Diabetes mellitus remission in a cat with pituitary-dependent hyperadrenocorticism after trilostane treatment

An 8-year-old male neutered Persian cat was presented with polyuria, polydipsia, polyphagia and muscle weakness associated with a 7 month history of diabetes mellitus (DM). The cat had initially been treated with neutral protamine Hagedorn (NPH) insulin 2 U q12h, followed by porcine lente insulin 2 U q12h and, most recently, 3 U glargine insulin q12h, without improvement of clinical signs. The cat also suffered from concurrent symmetrical bilateral alopecia of thorax and forelimbs, abdominal distension and lethargy. Hyperadrenocorticism (HAC), specifically pituitary-dependent HAC, was suspected and confirmed through abdominal ultrasonography demonstrating bilateral adrenal enlargement, and a low-dose dexamethasone suppression test using 0.1 mg/kg dexamethasone intravenously. Trilostane treatment (initially 10 mg/cat PO q24h then increased to 10 mg/cat PO q12h) was started and insulin sensitivity gradually improved, ultimately leading to diabetic remission after an increased in trilostane dose to 13mg/cat PO q12h, 14 months after the DM diagnosis and 7 months after the initiation of trilostane therapy

Aspectos epidemiológicos e clínico-laboratoriais da Diabetes Mellitus em cães

A diabetes mellitus canina vem aumentando no sul do Brasil. Na etiologia, obesidade, vida sedentária e estresse são os principais fatores. Após o diagnóstico recomenda-se identificar doenças que possam causar intolerância à glucose. Para este fim, perfil bioquímico sérico, urinálise e hemograma devem ser determinados. O objetivo deste trabalho foi identificar as principais alterações clínico-patológicas de cães diabéticos e estabelecer valores de referência para fructosamina. Dez cadelas atendidas por um hospital veterinário universitário do sul do Brasil foram incluídas no estudo para realizar hemograma, testes bioquímicos e urinálise. Foram dosados no soro creatinina, uréia, ALT, AST, GGT, ALP, albumina, proteína total, globulinas, colesterol, triglicerídeos, b-OH-butirato, amilase pancreática, glicose e fructosamina. Vinte e cinco cães sadios foram usados como controle. O hemograma mostrou leucocitose em 30% dos cães diabéticos. Foi observada glicosúria em todos os cães. Proteinúria (50%), cetonúria (40%) e alta densidade urinária (30%) foram as maiores alterações da urina dos animais diabéticos. As concentrações de glicose e colesterol estiveram acima dos valores de referência em todos os diabéticos. Os triglicerídeos foram mais altos, comparados com o grupo controle, em 90% dos cães diabéticos. Altos valores de proteína total (70%), FAS (70%), GGT (50%), ALT e b-OH-butirato (40%) foram observados nos cães com diabetes. A concentração sérica de fructosamina nos animais do grupo controle foi de 1.53 mmol/L ± 0.27 e nos diabéticos de 3.24 mmol/L ± 1.16

Granulosa Cell Tumor Associated with Occult Hyperadrenocorticism in a Yorkshire Terrier Bitch

