dogs. We have identified fundamental mechanism(s) associated with alginate-based microcapsule fibrosis, and have devised methods to ameliorate this problem. These include the use of purified alginate of low mannuronic acid content and cytokine suppression. Ten insulin-dependent, spontaneous diabetic dogs (insulin requirement 1-4 units/kg/day; absence of circulating C-peptide and diabetic K-values of 0.6 +/- 0.4) were entered into the study. Islets from mongrel donor pancreata were isolated and transplanted intraperitoneally either as free islet controls (n = 3) or as microencapsulated islet allografts (n = 7). In all seven encapsulated islet recipients, euglycemia was achieved within 24 hr (serum glucose failing from 304 +/- 117 to 116 +/- 72 mg/dl). IVGTT performed 14 days after islet transplant demonstrated normalization of K-values changing from a pretransplant level of 0.6 +/- 0.4 to 2.6 +/- 0.6. All animals receiving encapsulated islets remained euglycemic, free of the need for exogenous insulin, for a period of 63-172 days, with a median insulin-independence for 105 days. In contrast, recipients receiving free islets rejected their graft within seven days of implantation. In conclusion, this is the first report of long-term successful reversal of spontaneous diabetes in the large animal model by an intraperitoneal injection of encapsulated islets. The potential exists for this form of therapy to be explored in the treatment of type I diabetes in man.
Purified beta cells from a radiation-induced transplantable rat insulinoma were used to detect beta cell antibodies in serum from untreated diabetic dogs. Serum from dogs in which anti-beta cell antibodies were induced by injecting a purified beta cell suspension subcutaneously was used as positive control. Following incubation with test sera, fluorescein-labeled anti-dog immunoglobulins were used to visualize binding between the beta cells and dog gamma globulins. Nine of the 23 diabetic dogs showed a strongly positive reaction which was characterized by a ring fluorescence, three showed a weak reaction and 11 were negative, i.e. they showed diffuse fluorescence. In contrast, 14 of the 15 healthy dogs showed diffuse fluorescence and one dog showed a weakly positive reaction. Thyroid, liver and kidney cells did not elicit ring fluorescence. Although females (spayed and intact) represented the majority of the diabetic dogs, there was no correlation between sex and the occurrence of antibodies in the diabetic dogs. There was also no correlation to the age of the dogs. In conclusion, we have developed a specific test for anti-beta cell antibodies. The test is reproducible and economical to perform on a large number of samples.
The effect of a high insoluble-fiber ( if ) diet containing 15% cellulose in dry matter, high soluble-fiber ( sf ) diet containing 15% pectin in dry matter, and low-fiber ( lf ) diet on glycemic control in 6 dogs with alloxan-induced insulin-dependent diabetes mellitus was evaluated. Each diet contained > 50% digestible carbohydrate in dry matter. A crossover study was used with each dog randomly assigned to a predetermined diet sequence. Each dog was fed each diet for 56 days. Caloric intake was adjusted weekly as needed to maintain each dog within 1.5 kg of its body weight measured prior to induction of diabetes mellitus. All dogs were given pork lente insulin and half of their daily caloric intake at 12-hour intervals.
Mean (± sem ) daily caloric intake was significantly ( P < 0.05) less when dogs consumed the if diet vs the sf and lf diets (66 ± 3 kcal/kg, 81 ± 5 kcal/kg, and 79 ± 4 kcal/kg, respectively). Serum alkaline phosphatase activity was significantly ( P < 0.05) higher when dogs consumed the lf diet vs the if and sf diets (182 ± 37 IU/L, 131 ± 24 IU/L, and 143 ± 24 IU/L, respectively). Mean postprandial plasma glucose concentration measured every 2 hours for 24 hours, beginning at the time of the morning insulin injection, was significantly ( P < 0.05) lower at most blood sampling times in dogs fed if and sf diets, compared with dogs fed the lf diet. As a result, 24-hour mean plasma concentration of glucose ( if , 165 ± 17 mg/dl; sf , 169 ± 19 mg/dl; lf , 218 ± 29 mg/dl), 24-hour mean plasma-glucose fluctuation ( if , 49 ± 2 mg/dl; sf , 47 ± 4 mg/dl; lf , 63 ± 7 mg/dl), and 24-hour urine-glucose excretion ( if , 31 ± 10 g/d; sf , 42 ± 16 g/d; lf , 67 ± 13 g/d) were significantly ( P < 0.05) lower in dogs fed if and sf diets, compared with dogs fed the lf diet. These variables were not significantly different between dogs fed if and sf diets. Mean glycosylated hemoglobin concentration also was significantly ( P < 0.05) lower when dogs consumed the if diet, compared with the lf diet (4.3 ± 0.4% vs 5.2 ± 0.4%, respectively).
