A dose titration protocol for once-daily insulin glargine 300 U/mL for the treatment of diabetes mellitus in dogs.

BACKGROUND: In purpose-bred dogs, insulin glargine 300 U/mL (IGla300) has long duration of action, peakless time-action profile, and low potency, making it suitable for use as a basal insulin. HYPOTHESIS: To evaluate IGla300 in client-owned diabetic dogs monitored using a flash glucose monitoring system (FGMS). ANIMALS: Ninety-five client-owned diabetic dogs, newly diagnosed or previously treated with other insulin formulations, with or without concurrent diseases. METHODS: Prospective multi-institutional study. Clinical signs and standardized assessment of FGMS data, using treatment and monitoring guidelines established a priori, guided dose adjustments and categorization into levels of glycemic control. RESULTS: The initial IGla300 dose was 0.5 U/Kg q24h for newly diagnosed dogs and (median dose [range]) 0.8 U/Kg (0.2-2.5) q24h for all dogs. Glycemic control was classified as good or excellent in 87/95 (92%) dogs. The IGla300 was administered q24h (1.9 U/kg [0.2-5.2]) and q12h (1.9 U/kg/day [0.6-5.0]) in 56/95 (59%) and 39/95 (41%) dogs, respectively. Meal-time bolus injections were added in 5 dogs (0.5 U/kg/injection [0.3-1.0]). Clinical hypoglycemia occurred in 6/95 (6%) dogs. Dogs without concurrent diseases were more likely to receive IGla300 q24h than dogs with concurrent diseases (72% vs 50%, respectively; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Insulin glargine 300 U/mL can be considered a suitable therapeutic option for once-daily administration in diabetic dogs. Clinicians should be aware of the low potency and wide dose range of IGla300. In some dogs, twice-daily administration with or without meal-time bolus injections may be necessary to achieve glycemic control. Monitoring with FGMS is essential for dose titration of IGla300.

Drug release profile of a novel exenatide long-term drug delivery system (OKV-119) administered to cats.

Beneficial weight-loss properties of glucagon-like peptide-1 receptor agonists (GLP-1RA) in obese people, with corresponding improvements in cardiometabolic risk factors, are well established. OKV-119 is an investigational drug delivery system that is being developed for the long-term delivery of the GLP-1RA exenatide to feline patients. The purpose of this study was to evaluate the drug release characteristics of subcutaneous OKV-119 implants configured to release exenatide for 84 days. Following a 7-day acclimation period, five purpose-bred cats were implanted with OKV-119 protypes and observed for a 112-day study period. Food intake, weekly plasma exenatide concentrations and body weight were measured. Exenatide plasma concentrations were detected at the first measured timepoint (Day 7) and maintained above baseline for over 84 Days. Over the first 28 days, reduced caloric intake and a reduction in body weight were observed in four of five cats. In these cats, a body weight reduction of at least 5% was maintained throughout the 112-day study period. This study demonstrates that a single OKV-119 implant can deliver the GLP-1RA exenatide for a months long duration. Results suggest that exposure to exenatide plasma concentrations ranging from 1.5 ng/ml to 4 ng/ml are sufficient for inducing weight loss in cats.

Magnet-assisted endoscopic removal of ferromagnetic metallic gastric foreign bodies in 4 dogs.

OBJECTIVE: Describe presenting signs, diagnostic findings, and magnet-assisted endoscopic removal method of ferromagnetic gastric foreign bodies (FBs) in dogs. CLINICAL PRESENTATION: Four dogs presented with ingestion of sharp metallic FBs. The presence of gastric FBs was confirmed by abdominal radiography. RESULTS: In 3 cases, initial attempts at endoscopic removal were unsuccessful because of ingesta and fluid in the stomach. A magnet contained within a Roth net was introduced endoscopically. Magnet and attached objects were successfully removed from the stomach. In the fourth case, removal with a magnet was judged to be the most expedient method of removal because multiple metallic objects were present. CLINICAL RELEVANCE: An endoscopic technique was used for the removal of difficult-to-visualize or multiple metallic FBs. The use of this technique allows the removal of ferromagnetic gastric FBs without surgery or risk of complications associated with the passage of sharp material through the gastrointestinal (GI) tract.