Background: Hyperadrenocorticism (HAC), is considered a set of symptoms due to excessive exposure to cortisol. Naturally occurring HAC is most often related to pituitary tumors (pituitary-dependent HAC - PDH). Occult HAC, is referred as a clinical picture highly consistent with HAC; however, routine screening tests are negative. In addition, one or more steroids are elevated following administration of adrenocorticotrophic hormone (ACTH). Ovarian granulosa cell tumors, can produce steroids leading to paraneoplastic syndromes. The objective of this study was to report an unpublished case of ovarian granulosa cell tumor associated with occult hyperadrenocorticism in a Yorkshire Terrier.Case: A 13-year-old intact female dog, Yorkshire Terrier, was brought for consultation with slight weight loss, polyuria, polydipsia, irregular estrous cycles, increased abdominal volume and thin coat. On physical examination the animal was gasping and presented severe periodontal disease, bulging abdomen, alopecia and skin hyperpigmentation. Complete blood count presented no changes; however, serum biochemistry evaluation highlighted hyperalbuminemia, hypertriglyceridemia, alkaline phosphatase increased activity, and urinary specific gravity and creatinine below reference values. On abdominal ultrasonography left adrenal gland measured 2.08 cm x 1.08 cm and the right adrenal gland measured 2.11 cm x 0.84 cm, indicating bilateral adrenomegaly compatible with PDH. In the hypogastric abdomen, a large heterogeneous hypoechogenic mass was also observed, with areas of cystic cavities, measuring 5.80 cm x 7.30 cm. A low dose dexamethasone suppression test (LDDST) was performed, due to PDH suspicion. The test did not confirm HAC, suspecting, then, to be a case of occult/atypical HAC. Due to the strong clinical suspicion, and owner financial problems for further investigated occult HAC, trilostane treatment was initiated. Approximately one month after starting treatment, an ACTH stimulation test (AST) for cortisol and 17-hydroxyprogesterone (17-OHP) determination was performed, revealing high values for both hormones. Exploratory laparotomy was indicated due to the tumor image on hypogastric region visualized on abdominal ultrasonography. A cranial pole mass of the left ovary measuring 8.5 x 7.0 x 4.5 cm, of friable consistency and brownish color, was removed through ovariohysterectomy. A granulosa cell tumor on left ovary, as well as leiomyoma and cystic endometrial hyperplasia in the uterus, became clear through histopathological examination. Trilostane treatment was sustained after surgery. Few weeks later, the patient presented a clinical picture suggestive of hypoadrenocorticism, associated with a low sodium:potassium ratio (25:1), and AST results (basal and post-ACTH cortisol) below reference range, confirming Addisonian´ crises. The patient deceives within two days.Discussion: Granulosa cell tumors can produce estrogen and progesterone, as well as other steroids, leading to paraneoplastic syndromes with peculiar clinical presentations. Steroids transport in plasma occurs via specific carrier proteins. Increased production of other steroid hormones may result in higher concentration of free cortisol, thus leading to clinical manifestations of hypercortisolism. As 17-OHP is one of the precursors in cortisol synthesis and has been shown elevated on AST, it can be assumed that altered steroid hormone levels due to the granulosa cell tumor interfered on cortisol biodisponibility, leading to HAC signs. Dexamethasone suppression test results indicated that pituitary-adrenal axis was responsive to negative feedback. The Addisonian crises after tumor removal indicate that the main source for systemic excessive cortisol effects was the eminent steroid secretion by the granulosa cell tumor

Müller´s Duct Persistence Syndrome Associated with Cryptorchidism, Sertoli Cell Tumor and Pyometra in a Miniature Schnauzer

Background: Sexual development disturbances (SDD) are divided in SDD with XX genotype (SDD XX) and SDD with XY genotype (SDD XY). Among SDD XY, the Müller´s duct persistence syndrome (MDPS) is characterized by XY karyotype individuals with male external genitals; however, with internal female reproductive organs such as uterine horns, uterus, and cranial vagina portion. The MDPS cases and their related complications are considered very rare in veterinary medicine. The aim of the present case report is to describe the clinical and pathological aspects of a MDPS case associated with cryptorchidism, Sertoli cell tumor, and pyometra in a Miniature Schnauzer dog.Case: A 7-year-old male Miniature Schnauzer weighting 7 kg was brought to veterinary consultation due to owner´s complain of frequent vomiting, apathy, abdominal algia and progressive scrotal enlargement in the last two months. Physical exam reveals hyperthermia (39.7°C), discrete dehydration, enlarged popliteal lymph nodes as well as scrotum enlargement with only one palpable testicle. A blood sample collected for complete blood count showed regenerative anemia, thrombocytopenia, and neutrophilia with left shift in the leukogram. Abdominal ultrasound examination indicated the presence of a tubular structure filled by anechoic content extending from the scrotum to caudal abdomen. Moreover, a 6.39 x 8.54 cm heterogeneous mass in the medial mesogastric region became evident. The patient was hospitalized and submitted to exploratory laparotomy after 24 h due to rectal temperature increase (41°C), worsened abdominal pain and intense apathy. There was free purulent liquid in abdominal cavity and two uterine horns were documented. The left uterine horn passes through inguinal ring and both horns were filled by purulent material. At the right uterine horn extremity there was the mass previously document at ultrasound. The structures were removed and sent to histopathological examination. The microscopic exam confirmed testicular and uterine tissue; furthermore, a Sertoli cell tumor and pyometra were also characterized. The dog was kept at the hospital receiving fluid, antibiotics, analgesics, and anti-inflammatory therapy. After five days the animal was discharged with clear clinical recover. A sample for karyotyping was collected from the oral mucosa which reveals a XY karyotype in the dog. By this way it was concluded that the dog suffers from a SDD XY with MDPS associated to cryptorchidism, Sertoli cell tumor and pyometra.  Discussion: The MDPS cases are often associated with cryptorchidism and testicular tumors. Miniature Schnauzers is one of the most affected dog breeds with this condition, and the heritability pattern is already described. Most cases are identified in adult to old-aged dogs after vague clinical signs investigation such as apathy, anorexia and abdominal or inguinal enlargement, as observed in the present report. When Sertoli cell tumor are present, the hormone secretion pattern of this neoplasia may influence complications occurrence. Once higher estrogen levels may induce endometrial gland proliferation, hydrometra and pyometra are among these complications, as well as reduced hematopoiesis. Moreover, progesterone levels could be also increased favoring pyometra pathophysiology. By conclusion, despite very rare, MDPS should be investigated in Miniature Schnauzers with vague clinical signs, especially cryptorchidic ones. Karyotyping and histopathology were crucial to confirm the diagnosis. Moreover, no other case with MDPS, cryptorchidism, Sertoli cell tumor, and pyometra was found in the published literature consulted.

