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Diabetes Mellitus (DM) is a syndrome caused by various etiologies. The clinical manifestations of DM are not indicative of the cause of the disease, but might be indicative of the stage and severity of the disease process. Accurately diagnosing and classifying diabetic dogs and cats by the underlying disease process is essential for current and future studies on early detection, prevention, and treatment of underlying disease. Here, we review the current etiology-based classification of DM and definitions of DM types in human medicine and discuss key points on the pathogenesis of each DM type and prediabetes. We then review current evidence for application of this etiology-based classification scheme in dogs and cats. In dogs, we emphasize the lack of consistent evidence for autoimmune DM (Type 1) and the possible importance of other DM types such as DM associated with exocrine pancreatic disease. While most dogs are first examined because of DM in an insulin-dependent state, early and accurate diagnosis of the underlying disease process could change the long-term outcome and allow some degree of insulin independence. In cats, we review the appropriateness of using the umbrella term of Type 2 DM and differentiating it from DM secondary to other endocrine disease like hypersomatotropism. This differentiation could have crucial implications on treatment and prognosis. We also discuss the challenges in defining and diagnosing prediabetes in cats.

Background: Options for treatment of diabetes mellitus in cats are limited to insulin injections and monitoring for hypoglycemia., Hypothesis: Once daily sodium-glucose cotransporter-2 inhibitor velagliflozin PO is noninferior to insulin injections., Animals: Client-owned diabetic cats (127 safety; 116 efficacy assessment)., Methods: Prospective, randomized (1 mg/kg velagliflozin), positive controlled (titrated Caninsulin), open label, noninferiority field trial, comparing number of cats with treatment success in ≥1 clinical variable and ≥1 glycemic variable (margin Δ: 15%) on Day 45; secondary endpoints included glycemic and clinical assessments during 91 days., Results: On Day 45, 29/54 (54%) velagliflozin-treated cats and 26/62 (42%) Caninsulin-treated cats showed treatment success, demonstrating noninferiority (difference -11.8%; upper 1-sided 97.5% confidence interval, -∞ to 6.3%). By Day 91, quality of life (QoL), polyuria, and polydipsia had improved in 81%, 54% and 61% (velagliflozin); on blood glucose (BG) curves, mean BG was <252 mg/dL in 42/54 (78%; velagliflozin) and 37/62 (60%; Caninsulin); minimum BG was <162 mg/dL in 41/54 (76%; velagliflozin) and 41/62 (66%; Caninsulin); serum fructosamine was <450 μmol/L in 41/54 (76%; velagliflozin) and 38/62 (61%; Caninsulin). Velagliflozin's most frequent adverse events were loose feces/diarrhea (n = 23/61, 38%), positive urine culture (n = 19/61, 31%), and nonclinical hypoglycemia (BG <63 mg/dL; n = 8/61, 13%); Caninsulin's: clinical and nonclinical hypoglycemia (n = 35/66, 53%), positive urine culture (n = 18/66, 27%), and loose feces/diarrhea (n = 10/66, 15%). Diabetic ketoacidosis occurred in 4/61 (7%; velagliflozin) and 0/66 (Caninsulin)., Conclusions and Clinical Importance: Once daily oral administration of velagliflozin was noninferior to insulin injections, showed good QoL and glycemia without clinical hypoglycemia., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: A prediction tool was developed and internally validated to aid the diagnosis of Cushing's syndrome in dogs attending UK primary-care practices. External validation is an important part of model validation to assess model performance when used in different populations., Objectives: To assess the original prediction model's transportability, applicability, and diagnostic performance in a secondary-care practice in the Netherlands., Animals: Two hundred thirty client-owned dogs., Methods: Retrospective observational study. Medical records of dogs under investigation of Cushing's syndrome between 2011 and 2020 were reviewed. Dogs diagnosed with Cushing's syndrome by the attending internists and fulfilling ALIVE criteria were defined as cases, others as non-cases. All dogs were scored using the aforementioned prediction tool. Dog characteristics and predictor-outcome effects in development and validation data sets were compared to assess model transportability. Calibration and discrimination were examined to assess model performance., Results: Eighty of 230 dogs were defined as cases. Significant differences in dog characteristics were found between UK primary-care and Dutch secondary-care populations. Not all predictors from the original model were confirmed to be significant predictors in the validation sample. The model systematically overestimated the probability of having Cushing's syndrome (a = -1.10, P < .001). Calibration slope was 1.35 and discrimination proved excellent (area under the receiver operating curve = 0.83)., Conclusions and Clinical Importance: The prediction model had moderate transportability, excellent discriminatory ability, and overall overestimated probability of having Cushing's syndrome. This study confirms its utility, though emphasizes that ongoing validation efforts of disease prediction tools are a worthwhile effort., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Human patients with mutations within NPPC or NPR2 genes (encoding C-type natriuretic peptide (CNP) and guanylyl cyclase-B (GC-B), respectively) display clinical signs associated with skeletal abnormalities, such as overgrowth or short stature. Mice with induced models of Nppc or Npr2 deletion display profound achondroplasia, dwarfism and early death. Recent pharmacological therapies to treat short stature are utilizing long-acting CNP analogues, but the effects of manipulating CNP expression during development remain unknown. Here, we use Danio rerio (zebrafish) as a model for vertebrate development, employing both pharmacological and reverse genetics approaches to alter expression of genes encoding CNP in zebrafish. Four orthologues of CNP were identified in zebrafish, and spatiotemporal expression profiling confirmed their presence during development. Bioinformatic analyses suggested that nppcl is the most likely the orthologue of mammalian CNP. Exogenous CNP treatment of developing zebrafish embryos resulted in impaired growth characteristics, such as body length, head width and eye diameter. This reduced growth was potentially caused by increased apoptosis following CNP treatment. Expression of endogenous nppcl was downregulated in these CNP-treated embryos, suggesting that negative feedback of the CNP system might influence growth during development. CRISPR knock-down of endogenous nppcl in developing zebrafish embryos also resulted in impaired growth characteristics. Collectively, these data suggest that CNP in zebrafish is crucial for normal embryonic development, specifically with regard to growth.