Isolation of feline islets of Langerhans by selective osmotic shock produces glucose responsive islets.

Introduction: Pancreatic islet isolation is essential for studying islet physiology, pathology, and transplantation, and feline islets could be an important model for human type II diabetes mellitus (T2D). Traditional isolation methods utilizing collagenases inflict damage and, in cats, may contribute to the difficulty in generating functional islets, as demonstrated by glucose-stimulated insulin secretion (GSIS). GLUT2 expression in ß cells may allow for adaptation to hyperosmolar glucose solutions while exocrine tissue is selectively disrupted. Methods: Here we developed a protocol for selective osmotic shock (SOS) for feline islet isolation and evaluated the effect of different hyperosmolar glucose concentrations (300 mmol/L and 600 mmol/L) and incubation times (20 min and 40 min) on purity, morphology, yield, and GSIS. Results: Across protocol treatments, islet yield was moderate and morphology excellent. The treatment of 600 mmol/L glucose solution with 20 min incubation resulted in the highest stimulation index by GSIS. Discussion: Glucose responsiveness was demonstrated, permitting future in vitro studies. This research opens avenues for understanding feline islet function and transplantation possibilities and enables an additional islet model for T2D.

Spontaneous remission and relapse of diabetes mellitus in a male dog.

An 8-year-old male neutered Miniature Schnauzer was diagnosed with diabetes mellitus based on fasting hyperglycemia and glucosuria after a 2-week history of polydipsia and periuria, in line with the Agreeing Language in Veterinary Endocrinology consensus definition. Treatment of insulin and dietary management was initiated. The insulin dose was gradually reduced and eventually discontinued over the next year based on spot blood glucose concentrations that revealed euglycemia or hypoglycemia. After discontinuation, the dog remained free of clinical signs for 1 year until it was again presented for polyuria/polydipsia with fasting hyperglycemia and glucosuria. Insulin therapy was resumed and continued for the remainder of the dog's life. Although diabetic remission often occurs in cats and humans, the presumed etiopathogenesis of pancreatic beta cell loss makes remission rare in dogs, except for cases occurring with diestrus or pregnancy. This case demonstrates that diabetic remission is possible in dogs, even in cases without an identifiable reversible trigger.

Laparoscopic partial pancreatectomy of the left limb using a harmonic scalpel in nine cats.

OBJECTIVE: To describe a laparoscopic technique and outcome for partial pancreatectomy in cats. STUDY DESIGN: Prospective cohort study. ANIMALS: Nine cats. METHODS: Laparoscopic pancreatectomy was performed using a single incision laparoscopic surgery port and an additional 5.5 mm port. The left pancreatic limb was dissected, sealed and divided at the level of the splenic vein insertion to the portal vein using a harmonic device. Surgical time and complications were recorded. The weight and length of the resected pancreatic limb was recorded. Pre- and postoperative trypsin-like immunoreactivity (TLI), pancreatic lipase immunoreactivity (PLI), and hemoglobin A1C were documented. RESULTS: Laparoscopic partial pancreatectomy was performed successfully in all cats. One grade 1 intraoperative complication occurred (1/9; 11%) resulting in minor hemorrhage from a caudal splenic vein branch. A grade 2 postoperative complication occurred within 3 days after surgery in one cat (1/9; 11%), involving localized, sterile peritonitis in the region of the pancreatic angle. Signs resolved with conservative management. No cats exhibited signs of pancreatitis postoperatively. Long-term, mean TLI decreased by 37% ± 38% (p = .03) following partial pancreatectomy, while PLI and A1C were unchanged. All cats were alive and clinically well at last follow-up 250 to 446 days following surgery. CONCLUSIONS: Laparoscopic partial pancreatectomy using a harmonic device is effective in cats, and offers a minimally-invasive alternative to open surgical pancreatectomy techniques. Laparoscopic pancreatectomy of the left limb results in adequate exocrine and endocrine function in the long-term.