Osmotic Demyelination Syndrome after Primary Hypoadrenocorticism Crisis Management

Background: Primary hypoadrenocorticism is a rare condition resulting from immune-mediated destruction of the adrenal cortices. It can also occur due to necrosis, neoplasms, infarctions and granulomas. The clinical and laboratory changes are due to deficient secretion of glucocorticoids and mineralocorticoids, which leads to electrolyte disorders associated with hyponatremia and hyperkalemia. These disorders can cause hypotension, hypovolemia and shock, putting a patient's life at risk if inadequate hydroelectrolytic supplementation and hormone replacement is provided. Nevertheless, rapid sodium chloride supplementation is contraindicated due to the risk of central pontine myelinolysis induction. The present study aims to describe a thalamic osmotic demyelination syndrome after management of a primary hypoadrenocorticism crisis in a 2-year-old, female West White Highland Terrier. Case: The patient had a presumptive diagnosis of hypoadrenocorticism already receiving oral prednisolone and gastrointestinal protectants in the last 2 days. After prednisolone dose reduction the dog presented a severe primary hypoadrenocorticism crisis treated with intravenous sodium chloride 0.9% solution along with supportive therapy. Four days after being discharged from the hospital, the patient showed severe neurological impairment and went back to the clinic where a neurological examination revealed mental depression, drowsiness, ambulatory tetraparesis and proprioceptive deficit of the 4 limbs, postural deficits, and cranial nerves with decreased response. Due to these clinical signs, a magnetic resonance imaging was performed. It showed 2 intra-axial circular lesions, symmetrically distributed in both thalamus sides, with approximately 0.8 cm in diameter each without any other anatomical changes on magnetic resonance imaging. The images were compatible with metabolic lesions, suggesting demyelination. Furthermore, liquor analysis did not show relevant abnormalities, except for a slight increase in density and pH at the upper limit of the reference range. After treatment, the patient had a good neurological evolution secondary to standard primary hypoadrenocorticism treatment, without sequelae. Discussion: In the present case report, primary hypoadrenocorticism gastrointestinal signs seemed to be triggered by a food indiscretion episode, not responsive to the symptomatic therapies employed. The patient´s breed and age (young West White Highland Terrier bitch) is in accordance with the demographic profile of patients affected by the disease, where young females are frequently more affected. Regarding the probable thalamic osmotic demyelination syndrome documented in this case, is important to notice that myelinolysis or demyelination is an exceedingly rare noninflammatory neurological disorder, initially called central pontine myelinolysis, which can occur after rapid correction of hyponatremia. It has already been observed in dogs after correction of hyponatremia of different origins, including hypoadrenocorticism and parasitic gastrointestinal disorders. Currently, the terms "osmotic myelinolysis" or “osmotic demyelination syndrome" are considered more suitable when compared to the term "central pontine myelinolysis" since it has been demonstrated in dogs and humans the occurrence of demyelination secondary to the rapid correction of hyponatremia in distinct regions of the central nervous system including pons, basal nuclei, striatum, thalamus, cortex, hippocampus and cerebellum. The present case report emphasizes the difficulties for hormonal confirmation of primary hypoadrenocorticism in a patient already on corticosteroid treatment, as well as proposes that the current term osmotic demyelination syndrome replace the term “central pontine myelinolysis” in veterinary literature related to the management of hypoadrenocorticism crisis.Keywords: Addison Syndrome, hyponatremia, osmotic myelinolysis, magnetic resonance imaging