True insulin resistance should be differentiated from management-related difficulties (eg, short insulin duration, inappropriate insulin injection, inappropriate storage). Hypersomatotropism (HST) is the number one cause of insulin resistance in cats, with hypercortisolism (HC) occupying a more distant second place. Serum insulinlike growth factor-1 is adequate for screening for HST, and screening at the time of diagnosis, regardless of presence of insulin resistance, is advocated. Treatment of either disease centers on removal of the overactive endocrine gland (hypophysectomy, adrenalectomy) or inhibition of the pituitary or adrenal glands by using drugs such as trilostane (HC), pasireotide (HST, HC) or cabergoline (HST, HC)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To estimate the frequency and risk factors for Cushing's syndrome in dogs under UK primary veterinary care., Materials and Methods: Dogs with Cushing's syndrome were identified by searching electronic patient records of primary-care veterinary practices. Pre-existing and incident cases of Cushing's syndrome during 2016 were included to estimate the 1-year period prevalence. Incident cases were used to estimate the annual incidence and to identify demographic risk factors for the diagnosis of Cushing's syndrome in dogs, through multivariable logistic regression., Results: Analysis included 970 pre-existing and 557 incident cases of Cushing's syndrome from a population of 905,544 dogs. The estimated 1-year period prevalence for Cushing's syndrome in dogs under veterinary care was 0.17% (95% confidence interval 0.16 to 0.18) and incidence was 0.06% (95% confidence interval 0.05 to 0.07). In multivariable logistic regression modelling, the Bichon frise (odds ratio=6.17, 95% confidence interval 4.22 to 9.00), Border terrier (5.40, 95% confidence interval 3.66 to 7.97) and Miniature schnauzer (3.05, 95% confidence interval 1.67 to 5.57) had the highest odds of Cushing's syndrome. The Golden retriever (0.24, 95% confidence interval 0.06 to 0.98) and Labrador retriever (0.30, 95% confidence interval 0.17 to 0.54) were the most protected breeds. Increasing age, bodyweight greater than the breed-sex mean and being insured also showed increased odds of Cushing's syndrome., Clinical Significance: As Cushing's syndrome is predominately diagnosed and managed in primary-care practice, this study provides valuable new information of its epidemiology in this setting. Demographics reported are supportive of previous work and additional novel associations identified, such as the Border terrier, could enhance the index of suspicion for veterinarians., (© 2021 The Authors. Journal of Small Animal Practice published by John Wiley & Sons Ltd on behalf of British Small Animal Veterinary Association.)