In dogs with alloxan-induced insulin-dependent diabetes mellitus, consumption of diets containing 15% cellulose or 15% pectin and > 50% digestible carbohydrate on a dry-matter basis resulted in improvement in glycemic control, compared with consumption of a diet containing > 50% digestible complex carbohydrate without added fiber.
There is considerable variation among bitches in commonly encountered intervals between cycles (5-12 months), durations of anoestrus (1-8 months), durations of follicular phase pro-oestrus (3-21 days) and periovulatory oestrous behavior (3-21 days), intervals from preovulatory LH surge to oestrus onset (-2 to 5 days), and intervals from fertile mating to parturition (57-68 days). The extent of variation within bitches ranges from slight to great. However, there appears to be very little variation in the intervals from LH surge to ovulation (2 days), to post-ovulatory oocyte maturation (approximately 4 days), to implantation (approximately 18 days), to selected developmental stages of pregnancy, or to parturition (64-66 days). There are no tests diagnostic of early pregnancy. The onset times of persistent pregnancy-specific changes have been estimated, including radio-opaque fetal details (Day 46), elevated blood prolactin values (Day 35), elevated blood relaxin values (Day 25), echogenic heart beats (Day 24) and embryonic vesicles (Day 19), and potentially palpable uterine enlargements (Day 21). As in humans, there is an anaemia of pregnancy involving a 30% reduction in haematocrit and an increased incidence of insulin resistance during the second half of gestation. Ovarian progesterone is required throughout pregnancy. LH and prolactin are luteotrophic in the pregnant bitch as well as during the 2-month luteal phase of the non-pregnant bitch. Parturition follows a luteolysis which occurs during an increase in prostaglandin F-2 alpha that begins 36 h pre partum. Factors regulating the duration of anoestrus are not known but termination of anoestrus is associated with increased pulsatile secretion of LH.
In contrast to the large variation in canine gestation lengths based on mating-to-whelping intervals (56 to 70 days), gestation length based on intervals from the preovulatory LH surge to whelping shows little variation (64 to 66 days). By considering the preovulatory LH surge as the central endocrine event of the fertile cycle, various events can be reasonably timed, including ovulation on day 2, oocyte maturation on day 4, reduced fertility after day 6, implantation around day 17, and development of fetal radiopacity after day 45. Throughout pregnancy, gestation is dependent on ovarian progesterone secretion and, thus, on pituitary LH and prolactin for luteotrophic support. Because prostaglandin F2 alpha is luteolytic in the bitch, it may be involved in the luteolysis observed immediately prepartum in association with rises in maternal cortisol and prolactin levels.
Histopathologic and immunocytochemical alterations in the pancreas of 18 dogs with spontaneous diabetes mellitus were evaluated. In 5 of 18 dogs (28%), extensive pancreatic damage appeared to be responsible for the development of diabetes mellitus. In the other 13 dogs, there was substantial reduction in the number of well-granulated beta cells, but the number of well-granulated alpha and delta cells was normal in 70% and 85% of the dogs, respectively. Also, insulitis lesions composed of infiltrating mononuclear cells, predominantly lymphocytes, were observed in 6 of 13 dogs (46%), but evidence of islet-directed humoral autoimmunity was not detected. Each pancreas had dense Ia (class II antigen) expression on ductal epithelia but not on islet endocrine cells. The importance of the insulitis lesions and class II antigen expression on ductal epithelial cells remains unclear. Of the 18 dogs, 8 received multidonor intrahepatic islet allografts. Allograft rejection was prevented by administration of cyclosporin. Five dogs were administered cyclosporin continuously. One dog with an allograft failed to sustain euglycemia at 231 days after transplantation, and one dog with fasting euglycemia died of pneumonia at 186 days after transplantation. In the other dogs, euglycemia was sustained for periods that ranged from 253 to 716 days.