Anemia in canine chronic kidney disease is multifactorial and associated with decreased erythroid precursor cells, gastrointestinal bleeding, and systemic inflammation.

OBJECTIVE: Compare erythropoiesis-related factors between different stages of canine chronic kidney disease (CKD). ANIMALS: 8 healthy adult dogs (controls), and 24 dogs with CKD, equally divided into 3 groups based on International Renal Interest Society-CKD Guidelines (stage 2, 3, and 4) were recruited between December 2012 and December 2014. METHODS: The following were assessed in all dogs and then compared between groups: bone marrow cytology, CBC, reticulocyte count, urinalysis, serum biochemistry, blood pressure, occult gastrointestinal bleeding, and serum concentrations of parathyroid hormone (PTH), erythropoietin, interleukin-1ß, interleukin-3, tumor necrosis factor-α (TNFα), and interferon-γ. RESULTS: Erythropoiesis inducing and suppressing factors and the results of the bone marrow cytology of dogs in stage 2 CKD did not differ from the control group. The presence of reticulocytosis in CKD stage 2 suggests that blood loss or erythrocyte destruction might be contributing to developing anemia. Anemia in dogs with progressive CKD was associated with increasing PTH and TNFα and with elevation of the ratio of myeloid to erythroid precursor cells caused by hypoplasia of the erythroid series. The latter was represented mainly by a decrease in the population of polychromatophilic rubricytes and metarubricytes. CLINICAL RELEVANCE: Increased PTH and TNFα seem to contribute to the reduced percentage of polychromatophilic rubricytes and erythroid population, thereby aggravating the anemia of dogs with advanced CKD. Gastrointestinal blood loss contributes to anemia in all canine CKD stages.

Assessment of the FreeStyle Libre 2 interstitial glucose monitor in hypo- and euglycemic cats.

BACKGROUND: Continuous glucose monitoring systems have been validated for eu- and hyperglycemic cats. The FreeStyle Libre 2 (FSL2) is sufficiently accurate in people during hypoglycemia to guide critical treatment decisions without confirmation of blood glucose concentration (BG). OBJECTIVES: Assess FSL2 accuracy in cats with hypoglycemia. ANIMALS: Nine healthy, purpose-bred cats. METHODS: Hyperinsulinemic-hypoglycemic clamps were performed by IV infusion of regular insulin (constant rate) and glucose (variable rate). Interstitial glucose concentration (IG), measured by FSL2, was compared to BG measured by AlphaTrak2. Data were analyzed for all paired measurements (n = 364) and separately during stable BG (≤1 mg/dL/min change over 10 minutes). Pearson's r test, Bland-Altman test, and Parkes Error Grid analysis respectively were used to determine correlation, bias, and clinical accuracy (P < .05 considered significant). RESULTS: Overall, BG and IG correlated strongly (r = 0.83, P < .0001) in stable glycemia and moderately at all rates of change (r = 0.69, P < .0001). Interstitial glucose concentration underestimated BG in euglycemia, but the BG-IG difference was progressively smaller as BG decreased (12.9 ± 12.2, 8.8 ± 11.2, -3.2 ± 7.4, and -7.8 ± 5.2 mg/dL in the ranges of 80-120 [n = 64], 60-79 [n = 29], 50-59 [n = 71], and 29-49 mg/dL [n = 53], respectively). CONCLUSIONS: Although IG underestimates BG throughout most of the hypo-euglycemic range, IG generally overestimates BG in marked hypoglycemia (<60 mg/dL). It is therefore imperative to evaluate FSL2 results in this critical range with caution.

Establishment of a feline glycated hemoglobin reference interval for a novel dried-blood-spot assay and the effects of anemia on assay results.