Cushing's syndrome is an endocrine disease in dogs that negatively impacts upon the quality-of-life of affected animals. Cushing's syndrome can be a challenging diagnosis to confirm, therefore new methods to aid diagnosis are warranted. Four machine-learning algorithms were applied to predict a future diagnosis of Cushing's syndrome, using structured clinical data from the VetCompass programme in the UK. Dogs suspected of having Cushing's syndrome were included in the analysis and classified based on their final reported diagnosis within their clinical records. Demographic and clinical features available at the point of first suspicion by the attending veterinarian were included within the models. The machine-learning methods were able to classify the recorded Cushing's syndrome diagnoses, with good predictive performance. The LASSO penalised regression model indicated the best overall performance when applied to the test set with an AUROC = 0.85 (95% CI 0.80-0.89), sensitivity = 0.71, specificity = 0.82, PPV = 0.75 and NPV = 0.78. The findings of our study indicate that machine-learning methods could predict the future diagnosis of a practicing veterinarian. New approaches using these methods could support clinical decision-making and contribute to improved diagnosis of Cushing's syndrome in dogs.

Background: Hypersomatotropism (HST) is an increasingly recognized endocrinopathy in cats and is mostly described associated with diabetes mellitus (DM)., Objectives: To evaluate the efficacy and safety of transsphenoidal hypophysectomy in treating HST and DM in cats., Animals: Sixty-eight client-owned cats with HST and DM treated by transsphenoidal hypophysectomy., Methods: Retrospective cohort study. Medical records were reviewed for glycemic control and serum insulin-like growth factor-1 (IGF-1) concentrations. Postoperative complications, death within 4 weeks, and proportion achieving diabetic remission were recorded. Survival times and DM-free intervals were calculated., Results: Fifty-eight cats (85.3%) were alive 4 weeks postoperatively with 10 (15%) postoperative deaths. Complications included hypoglycemia (n = 9), electrolyte imbalance (n = 9), and transient congestive heart failure (n = 5). Fifty-five cats (95% of 58 surviving cats [81% of all cats undergoing surgery]) had improved control of diabetes. Diabetic remission occurred in 41 cats (71% of 58 surviving cats [60% of all cats]) with insulin administration discontinued after a median of 9 days (range, 2-120). Postoperative 4-week serum IGF-1 concentration nadir was significantly lower in cats achieving diabetic remission (median 20 ng/mL [15-708] than those that did not (324 ng/mL [15-1955]; P = .03). All cats received long-term levothyroxine and hydrocortisone PO, alongside desmopressin (conjunctival) in 38 of 53 cats (72%). Recurrence of DM occurred in 5 of 41 cats (12%) after a median of 248 days (range, 84-1232). Median survival time of all cats was 853 days (range, 1-1740)., Conclusions and Clinical Importance: Transsphenoidal hypophysectomy is an effective treatment for cats with HST and DM, with a long-term outcome that compares favorably to existing options., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