Chronic clamping of plasma glucose levels at greater than or equal to 250 mg/dl in four partially depancreatized but previously nondiabetic dogs was followed within 2 wk by persistent hyperglycemia and glycosuria of less than or equal to 500 g/day, ketonuria, and weight loss. Three of the four dogs required daily insulin injections to control these catabolic manifestations. There was no evidence of spontaneous improvement of the severe diabetic state during the 39-69 days of observation after discontinuation of intravenous glucose infusion. Impairment of intravenous glucose tolerance, loss of the insulin response to glucose and arginine, fasting hyperglucagonemia, exaggerated glucagon responsiveness to arginine, and a significant reduction in sensitivity to insulin were characteristic of all diabetic dogs. Morphometric analysis of the endocrine pancreas revealed a profound reduction in the number and size of identifiable islets of the hyperglycemic dogs compared with islets from their own pancreases resected months earlier and with those from pancreatic remnants of eight subtotally depancreatized control dogs that had not been subjected to chronic hyperglycemic clamping. The reduction in number and size of islets of the hyperglycemic dogs was largely the consequence of depletion of insulin-containing cells and was similar to that of dogs with long-standing alloxan-induced diabetes. In the eight control dogs, clinical evidence of diabetes did not develop during a follow-up period of 193-296 days. In this group, there was no evidence of diminution of intravenous glucose tolerance, of the insulin response to glucose or arginine, or of insulin sensitivity as determined by an acute hyperinsulinemic hyperglycemic clamp. The number and size of islets and number of beta-cells in pancreatic remnants from these dogs did not differ morphometrically from those of the pancreatic segment that had been resected. We conclude that in subtotally depancreatized but nondiabetic dogs, maintenance of constant hyperglycemia of greater than or equal to 250 mg/dl by means of intravenous glucose infusion causes a severe, persistent, and often insulin-requiring diabetic state that does not occur in the absence of the hyperglycemia.
Serum samples were obtained from 48 dogs with recently diagnosed untreated diabetes mellitus. Serums were tested for cytoplasmic autoantibodies to normal canine pancreatic islet antigens by indirect immunofluorescence, peroxidase-anti-peroxidase, and avidin-biotin complex, immunohistochemistry. Autoantibodies were not detectable in any of the samples. Serums were also examined from 20 diabetic dogs maintained on exogenous insulin therapy for periods of one month to five years. Positive reactions were seen in 11 dogs. These positive responses were completely absorbed by preincubation of serums with commercial insulin preparations or with purified pork or beef insulin. Newly diagnosed diabetic dogs do not have readily detectable autoantibodies to islet cytoplasmic antigens. Our previous report (Haines and Penhale, 1985) of islet antibody in diabetic dogs with unknown clinical histories was likely demonstrating antibody to insulin in patients treated with exogenous insulin. Antibodies to insulin were detected in approximately half of the insulin treated dogs tested. These antibodies were induced by commercial beef and pork insulin preparations and were found to be broadly cross-reactive recognizing epitopes on canine, bovine and porcine insulins.
Radioimmunoassay of canine C-peptide (CCP) was developed for the characterization of endogenous beta cell function in experimentally diabetic dogs. The animals were rendered diabetic by subtotal pancreatectomy and intrasurgical infusion of 2 mg kg-1 streptozotocin into the superior pancreaticoduodenal artery. After an average duration of diabetes of 5 months the animals showed zero peripheral venous fasting CCP levels with no response to feeding, OGTT/i.v. glucagon loading or i.v. glucose tolerance testing. The data on CCP levels were entirely coincident with simultaneously measured plasma IRI levels. In non-diabetic control animals there were clear-cut CCP increases after all stimuli. The experimental model provided an IDDM-type diabetes without toxic symptoms but with sufficient exocrine pancreatic function. The comparison showed that plasma IRI analyses would also allow a reliable characterization of insulinogenic functions in these animals.