Índices de sensibilidade à insulina em fêmeas caninas: efeito do ciclo estral e da piometra

A ocorrencia do estro e diestro em femeas caninas esta associada a presenca de resistencia a insulina. Alem disso, estados septicos e inflamatorios, como observado frente a piometra, tambem cursam com resistencia a acao insulinica. O objetivo deste estudo foi verificar qual o efeito das diferentes fases do ciclo estral e da piometra sobre diferentes indices de sensibilidade a insulina. Com base em medidas de glicemia e insulinemia basal em femeas caninas em diferentes fases do ciclo estral, e em pacientes com piometra, foram calculados os indices HOMA B, HOMA R, indice insulinogenico, relacao insulina:glicose corrigida, determinacao da fructosaminemia e relacao fructosamina/albumina. O indice insulinogenico e a relacao insulina:glicose corrigida mostraram-se mais sensiveis na deteccao de hiperinsulinemia relativa, especialmente em pacientes com piometra. A falta de valores de corte para os indices HOMA prejudicou sua avaliacao, apesar de terem sido eficazes em demonstrar resistencia a insulina e maior secrecao pancreatica de insulina em femeas com piometra. Os diferentes indices de sensibilidade mostraram-se como ferramentas de facil aplicacao, uteis e relativamente pouco onerosas, apresentando vantagens em relacao a determinacao isolada de glicose e insulina sericas em jejum. A fructosamina nao foi eficaz em evidenciar diferencas significativas entre as diferentes fases do ciclo estral, apesar de ter sofrido forte influencia da albuminemia nas pacientes com piometra. A determinacao da relacao fructosamina:albumina e mais indicada do que a avaliacao da fructosamina isolada, sendo necessarios estudos para determinar valores de referencia desta relacao, bem como para os indices HOMA B e HOMA R em caninos

Mixossarcoma esplênico em cão

Background: Myxosarcomas (MXS) are malignant mesenchymal neoplasms originated from mainly mucin producing fibroblasts than collagen. Despite malignant neoplasms, MXS is believed to have low metastase generation ability. Myxosarcomas reports in dogs are widespread, usually involving trunk and limbs subcutaneous tissue. The aim of this report is to describe clinical, pathological, and immunohistochemistry aspects of a rare case of splenic myxosarcoma in a dog.Case: A 10-year-old, intact male Basset Hound, weiging 25 kg, showing signals such apathy, dark soft-stooled stools, progressive thinning, and increasing abdominal enlargement, perceived three months ago was brought to clinical consultation. Physical examination showed extremely pale oral and ocular mucosas, in addition to mild dehydration (6%), 35.4°C rectal temperature, and a very bulging abdomen, with no fluids or gases, evidence at abdominal percussion. A complete blood count (CBC) revealed neutrophilic leukocytosis and anemia. Patient´s abdominal cavity ultrasound examination showed an heterogeneous mass, occupying large part of cavity, and apparently from spleen origin. A spleenic multilobulated mass measuring 25 x 12 x 20 cm was obtained after exploratory laparotomy. The mass showed predominantly soft consistency with some firm areas, and no visible mesentery or other abdominal organs adhesions. Mass and spleen histopathological examination were routinely processed for histological analysis with haematoxylin and eosin and alcian blue staining. In addition, fragments of the neoplasm were submitted to immunohistochemistry (IHC) which confirmed myxosarcoma diagnosis. The owner returned to hospital two months after, complaining for apathy, prostration, anorexia, and abdominal pain. A new ultrasound examination were suggestive of liver and kidneys neoplasms. The tutor opted for patient´s euthanasia. However, dog´s necropsy was not authorized.Discussion: Myxosarcomas are malignant tumors considered rare in small animals, affecting mainly middle age or advanced age patients. Corroborating with the present case, the main clinical signs identified in cases of splenic neoplasias, in general, are abdominal distention and algia, emaciation, prostration, anemia, hypothermia, and inappetence. Regarding neutrophilic leukocytosis and anemia in CBC, those alterations are atributable to paraneoplastic syndromes commonly observed in small animals. The diagnosis of myxosarcoma was based on the pathological and IHC findings. The mesenchymal origin of the neoplastic cells was confirmed by the expression of vimentin and by the absence of cytokeratin labeling in the immunohistochemical examination. It was possible to confirm the diagnosis due to the presence of large amount of mucopolysaccharides between the neoplastic cells, demonstrated through Alcian Blue staining. Although rare, there have been reports of metastasis from cardiac myxosarcoma in humans and splenic myxosarcomas in dogs. The patient’s resubmission in two months with a new nonspecific clinical picture and documentation of hepatic and renal masses supports the possibility of agressive metastatic disease in the present case, despite the non-authorization of the autopsy examination. It was concluded by the present case report that MXS, although uncommon in small animals, should be included as a differential diagnosis in cases of abdominal neoplasias. The histopathological analysis and the immunohistochemical examination of neoplasms are important and should be considered in order to establish diagnosis and prognosis in dogs. Despite not confirmed by post-morten examination, agressive metastic disease seems likely in the present report, and emphasize MXS´malignat nature