BACKGROUND: Glycated hemoglobin A1c (HbA1c) reflects long-term (months) glycemic control and has been previously investigated as a monitoring and diagnostic tool in diabetic cats. However, a standardized, reliable, and globally available test and reference intervals (RIs) have not been established. A novel dried-blood-spot card system (A1Care, Baycom Diagnostics) allows for easy collection and evaluation of HbA1c levels in feline patients. OBJECTIVE: We aimed to establish an RI for HbA1c values in healthy adult cats using the A1Care (Baycom Diagnostics) dried-blood-spot card system. METHODS: Forty-one healthy client-owned adult cats were enrolled in this study. The RI for HbA1c was calculated according to the recommendation of the American Society for Veterinary Clinical Pathology. RESULTS: The A1Care HbA1c RI for cats was determined to be 1.9%-3.1%. In healthy cats, A1Care HbA1c values were positively correlated with age (Spearman rho = 0.4 [95% CI 0.1 to 0.6], P = 0.01). In 50% of anemic cats, the A1Care HbA1c value was above 3.1%. There was a weak negative correlation between the A1Care HbA1c value and PCV (Spearman rho = -0.4 [95% CI -0.6 to -0.1]). CONCLUSIONS: This study established an RI for HbA1c in healthy adult cats similar to previously reported RIs. Future clinical studies are necessary to substantiate that this RI can differentiate diabetic from nondiabetic cats. Further long-term clinical studies will be valuable to determine if HbA1c values can be used as a screening test for prediabetes in cats.

Case report: Androgen-secreting adrenocortical tumors in eight cats.

Urine marking, aggression, and other behavioral concerns are common reasons for cat owners to seek veterinary care. Empiric treatment for lower urinary tract disease or primary behavior disorders are commonly pursued, especially in those cases with normal routine laboratory evaluations. Herein, we report the clinicopathologic findings in eight sexually altered cats that were diagnosed with androgen-secreting adrenocortical tumors. Nearly all cats (n = 7) initially were evaluated for inappropriate urination and pungent urine, with additional behavioral concerns including aggression (n = 3) and excess vocalization (n = 4) commonly reported. Penile barbs (n = 5) were identified in all five male cats, and an enlarged clitoris was observed in one female cat. Testing of serum androgen concentrations revealed abnormally high androstenedione (n = 1) or testosterone (n = 7) concentrations. In the five cases with available adrenal tissue, histopathologic evaluation identified either an adrenocortical adenoma (n = 3) or adrenocortical carcinoma (n = 2). Hormonal abnormalities resolved and clinical signs improved in the four cats that underwent surgical adrenalectomy, with each of these cats surviving >1 year. However, clinical signs were minimally impacted with medical treatments, including one cat in which trilostane treatment failed to improve clinical signs or testosterone concentrations. This collection of cases underscores the importance of a detailed physical examination as well as the consideration of endocrine disturbances in cats undergoing evaluation for inappropriate urination or aggression. Furthermore, this report adds to the growing body of evidence that sex-hormone secreting adrenal tumors in cats may be an under-recognized syndrome.

Both Feline Coronavirus Serotypes 1 and 2 Infected Domestic Cats Develop Cross-Reactive Antibodies to SARS-CoV-2 Receptor Binding Domain: Its Implication to Pan-CoV Vaccine Development.