A sensitive radioimmunoassay (RIA) for canine C-peptide (CCP) was established using synthetic CCP, a specific antiserum, and rabbit anti-guinea pig serum. Radioiodination was performed according to a modified chloramine-T method. Tracer preparations were used for long as 6 weeks after iodination. The standard curve ranges from 0.028 to 3.0 nmol/l. The intra-assay coefficient of variation (CV) was 3-5% and the inter-assay CV was 6-9% in the optimal range between 0.3 and 0.8 nmol/l. The average recovery of CCP added to plasma samples was 100.6% (n = 9). Canine insulin, porcine proinsulin, bovine proinsulin, and human C-peptide exhibited no cross-reactivity. The mean fasting plasma CCP concentration was 0.089 +/- 0.021 nmol/l in normal dogs and -0.005 +/- 0.007 nmol/l (mean +/- SEM) in diabetic dogs, respectively.
C-peptide immunoreactivity (CPR) levels were measured in dog superior pancreaticoduodenal vein using synthetic dog C-peptide and its antiserum. The basal CPR level was approximately twice as high as the basal immunoreactive insulin (IRI) level on a molar basis. Glucose (10 mg/kg/min) or arginine (250 mg/kg/min) infusion for 5 min into the superior pancreaticoduodenal artery caused a prompt, parallel increase in IRI and CPR. IRI and CPR were closely equimolar at peak secretions. One bolus administration of synthetic neurotensin (10 microgram/kg) into the same artery produced a mild hyperglycemic response and biphasic IRI and CPR responses at 30 min in the vein. The IRI and CPR increases were closely equimolar during the first phase of secretion, but during the second peak a larger increase was found in CPR than IRI. Upon infusion of synthetic substance P (50 ng/kg/min) for 30 min, IRI and CPR concentrations showed a parallel and closely equimolar fall. These results indicate that insulin and C-peptide were released from beta cells in equimolar concentrations.
Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 +/- 1.9 mM, mean +/- SEM) were accompanied by fasting hyperinsulinaemia (144 +/- 21 microU/ml, mean +/- SEM) and drastic elevation of plasma growth hormone (GH) levels (112.6 +/- 45 ng/ml, mean +/- SEM). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.
The in vivo hepatic metabolism of connecting peptide (C-peptide) in relation to that of insulin has not been adequately characterized. A radioimmunoassay for dog C-peptide was therefore developed and its metabolism studied in conscious mongrel dogs, with sampling catheters chronically implanted in their portal and hepatic veins and femoral artery. The hepatic extraction of endogenous C-peptide under basal conditions was negligible (4.3 +/- 4.5%) and was similar to the hepatic extraction of C-peptide measured during the constant exogenous infusion of C-peptide isolated from dog pancreas. Simultaneously measured hepatic extraction of endogenous and exogenously infused insulin were 43.8 +/- 7.6 and 47.5 +/- 4.4%, respectively. The metabolic clearance rate of infused C-peptide was 11.5 +/- 0.8 ml/kg per min and was constant over the concentration range usually encountered under physiological conditions. In additional experiments, the effect of parenteral glucose administration on the hepatic extraction of C-peptide and insulin was investigated. The hepatic extraction of C-peptide (6.2 +/- 4.0%) was again negligible in comparison with that of insulin (46.7 +/- 3.4%). Parenteral glucose administration did not affect the hepatic extraction of either peptide irrespective of whether it was infused peripherally, intraportally, or together with an intraportal infusion of gastrointestinal inhibitory polypeptide. The fasting C-peptide insulin molar ratio in both the portal vein (1.2 +/- 0.1) and femoral artery (2.1 +/- 0.3) was also unaffected by the glucose stimulus. These results therefore indicate that, since the hepatic extraction of C-peptide is negligible and its clearance kinetics linear, the peripheral C-peptide concentration should accurately reflect the rate of insulin secretion. New approaches to the quantitation of hepatic extraction and secretion of insulin by noninvasive techniques are now feasible.
Anti-islet immunity was studied in six spontaneously insulin-dependent diabetic (IDD) dogs, using mouse islets of Langerhans cells as targets, in vitro. Insulinopenia was demonstrated in all dogs by an i.v. glucose tolerance test. A significant lymphocytopenia was detected in the peripheral blood of this diabetic group. Pancreatic tissue from one of these animals was obtained shortly after death and the islets displayed a marked loss in beta cells without significant changes in the other types of islet cells. No insulitis was observed.
