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

Diabetes mellitus remission in three cats with hypersomatotropism after cabergoline treatment

Three diabetic cats presented with polyuria, polydipsia, polyphagia and poor glycemic control. Cat 1 displayed prognathia inferior and had a body condition score (BCS) of 4/5; cat 2 had a BCS of 5/5; and cat 3 had broad facial features. Serum insulin-like growth factor 1 concentrations were compatible with hypersomatotropism in cat 1 and cat 2 (>1500 ng/ml and 1200 ng/ml, respectively) and just below the cut-off of 1000 ng/ml (947 ng/ml) in cat 3; in this last cat diagnosis was further supported by the presence of pituitary enlargement on MRI. Oral cabergoline (10 μg/kg q48h) was initiated. Insulin requirements progressively reduced, as evidenced by daily blood glucose monitoring and weekly blood glucose curves. Diabetic remission occurred in all three cats between the second and third months of cabergoline treatment. At the time of writing, remission has persisted thus far (cat 1: 23 months; cat 2: 14 months; cat 3: 38 months). Relevance and novel information: To our knowledge, these are the first reported cases of diabetic remission in cats with hypersomatotropism after cabergoline treatment, despite previous reports of this being an ineffective treatment. Further work is indicated to determine why some cats do, and others do not, respond to this treatment.Fil: Miceli, Diego Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires; ArgentinaFil: Vidal, Patricia Noemi. Universidad de Buenos Aires; ArgentinaFil: Pompili, Gustavo A. Universidad de Buenos Aires; ArgentinaFil: Castillo, Víctor A. Universidad de Buenos Aires; ArgentinaFil: Soler Arias, Elber A. Universidad de Buenos Aires; ArgentinaFil: Niessen, Stijn JM. Royal Veterinary College University ; Reino Unid

Pegylated-l-asparaginase therapy for feline large cell lymphoma: 82 cases (2017-2020)

OBJECTIVES: The present study aimed to investigate pegylated-l-asparaginase monotherapy for feline large cell lymphoma as a potential alternative to palliative corticosteroids treatment in animals whose owners declined cytotoxic chemotherapy. METHODS: A retrospective, descriptive case series of cats treated initially with pegylated-l-asparaginase as a sole therapy for feline large cell lymphoma is reported. The treatment protocol consisted of 12 intramuscular injections of pegylated-l-asparaginase with increasing intervals. If cats were unresponsive to pegylated-l-asparaginase monotherapy, a second-line treatment was initiated. Signalment, origin of lymphoma, staging, treatment, possible adverse events and follow-up data were extracted from the medical records. Responses and survival data were analysed. RESULTS: Eighty-two cats with lymphoma of five different anatomic types were included: alimentary, abdominal extra-alimentary, peripheral nodal, nasal/nasopharyngeal and other (mediastinal, renal [solitary] and miscellaneous combined in one group for analytical purposes). The response rate was 74.1% (95% confidence interval = 63.4-83.5) with 38.3% (95% confidence interval = 27.8-48.8) in complete remission. The median disease-free period and calculated overall survival time were 70 days (12-1702+) and 79 days (1-1715+), respectively. The response rate was significantly correlated with the origin of the lymphoma and the combined group had a significantly lower response rate ( P  = 0.035). Twenty-four cats were also treated with corticosteroids. There was no significant difference in outcomes between the group treated with or without corticosteroids. Adverse events were present in a small number of cats (14/82). The majority of these adverse events were mild to moderate in 5/14 cats; however, the adverse events were severe enough to cause discontinuation of therapy. CONCLUSIONS AND RELEVANCE: Based on the response rate and median disease-free period, treatment with pegylated-l-asparaginase is inferior when compared with historical chemotherapy protocols. However, some cats demonstrated an exceptional long disease-free period. Therefore, pegylated-l-asparaginase could be offered as an alternative to corticosteroid therapy alone. Further studies are needed to evaluate the additional benefit over palliative corticosteroid monotherapy

Time spent with cats is never wasted: Lessons learned from feline acromegalic cardiomyopathy, a naturally occurring animal model of the human disease

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p></div

Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes.

The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells. Stimulation of GH3 cells with CNP resulted in a rapid and sustained enhancement of ERK1/2 phosphorylation (P-ERK1/2), an effect that was not mimicked by dibutryl-cGMP. Furthermore, CNP-stimulated P-ERK1/2 occurred at concentrations below that required for cGMP accumulation. The effect of CNP on P-ERK1/2 was sensitive to pharmacological blockade of MEK (U0126) and Src kinases (PP2). Silencing of the GC-B1 and GC-B2 splice variants of the GC-B receptor by using targeted short interfering RNAs completely blocked the CNP effects on P-ERK1/2. CNP failed to alter GH3 cell proliferation or cell cycle distribution but caused a concentration-dependent increase in the activity of the human glycoprotein α-subunit promoter (αGSU) in a MEK-dependent manner. Finally, CNP also activated the p38 and JNK MAPK pathways in GH3 cells. These findings reveal an additional mechanism of GC-B signalling and suggest additional biological roles for CNP in its target tissues

Pharmacological and Genetic Disruption of C-Type Natriuretic Peptide (nppcl) Expression in Zebrafish (Danio rerio) Causes Stunted Growth during Development.

Peer reviewed: TrueFunder: Society for EndocrinologyHuman 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

Quality of life and response to treatment in cats with hypersomatotropism: the owners’ point of view

Objectives The aim of this study was to collect clinical information from owners of cats with hypersomatotropism (HS) distributed worldwide, assessing the impact of HS and its treatments on cats’ quality of life (QoL) and survival time. Methods A survey focused on clinical presentation, diagnostic procedures, treatments, cats’ QoL and disease progression was distributed worldwide to owners of cats with HS. The owner’s perception of the cats’ QoL before and after or during treatment was defined using a score ranging from 1 (poor) to 5 (excellent). Improvement following treatment (IFT) was quantified using a score ranging from 1 (absent) to 5 (obvious). Different treatment groups, including at least five cases, were compared. Results A total of 127 cats were included from at least 11 different countries. Among these, 120 (95%) were diabetic and 7 (5%) were not. Out of 120 diabetic cats, 55 (46%) were treated with insulin as a single treatment (INS). Other treatments were not mentioned to owners in 35/120 (29%) cases. The median QoL score at diagnosis was 2 (range 1–5) and improved after treatment in all groups. Cabergoline (4; range 1–5), radiotherapy (4; range 2–5) and hypophysectomy (5; range 4–5) showed better median IFT scores compared with INS (3; range 1–5) ( P = 0.046, P <0.002 and P <0.0001, respectively). Hypophysectomy IFT proved superior to cabergoline ( P = 0.047) and was equal to radiotherapy IFT ( P = 0.32). No difference was found between cabergoline and radiotherapy IFT ( P = 0.99). The median survival time (MST) was 24 months (range 0–75 months). Cats treated with INS showed shorter MST (22 months; range 0–69 months) compared with cats treated with causal treatments combined (36 months; range 3–75 months) ( P = 0.04). Conclusions and relevance Not all cats with HS will have diabetes mellitus. Causal treatments seem associated with the greatest improvements in perceived cats’ QoL and survival; such treatments should therefore be discussed with owners. Cabergoline could be an effective alternative management option