The current study was initiated when our specific-pathogen-free laboratory toms developed unexpectedly high levels of cross-reactive antibodies to human SARS-CoV-2 (SCoV2) receptor binding domain (RBD) upon mating with feline coronavirus (FCoV)-positive queens. Multi-sequence alignment analyses of SCoV2 Wuhan RBD and four strains each from FCoV serotypes 1 and 2 (FCoV1 and FCoV2) demonstrated an amino acid sequence identity of 11.5% and a similarity of 31.8% with FCoV1 RBD (12.2% identity and 36.5% similarity for FCoV2 RBD). The sera from toms and queens cross-reacted with SCoV2 RBD and reacted with FCoV1 RBD and FCoV2 spike-2, nucleocapsid, and membrane proteins, but not with FCoV2 RBD. Thus, the queens and toms were infected with FCoV1. Additionally, the plasma from six FCoV2-inoculated cats reacted with FCoV2 and SCoV2 RBDs, but not with FCoV1 RBD. Hence, the sera from both FCoV1-infected cats and FCoV2-infected cats developed cross-reactive antibodies to SCoV2 RBD. Furthermore, eight group-housed laboratory cats had a range of serum cross-reactivity to SCoV2 RBD even 15 months later. Such cross-reactivity was also observed in FCoV1-positive group-housed pet cats. The SCoV2 RBD at a high non-toxic dose and FCoV2 RBD at a 60-400-fold lower dose blocked the in vitro FCoV2 infection, demonstrating their close structural conformations essential as vaccine immunogens. Remarkably, such cross-reactivity was also detected by the peripheral blood mononuclear cells of FCoV1-infected cats. The broad cross-reactivity between human and feline RBDs provides essential insights into developing a pan-CoV vaccine.

Glucose Counterregulation: Clinical Consequences of Impaired Sympathetic Responses in Diabetic Dogs and Cats.

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.

Insulin Therapy in Small Animals, Part 3: Dogs.

Insulin therapy should ideally mimic a basal-bolus pattern. Lente, NPH, NPH/regular mixes, PZI, glargine U100, and detemir are intermediate-acting formulations that are administered twice daily in dogs. To minimize hypoglycemia, intermediate-acting insulin protocols are usually geared towards alleviating (but not eliminating) clinical signs. Insulin glargine U300 and insulin degludec meet the criteria for an effective and safe basal insulin in dogs. In most dogs, good control of clinical signs is achieved when using a basal insulin alone. In a small minority, bolus insulin at the time of at least one meal per day may be added to optimize glycemic control.

Insulin Therapy in Small Animals, Part 2: Cats.

No insulin formulation should be considered best by default for management of feline diabetes. Rather, the choice of insulin formulation should be tailored to the specific clinical situation. In most cats that have some residual beta cell function, administering only a basal insulin might lead to complete normalization of blood glucose concentrations. Basal insulin requirements are constant throughout the day. Therefore, for an insulin formulation to be effective and safe as a basal insulin, its action should be roughly the same every hour of the day. At present, only insulin glargine U300 approaches this definition in cats.

Insulin Therapy in Small Animals, Part 1: General Principles.

Understanding the pharmacology of insulin and how it relates to the pathophysiology of diabetes can lead to better clinical outcomes. No insulin formulation should be considered "best" by default. Insulin suspensions (NPH, NPH/regular mixes, lente, and PZI) as well as insulin glargine U100 and detemir are intermediate-acting formulations that are administered twice daily. For a formulation to be an effective and safe basal insulin, its action should be roughly the same every hour of the day. Currently, only insulin glargine U300 and insulin degludec meet this standard in dogs, whereas in cats, insulin glargine U300 is the closest option.

Successful multimodal treatment of extreme hypertriglyceridemia in a juvenile diabetic dog.

OBJECTIVE: To describe the therapeutic protocol used to normalize severe hypertriglyceridemia in a dog. CASE SUMMARY: A 7-month-old, 1.2-kg female Pomeranian presented with acute polyuria, polydipsia, and ocular discoloration. Diagnoses included diabetic ketosis, severe hypertriglyceridemia (>225 mmol/L [>20,000 mg/dl]), lipemia retinalis, and bilateral uveitis. The triglyceride concentration was near normal within 2 days of initiating treatment with fenofibrate, regular insulin constant rate infusion (CRI), manual therapeutic plasma exchange (TPE), and a low-fat diet. All clinical signs resolved. The dog has had no relapse of hypertriglyceridemia at the time of writing the manuscript, 6 months later, with continued treatment of diabetes mellitus. NEW OR UNIQUE INFORMATION PROVIDED: This is the first case report documenting the combination of fenofibrate, insulin CRI, and manual TPE for treatment of severe hyperlipidemia in a dog. Detailed protocols for manual TPE and a novel insulin CRI are provided. A discussion of multiple spurious biochemical and hematologic errors associated with the severe hypertriglyceridemia is also provided.