Circulating mononuclear cells from the diabetic dogs induced an increased basal insulin (IRI) release from islet cells and a suppressed stimulated IRI release. Damage to or depth of beta cells may account for these findings.
The stimulated IRI release was also suppressed when islets were incubated with the diabetic sera + complement, while the D-cell response to arginine was not altered, and the A-cell response was reduced but not abolished. A lysis of islet cells in the presence of IDD sera + complement was demonstrated by an increased release of 51Cr from labeled cells. These anomalies were observed neither when complement was heat-inactivated nor in the presence of control sera + complement.
Canine IDD may be a new animal model for the study of anti-islet cellular and humoral immunities.
The IV glucose-tolerance test was performed in 71 diabetic dogs (fasting glycemia greater than 6.70 mmol/L) and in 20 healthy dogs. All diabetic dogs were characterized by various degrees of glucose intolerance as expressed by an abnormal glucose disappearance coefficient. On the basis of the fasting plasma insulin concentration (Io), insulin peak response (IPR), the insulinogenic index (delta I/delta G), and the total insulin secretion (TIS), the diabetic dogs were classified, as follows: Type I dogs (n = 32) which had the severe clinical signs of diabetes and an absence of certain diagnostic responses: Io, IPR, delta I/delta G, and TIS. Type II dogs (n = 15) which also had marked diabetic signs and an absence of IPR, delta I/delta G, and TIS responses. The dogs were further subdivided into obese and nonobese groups; the Io was within acceptable limits in the nonobese group (n = 8), but was markedly increased in the obese group (n = 7). Type III dogs (n = 24) had no diabetic signs and a fasting plasma glucose less than 12 mmol/L. They were also subdivided into obese and nonobese groups. The nonobese dogs (n = 13) had Io values within acceptable limits and decreased IPR, delta I/delta G, and TIS. In contrast, the obese dogs had increased Io, IPR, delta I/delta G, and TIS. Statistical analyses indicated that the TIS and IO were highly significant linear functions of obesity.(ABSTRACT TRUNCATED AT 250 WORDS)
Alterations in carbohydrate metabolism were evaluated in 60 dogs with untreated hyperadrenocorticism by measuring basal concentrations of plasma glucose and insulin and performing glucose and insulin tolerance tests. The 60 dogs could be divided into four groups based on paired glucose and insulin concentrations. Eight dogs had normal concentrations of both glucose and insulin. Twenty-four dogs (40 per cent) were euglycaemic with mild to moderate hyperinsulinaemia whereas 23 (38 per cent) had moderate hyperglycaemia with moderate to severe hyperinsulinaemia. The five dogs (8 per cent) with overt ketoacidotic diabetes mellitus had relative insulin deficiency. Of eight dogs tested, six had intravenous glucose intolerance; all of the dogs had increased total insulin secretion during glucose tolerance testing. Resistance to the hypoglycaemic effect of exogenous insulin was demonstrated in six of the seven dogs tested. In 20 dogs that had basal glucose and insulin again determined after correction of hyperadrenocorticism, mean concentrations of both glucose and insulin decreased into the normal range.
Spontaneous diabetes mellitus has been characterized in a line of nonobese purebred keeshond dogs as an insulin-requiring hereditary disorder with onset at between 2 and 6 mo of age. Diabetic dogs developed cataracts, became ketotic, hyperglycemic, hypercholesterolemic, lipemic, and hypoinsulinemic. Basal glucagon, cortisol, and T4 serum concentrations and responses to ACTH, TSH, and arginine were normal. Light microscopic studies of the pancreas by immunocytochemical procedures revealed the absence of islet B cells, the presence of A cells, and solitary B cells. Diabetic dogs had poor fecundity, and a single puberal diabetic male had poor semen quality and was unable to sire pups. Parents of diabetics and nondiabetic siblings were normal. This spontaneous form of diabetes mellitus, with similar lesions to the insulin-dependent diabetes of people, will be a valuable aid to comparative biomedical research of diabetes mellitus.