Hiperadrenocorticismo atípico canino asociado a hipotireoidismo

ABSTRACT Hyperadrenocorticism (HAC) is one of the most common endocrinopathies in dogs, caused by excessive synthesis of cortisol. Atypical or occult HAC is a syndrome characterized by the presentation of clinical, biochemical, and imaging alterations compatible with hypercortisolism, but normal results in endocrine tests that are conventionally used for HAC diagnosis. However, these patients present high serum concentrations of precursors or other corticoadrenal hormones. The present study describes the case of an 8 years old female canine, Bichón Frisé, epileptic and treated with phenobarbital, presenting clinical signs associated with HAC, in which the low-dose dexamethasone suppression test and stimulation with ACTH resulted within normal values. The measurement of adrenal steroids, after ACTH stimulation, showed abnormal elevation of estrogen and progesterone, the latter persisting after the patient was spayed. Treatment with trilostane allowed the reduction of progesterone levels and the partial resolution of clinical signs. However, full clinical recovery was only achieved after the diagnosis and treatment of concomitant hypothyroidism. The challenge that represent the diagnosis of atypical HAC highlights the importance of performing and having availability of panels that include measurement of adrenal steroid hormones other than cortisol, as well as considering the occurrence of other concomitant endocrine metabolic diseases.RESUMEN El hiperadrenocorticismo (HAC) es una de las endocrinopatías más frecuentes en caninos, producida por la síntesis excesiva de cortisol. El HAC atípico u oculto es un síndrome caracterizado por la presentación de alteraciones clínicas, bioquímicas e imagenológicas compatibles con hipercortisolismo, pero con resultados normales en las pruebas endocrinológicas utilizadas convencionalmente para diagnóstico de HAC. Sin embargo, estos pacientes presentan elevada concentración sérica de precursores u otras hormonas corticoadrenales. El presente estudio describe el caso de una canina hembra, Bichón Frisé de 8 años de edad, epiléptica y tratada con fenobarbital, presentando signos clínicos asociados a HAC, en la que el test de supresión con dexametasona a dosis bajas y de estimulación con ACTH arrojaron valores normales. La medición de esteroides adrenales, post estimulación con ACTH, mostró elevación anormal de estrógenos y progesterona, persistiendo esta última después de que la paciente fuera esterilizada. El tratamiento con trilostano permitió la disminución de los niveles de progesterona y la resolución parcial de los signos clínicos. Sin em bargo, la recuperación clínica en su totalidad sólo se obtuvo después del diagnóstico y tratamiento del hipotiroidismo concomitante. El desafio que representa el diagnóstico del HAC atípico resalta la importância de realizar y disponer de paneles que incluyan medición de hormonas esteroideas adrenales diferentes al cortisol, además de considerar la ocurrencia de otras enfermedades endocrinas metabólicas concomitantes