Background: Novel methods to aid identification of dogs with spontaneous Cushing's syndrome are warranted to optimize case selection for diagnostics, avoid unnecessary testing, and ultimately aid decision-making for veterinarians., Hypothesis/objectives: To develop and internally validate a prediction tool for dogs receiving a diagnosis of Cushing's syndrome using primary-care electronic health records., Animals: Three hundred and ninety-eight dogs diagnosed with Cushing's syndrome and 541 noncase dogs, tested for but not diagnosed with Cushing's syndrome, from a cohort of 905 544 dogs attending VetCompass participating practices., Methods: A cross-sectional study design was performed. A prediction model was developed using multivariable binary logistic regression taking the demography, presenting clinical signs and some routine laboratory results into consideration. Predictive performance of each model was assessed and internally validated through bootstrap resampling. A novel clinical prediction tool was developed from the final model., Results: The final model included predictor variables sex, age, breed, polydipsia, vomiting, potbelly/hepatomegaly, alopecia, pruritus, alkaline phosphatase, and urine specific gravity. The model demonstrated good discrimination (area under the receiver operating curve [AUROC] = 0.78 [95% CI = 0.75-0.81]; optimism-adjusted AUROC = 0.76) and calibration (C-slope = 0.86). A tool was developed from the model which calculates the predicted likelihood of a dog having Cushing's syndrome from 0% (score = -13) to 96% (score = 10)., Conclusions and Clinical Importance: A tool to predict a diagnosis of Cushing's syndrome at the point of first suspicion in dogs was developed, with good predictive performance. This tool can be used in practice to support decision-making and increase confidence in diagnosis., (© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Clinical signs and consequences of Cushing's syndrome are likely to impact upon a dog's life. Quantification of this impact on a dog's health-related quality-of-life (HRQoL) could contribute to optimized disease management., Hypothesis/objectives: To develop a novel HRQoL tool to aid assessment of dogs with Cushing's syndrome and to evaluate factors that impact upon dogs living with this disease., Animals: Two hundred and ten dogs with Cushing's syndrome and 617 dogs without Cushing's syndrome., Methods: Cross-sectional study design. Dog owners answered questions relating to the HRQoL of their dogs which were refined to develop the final tool. The tool was analyzed for reliability, validity, and interpretability, including Cronbach's alpha and principal components analysis. Factors impacting upon the HRQoL of dogs with Cushing's syndrome were assessed using appropriate nonparametric tests., Results: The tool was refined from 32 questions to 19 and showed good internal consistency (α = .83). Owners rated questions related to "owner impact" as more important and those related to demeanor as less important. There was a positive correlation between the tool score of dogs with Cushing's syndrome and owner's assessment of their dog's quality-of-life (r = .41, P < .001). Dogs currently on treatment with trilostane had a statistically better HRQoL (.33, interquartile range [IQR] .23-.44) than those not receiving trilostane (.36, IQR .33-.54, P = .04)., Conclusions and Clinical Importance: The developed tool quantifies the HRQoL of dogs with Cushing's syndrome and could assist clinicians in the clinical assessment of dogs with Cushing's syndrome., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

The prevalence of GH-secreting pituitary tumors in domestic cats ( Felis catus ) is 10-fold greater than in humans. The predominant inhibitory receptors of GH-secreting pituitary tumors are somatostatin receptors (SSTRs) and D 2 dopamine receptor (DRD2). The expression of these receptors is associated with the response to somatostatin analog and dopamine agonist treatment in human patients with acromegaly. The aim of this study was to describe pathological features of pituitaries from domestic cats with acromegaly, pituitary receptor expression, and investigate correlates with clinical data, including pituitary volume, time since diagnosis of diabetes, insulin requirement, and serum IGF1 concentration. Loss of reticulin structure was identified in 15 of 21 pituitaries, of which 10 of 15 exhibited acinar hyperplasia. SSTR1 , SSTR2 , SSTR5 , and DRD2 mRNA were identified in the feline pituitary whereas SSTR3 and SSTR4 were not. Expression of SSTR1 , SSTR2 , and SSTR5 was greater in acromegalic cats compared with controls. A negative correlation was identified between DRD2 mRNA expression and pituitary volume. The loss of DRD2 expression should be investigated as a mechanism allowing the development of larger pituitary tumors.