A line of keeshond dogs with an inherited condition causing them to become insulinopenic and diabetic at the age of 2-6 months has been identified. Insulinopenia is the result of aplasia of the B cell of the islet of Langerhans and persistence of a solitary B-cell population of the pancreas. Aplasia of islet B cells is evident at birth. The solitary B cells produce sufficient insulin to maintain growth until the body's insulin requirement exceeds insulin produced, and the onset of diabetes mellitus occurs. At the onset of diabetes, the pancreatic insulin concentration is very low, and pancreatic glucagon concentration is one third the normal concentration. Islet and solitary A cells are present. Basal serum glucagon concentration and the response of A cells to arginine is normal. The spontaneously diabetic dogs are not obese and, once diabetic, can live without insulin therapy for 2-5 months. They develop cataracts, cutaneous infections, glycosuria, ketonuria, ketoacidosis, hyperglycemia, and hypercholesterolemia, and growth is severely restricted. Marked lipemia is associated with abnormal serum lipoproteins and triglyceride values. In time, the dogs become cachectic and die. Routine insulin therapy controls the lesions and allows dogs to grow and live for as long as 4 years. Necropsy of untreated dogs reveals marked hepatic and renal lipidosis and oral and gastric ulcers. Histopathologic study of pancreatic tissue obtained at birth and at the time of onset of diabetes reveals the earlier listed changes in the endocrine pancreas and no lesions of the exocrine pancreas. No vascular lesions have been observed.
The duration of action and peak activity time of three delayed-absorption insulin preparations (protamine zinc insulin, isophane insulin and an insulin zinc suspension) were compared in eight naturally occurring, hypoinsulinaemic, non-ketotic diabetic dogs. Although the average responses were similar to previously suggested values, marked individual variation was demonstrated, particularly with the protamine zinc and isophane preparations.
A four-year-old, spayed female toy fox terrier presented with hyperglycemia and severe anemia. A diagnosis of immune-mediated diabetes mellitus was made based upon the finding of beta-cell specific antibodies. Immune-mediated hemolytic anemia was diagnosed based on findings of a regenerative anemia, spherocytosis, hyperbilirubinemia, hemoglobinuria, and bilirubinuria. The anemia resolved following two months of immunosuppressive therapy. The diabetes was treated with insulin for four months, after which time treatment was no longer necessary. However, the dog remained positive for beta-cell antibodies which may be a predictive marker for the recurrence of diabetes mellitus in the future.
Data were collected from the medical records of 123 nondiabetic dogs (182 eyes) and 30 diabetic dogs (57 eyes) in which phacoemulsification surgery was performed. Pre- and postoperative comparisons, including signalment, initial ophthalmic examination findings, surgical variables, and postoperative findings for the short-term follow-up period (mean, 5.75 weeks), between nondiabetic and diabetic dogs revealed that the complication rate was not greater in the diabetic group. Postoperative uveitis was evident with nearly equal frequency (in nondiabetic dogs, 90% or 164 of 182 eyes and in diabetic dogs, 88% or 50 of 57 eyes). In nondiabetic dogs, 1% prednisolone ophthalmic solution and prednisone were administered pre- and postoperatively, and amoxicillin and dichlorphenamide postoperatively. In diabetic dogs, the same treatment regimen, except for treatment with flunixin meglumine IV at surgery and substitution of aspirin for prednisone, was used. When nondiabetic and diabetic dogs were treated according to their respective pre- and postoperative medical regimens, clinical differences in postoperative findings were not apparent.
Selman PJ, Mol JA, Rutteman GR, Rijnberk A. Progestin treatment in the dog. I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis. Eur J Endocrinol 1994;131:413–21. ISSN 0804–4643
The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis. It is concluded that treatment with MPA and PROL results in similar increases in plasma levels of GH and IGF-I and leads to a similar degree of insulin resistance. The elevated GH levels can be neither stimulated nor inhibited, which is a feature compatible with autonomous secretion. These results are consistent with the recent finding of a progestin-induced ectopic production of GH in the mammary gland of the dog.