Hiperadrenocorticismo atípico e hipotiroidismo canino

Hyperadrenocorticism (HAC) is one of the most common endocrinopathies in dogs, caused by excessive synthesis of cortisol. Atypical or occult HAC is a syndrome characterized by the presentation of clinical, biochemical, and imaging alterations compatible with hypercortisolism, but normal results in endocrine tests that are conventionally used for HAC diagnosis. However, these patients present high serum concentrations of precursors or other corticoadrenal hormones. The present study describes the case of an 8 years old female canine, Bichón Frisé, epileptic and treated with phenobarbital, presenting clinical signs associated with HAC, in which the low-dose dexamethasone suppression test and stimulation with ACTH resulted within normal values. The measurement of adrenal steroids, after ACTH stimulation, showed abnormal elevation of estrogen and progesterone, the latter persisting after the patient was spayed. Treatment with trilostane allowed the reduction of progesterone levels and the partial resolution of clinical signs. However, full clinical recovery was only achieved after the diagnosis and treatment of concomitant hypothyroidism. The challenge that represent the diagnosis of atypical HAC highlights the importance of performing and having availability of panels that include measurement of adrenal steroid hormones other than cortisol, as well as considering the occurrence of other concomitant endocrine metabolic diseases.El hiperadrenocorticismo (HAC) es una de las endocrinopatías más frecuentes en caninos, producida por la síntesis excesiva de cortisol. El HAC atípico u oculto es un síndrome caracterizado por la presentación de alteraciones clínicas, bioquímicas e imagenológicas compatibles con hipercortisolismo, pero con resultados normales en las pruebas endocrinológicas utilizadas convencionalmente para diagnóstico de HAC. Sin embargo, estos pacientes presentan elevada concentración sérica de precursores u otras hormonas corticoadrenales. El presente estudio describe el caso de una canina hembra, Bichón Frisé de 8 años de edad, epiléptica y tratada con fenobarbital, presentando signos clínicos asociados a HAC, en la que el test de supresión con dexametasona a dosis bajas y de estimulación con ACTH arrojaron valores normales. La medición de esteroides adrenales, post estimulación con ACTH, mostró elevación anormal de estrógenos y progesterona, persistiendo esta última después de que la paciente fuera esterilizada. El tratamiento con trilostano permitió la disminución de los niveles de progesterona y la resolución parcial de los signos clínicos. Sin embargo, la recuperación clínica en su totalidad sólo se obtuvo después del diagnóstico y tratamiento del hipotiroidismo concomıtante. El desafío que representa el diagnóstico del HAC atípico resalta la importancia de realizar y disponer de paneles que incluyan medición de hormonas esteroideas adrenales diferentes al cortisol, además de considerar la ocurrencia de otras enfermedades endocrinas metabólicas concomitantes

Aspectos epidemiológicos e clínico-laboratoriais da Diabetes Mellitus em cães

A diabetes mellitus canina vem aumentando no sul do Brasil. Na etiologia, obesidade, vida sedentária e estresse são os principais fatores. Após o diagnóstico recomenda-se identificar doenças que possam causar intolerância à glucose. Para este fim, perfil bioquímico sérico, urinálise e hemograma devem ser determinados. O objetivo deste trabalho foi identificar as principais alterações clínico-patológicas de cães diabéticos e estabelecer valores de referência para fructosamina. Dez cadelas atendidas por um hospital veterinário universitário do sul do Brasil foram incluídas no estudo para realizar hemograma, testes bioquímicos e urinálise. Foram dosados no soro creatinina, uréia, ALT, AST, GGT, ALP, albumina, proteína total, globulinas, colesterol, triglicerídeos, b-OH-butirato, amilase pancreática, glicose e fructosamina. Vinte e cinco cães sadios foram usados como controle. O hemograma mostrou leucocitose em 30% dos cães diabéticos. Foi observada glicosúria em todos os cães. Proteinúria (50%), cetonúria (40%) e alta densidade urinária (30%) foram as maiores alterações da urina dos animais diabéticos. As concentrações de glicose e colesterol estiveram acima dos valores de referência em todos os diabéticos. Os triglicerídeos foram mais altos, comparados com o grupo controle, em 90% dos cães diabéticos. Altos valores de proteína total (70%), FAS (70%), GGT (50%), ALT e b-OH-butirato (40%) foram observados nos cães com diabetes. A concentração sérica de fructosamina nos animais do grupo controle foi de 1.53 mmol/L ± 0.27 e nos diabéticos de 3.24 mmol/L ± 1.16