An 8-year-old castrated male border terrier dog was diagnosed with acromegaly resulting from a growth hormone secreting pituitary tumor. Sixteen daily fractions of radiation therapy were delivered followed, approximately 1 year later, by administration of pasireotide. The aforementioned treatment was considered effective and should be further evaluated in similar cases., Competing Interests: Conflict of interest declaration: Dr. Herbert A. Schmid is employed by Novartis Pharma AG, Basel which manufactures and markets pasireotide for the treatment of hyperadrenocorticism and hypersomatotropism in humans.

Background: In humans, acromegaly due to a pituitary somatotrophic adenoma is a recognized cause of increased left ventricular (LV) mass. Acromegalic cardiomyopathy is incompletely understood, and represents a major cause of morbidity and mortality. We describe the clinical, echocardiographic and histopathologic features of naturally occurring feline acromegalic cardiomyopathy, an emerging disease among domestic cats., Methods: Cats with confirmed hypersomatotropism (IGF-1>1000ng/ml and pituitary mass; n = 67) were prospectively recruited, as were two control groups: diabetics (IGF-1<800ng/ml; n = 24) and healthy cats without known endocrinopathy or cardiovascular disease (n = 16). Echocardiography was performed in all cases, including after hypersomatotropism treatment where applicable. Additionally, tissue samples from deceased cats with hypersomatotropism, hypertrophic cardiomyopathy and age-matched controls (n = 21 each) were collected and systematically histopathologically reviewed and compared., Results: By echocardiography, cats with hypersomatotropism had a greater maximum LV wall thickness (6.5mm, 4.1-10.1mm) than diabetic (5.9mm, 4.2-9.1mm; Mann Whitney, p<0.001) or control cats (5.2mm, 4.1-6.5mm; Mann Whitney, p<0.001). Left atrial diameter was also greater in cats with hypersomatotropism (16.6mm, 13.0-29.5mm) than in diabetic (15.4mm, 11.2-20.3mm; Mann Whitney, p<0.001) and control cats (14.0mm, 12.6-17.4mm; Mann Whitney, p<0.001). After hypophysectomy and normalization of IGF-1 concentration (n = 20), echocardiographic changes proved mostly reversible. As in humans, histopathology of the feline acromegalic heart was dominated by myocyte hypertrophy with interstitial fibrosis and minimal myofiber disarray., Conclusions: These results demonstrate cats could be considered a naturally occurring model of acromegalic cardiomyopathy, and as such help elucidate mechanisms driving cardiovascular remodeling in this disease.

Current pet diabetes mellitus (DM) treatment necessitates the active daily involvement of owners and can be costly. The current study aimed to investigate the owner population which opts for euthanasia instead of DM treatment. A survey was designed using multiple feedback steps and made available online to veterinarians world-wide. A total of 1192 veterinarians completed the survey and suggested a median one in 10 diabetic pets are euthanased at diagnosis; a further median one in 10 within one year because of lack of success or compliance. Perceived most important motivating factors included "presence concurrent disease" (45% respondents); "costs" (44%); "animal age" (37%); "problems obtaining adequate control" (35%); "pet welfare" (35%); and "impact owner's lifestyle" (32%). Cats in Canadian (odds ratio (OR) 2.7), Australian (OR 2.3), rural (OR 1.6) and mixed (OR 1.7) practices were more likely to be euthanased because of DM diagnosis, while cats presented to referral/university were less likely to be euthanased (OR 0.6). Dogs were more likely to be euthanased because of DM in Canadian (OR 1.8), rural (OR 1.8) and mixed (OR 1.6) practices. The survey results suggest that benefit exists in improved DM education with emphasis on offering a choice of treatment styles ranging from intense and expensive to hands-off and cheap., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.