Characterization of clinicopathologic and abdominal ultrasound findings in dogs with glucocorticoid deficient hypoadrenocorticism.

BACKGROUND: Clinical findings of glucocorticoid-deficient hypoadrenocorticism (GDH) can overlap with other diseases, presenting a diagnostic challenge. OBJECTIVES: Describe clinicopathologic and ultrasonographic features of dogs with GDH and those suspected of having GDH that had the disease ruled out. ANIMALS: Six hundred twenty-three dogs. METHODS: Records from dogs with suspected GDH between 2003 and 2018 were reviewed. Dogs with hyperkalemia or hyponatremia were excluded. Dogs were categorized as controls when the resting serum cortisol or post-ACTH cortisol concentration were > 2 µg/dL. Clinicopathologic and ultrasonographic features were compared between groups. The optimal cut-point, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were calculated for individual features used to detect GDH. RESULTS: Dogs were categorized as GDH (n = 29) or controls (n = 594). Lymphocyte count (>1750 cells/L; sensitivity, 96.6%; 95% confidence interval [CI], 82.8%-99.8%; specificity, 60.3%; 95% CI, 56.3%-64.1%; AUC, 0.828; 95% CI, 0.762-0.894) and albumin/globulin ratio (<1.081; sensitivity, 86.2%; 95% CI, 69.4%-94.5%; specificity, 78.8%; 95% CI, 75.3%-81.9%; AUC, 0.886; 95% CI, 0.827-0.944) had the highest discriminatory power between groups. Left adrenal gland width <0.39 cm was 80% (95% CI, 58.4%-91.9%) sensitive and 82.4% (95% CI, 74.2-88.4) specific for GDH. Serum cobalamin concentrations and ultrasonographic abnormalities of the GI tract were not different between groups. CONCLUSION AND CLINICAL IMPORTANCE: No single variable could be used to confidently rule out GDH and obviate the need for cortisol testing in dogs with a clinical presentation consistent with GDH.

Evaluation of a machine learning tool to screen for hypoadrenocorticism in dogs presenting to a teaching hospital.

BACKGROUND: Dogs with hypoadrenocorticism (HA) have clinical signs and clinicopathologic abnormalities that can be mistaken as other diseases. In dogs with a differential diagnosis of HA, a machine learning model (MLM) has been validated to discriminate between HA and other diseases. This MLM has not been evaluated as a screening tool for a broader group of dogs. HYPOTHESIS: An MLM can accurately screen dogs for HA. ANIMALS: Dogs (n = 1025) examined at a veterinary hospital. METHODS: Dogs that presented to a tertiary referral hospital that had a CBC and serum chemistry panel were enrolled. A trained MLM was applied to clinicopathologic data and in dogs that were MLM positive for HA, diagnosis was confirmed by measurement of serum cortisol. RESULTS: Twelve dogs were MLM positive for HA and had further cortisol testing. Five had HA confirmed (true positive), 4 of which were treated for mineralocorticoid and glucocorticoid deficiency, and 1 was treated for glucocorticoid deficiency alone. Three MLM positive dogs had baseline cortisol ≤2 µg/dL but were euthanized or administered glucocorticoid treatment without confirming the diagnosis with an ACTH-stimulation test (classified as "undetermined"), and in 4, HA was ruled out (false positives). The positive likelihood ratio of the MLM was 145 to 254. All dogs diagnosed with HA by attending clinicians tested positive by the MLM. CONCLUSIONS AND CLINICAL IMPORTANCE: This MLM can robustly predict HA status when indiscriminately screening all dogs with blood work. In this group of dogs with a low prevalence of HA, the false positive rates were clinically acceptable.