JA Mol, Department of Clinical Sciences of Companion Animals, Utrecht University, PO Box 80. 154, 3508 TD Utrecht, The Netherlands
Type 1 diabetes mellitus in adults may present in a manner similar to that of Type 2 diabetes but with a late development of insulin dependency. We studied 65 patients who presented with 'adult-onset' diabetes after the age of 30 years. Of these patients, 19 required insulin therapy. The insulin-treated patients were significantly younger, their onset of diabetes was at an earlier age, and their postprandial serum C-peptide levels were lower than those of the non-insulin-treated group. Moreover, the insulin-treated subjects had a higher mean concentration of antibodies to glutamic acid decarboxylase (GAD) (66.8 +/- 10.2 units) than the patients who did not require insulin (9.9 +/- 1.9 units) (p < 0.001) and their frequency of anti-GAD positivity was 73.7% versus 4.3% (p < 0.001). Thus, among patients attending a diabetes clinic, the majority (73.7%) of subjects who presented with diabetes after 30 years of age and who subsequently required therapy with insulin, actually have the islet cell lesion of Type 1 diabetes which progresses at a slower tempo than in children. We conclude that testing for anti-GAD in adult-onset non-obese diabetic patients should be a routine procedure in order to detect latent insulin-dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.
Hypoglycemia has been incriminated as a possible factor responsible for development of the hypoglycemia unawareness phenomenon in patients with type I diabetes. Many patients with this condition, however, do not have a history of recent hypoglycemia. Because asymptomatic nocturnal hypoglycemia commonly occurs in type I diabetes, we tested the hypothesis that such episodes might be capable of inducing this phenomenon. Accordingly, autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive function were assessed during standardized insulin-induced hypoglycemia in 10 normal volunteer subjects on two occasions--once after induction of asymptomatic nocturnal hypoglycemia and once after control studies in which saline rather than insulin was infused overnight. Compared with control experiments, asymptomatic nocturnal hypoglycemia increased the threshold (required greater hypoglycemia for initiation) and reduced the magnitude of autonomic and neuroglycopenic symptoms, counterregulatory hormone responses, and cognitive dysfunction during subsequent hypoglycemia (all, P < 0.05). These results indicate that asymptomatic hypoglycemia may induce hypoglycemia unawareness and, thus, may explain why not every patient with this condition has a history of prior hypoglycemia. Our results therefore support the concept that in type I diabetes this phenomenon may be largely attributable to antecedent hypoglycemia.
Fructosamines are formed when glucose reacts non-enzymatically with amino groups on proteins, and previous studies have indicated that the serum fructosamine concentration could be of importance in the diagnosis of canine diabetes mellitus. Owing to the connection between the protein/albumin concentration and serum fructosamine concentration, it has been suggested that the serum fructosamine concentration should be corrected for the protein/albumin concentration. Thus, the purpose of the present study was to evaluate the uncorrected serum fructosamine concentration and various protein and albumin corrections of the serum fructosamine concentration in the separation of dogs with diabetes mellitus from dogs with other diseases that presented with clinical signs suggestive of diabetes mellitus. The evaluation was assisted by relative operating characteristic curves (ROC curves), which may be used to compare various diagnostic tests under equivalent conditions (equal true positive ratios or false positive ratios) and over the entire range of cutoff values. A total of 58 dogs (15 dogs with diabetes mellitus and 43 dogs with other diseases) were included in the study. Serum fructosamine concentration, serum total protein concentration and serum albumin concentration were measured in each dog, and various corrections of the serum fructosamine concentration for protein or albumin concentration were made. Comparing the ROC curves of the uncorrected and each corrected serum fructosamine concentration indicated that there was no decisive difference between the uncorrected and the corrected serum fructosamine concentrations in discriminating between dogs with and without diabetes mellitus. Hence, correcting the serum fructosamine concentration as a routine procedure cannot be advocated from the results of the study. Moreover, the sensitivity and specificity of the uncorrected serum fructosamine concentration were very high, 0.93 and 0.95, respectively, further evidence of the value of the uncorrected serum fructosamine concentration in the diagnosis of canine diabetes mellitus.
Insulin resistance resolved in 3 dogs with hypothyroidism and diabetes mellitus after treatment with sodium levothyroxine. A thorough diagnostic evaluation failed to identify any other cause of insulin resistance in these dogs. Hypothyroidism was diagnosed in each dog on the basis of clinical signs, physical findings, hyperlipidemia, and results of thyrotropin or thyrotropin-releasing hormone stimulation test. Hypoglycemia was documented in each dog within 2 weeks of starting sodium levothyroxine administration. The insulin dosage was decreased by 60 to 62% during the ensuing months and good glycemic control was obtained at these lower insulin dosages in all dogs. These findings would suggest hypothyroidism-induced insulin resistance in these dogs.