Yaiza Forcada

Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus

When confronted with a diabetic cat in clinical practice, it is tempting to assume it has a form of diabetes mellitus akin to human type 2 diabetes mellitus (diabetes). For most diabetic cats examined, this will indeed be justified. Nevertheless, a significant proportion have other specific types of diabetes with distinctly different etiologies. This article discusses the concept of other specific types of feline diabetes caused by endocrinopathies, and more specifically feline hypersomatotropism, acromegaly, and hyperadrenocorticism, including relevance, presentation, diagnosis, and therapy.

Studying Cat (Felis catus) Diabetes: Beware of the Acromegalic Imposter

Naturally occurring diabetes mellitus (DM) is common in domestic cats (Felis catus). It has been proposed as a model for human Type 2 DM given many shared features. Small case studies demonstrate feline DM also occurs as a result of insulin resistance due to a somatotrophinoma. The current study estimates the prevalence of hypersomatotropism or acromegaly in the largest cohort of diabetic cats to date, evaluates clinical presentation and ease of recognition. Diabetic cats were screened for hypersomatotropism using serum total insulin-like growth factor-1 (IGF-1; radioimmunoassay), followed by further evaluation of a subset of cases with suggestive IGF-1 (>1000 ng/ml) through pituitary imaging and/ or histopathology. Clinicians indicated pre-test suspicion for hypersomatotropism. In total 1221 diabetic cats were screened; 319 (26.1%) demonstrated a serum IGF-1>1000 ng/ml (95% confidence interval: 23.6–28.6%). Of these cats a subset of 63 (20%) underwent pituitary imaging and 56/63 (89%) had a pituitary tumour on computed tomography; an additional three on magnetic resonance imaging and one on necropsy. These data suggest a positive predictive value of serum IGF-1 for hypersomatotropism of 95% (95% confidence interval: 90–100%), thus suggesting the overall hypersomatotropism prevalence among UK diabetic cats to be 24.8% (95% confidence interval: 21.2–28.6%). Only 24% of clinicians indicated a strong pre-test suspicion; most hypersomatotropism cats did not display typical phenotypical acromegaly signs. The current data suggest hypersomatotropism screening should be considered when studying diabetic cats and opportunities exist for comparative acromegaly research, especially in light of the many detected communalities with the human disease.

Systematic review of feline diabetic remission: Separating fact from opinion

It is increasingly recognised that diabetic remission is possible in the cat. This systematic review, following Cochrane Collaboration (CC) guidelines, critically appraises the level of evidence on factors influencing remission rate and factors predicting remission. A systematic online, bibliographic search and reference list examination was conducted. A level of evidence was assigned to each identified article by five internists using the Newcastle-Ottawa Scale for follow-up, cohort, case-series and case-control studies, the CCs risk of bias tool for trials and the Cochrane Effective Practice and Organisation of Care Group risk of bias criteria for before and after trials. Twenty-two studies were included in the review, assessing influence of pharmaceutical intervention (n = 14) and diet (n = 4), as well as diagnostic tests (n = 9) and feline patient characteristics (n = 5) as predictors of remission. The current level of evidence was found to be moderate to poor. Common sources of bias included lack of randomisation and blinding among trials, and many studies were affected by small sample size. Failure to provide criteria for the diagnosis of diabetes, or diabetic remission, and poor control of confounding factors were frequent causes of poor study design. Addressing these factors would significantly strengthen future research and ultimately allow meta-analyses to provide an excellent level of evidence. No single factor predicts remission and successful remission has been documented with a variety of insulin types and protocols. Dietary carbohydrate reduction might be beneficial, but requires further study. A lack of well-designed trials prevents reliable remission rate comparison. Factors associated with remission resemble those in human medicine and support the hypothesis that reversal of glucotoxicity is a major underlying mechanism for feline diabetic remission.

Computed tomographic signs of acromegaly in 68 diabetic cats with hypersomatotropism

In order to describe the signs of acromegaly in cats, a case-control study was done based on computed tomography (CT) scans of the heads of 68 cats with hypersomatotropism and 36 control cats. All cats with a diagnosis of hypersomatotropism had diabetes mellitus, serum insulin-like growth factor-1 >1000 ng/ml and a pituitary mass. Measurements of bones and soft tissues were done by two independent observers without knowledge of the diagnosis. Pituitary masses were identified in CT images of 64 (94%) cats with hypersomatotropism. Analysis of variance found a moderate effect of gender on the size of bones and a large effect of hypersomatotropism on the size of bones and thickness of soft tissues. In cats with hypersomatotropism the frontal and parietal bones were, on average, 0.8 mm thicker (P <0.001); the distance between the zygomatic arches was, on average, 5.4 mm greater (P <0.001); and the mandibular rami were, on average, 1.1 mm thicker (P <0.001) than in control cats. The skin and subcutis dorsal to the frontal bone were, on average, 0.4 mm thicker (P = 0.001); lateral to the zygomatic arch were, on average, 0.7 mm thicker (P <0.001); and ventral to the mandibular rami were, on average, 1.1 mm thicker (P = 0.002) in cats with hypersomatotropism than in control cats. The cross-sectional area of the nasopharynx was, on average, 11.1 mm2 smaller in cats with hypersomatotropism than in control cats (P = 0.02). Prognathia inferior and signs of temporomandibular joint malformation were both observed more frequently in cats with hypersomatotropism than in control cats (P = 0.03). Overall, differences between affected and unaffected cats were small. Recognising feline acromegaly on the basis of facial features is difficult.

Pasireotide for the Medical Management of Feline Hypersomatotropism.

Background Feline hypersomatotropism (HST) is a cause of diabetes mellitus in cats. Pasireotide is a novel multireceptor ligand somatostatin analog that improves biochemical control of humans with HST. Hypothesis/Objectives Pasireotide improves biochemical control of HST and diabetes mellitus in cats. Animals Hypersomatotropism was diagnosed in diabetic cats with serum insulin‐like growth factor‐1 (IGF‐1) concentration >1,000 ng/mL by radioimmunoassay and pituitary enlargement. Methods Insulin‐like growth factor 1 was measured and glycemic control assessed using a 12‐hour blood glucose curve on days 1 and 5. On days 2, 3, and 4, cats received 0.03 mg/kg pasireotide SC q12h. IGF‐1, insulin dose, and estimated insulin sensitivity (product of the area under the blood glucose curve [BGC] and insulin dose) were compared pre‐ and post treatment. Paired t‐tests or Wilcoxon signed rank tests were employed for comparison where appropriate; a linear mixed model was created to compare BGC results. Results Insulin‐like growth factor 1 decreased in all 12 cats that completed the study (median [range] day 1: 2,000 ng/mL [1,051–2,000] and day 5: 1,105 ng/mL [380–1,727], P = .002, Wilcoxon signed rank test). Insulin dose was lower on day 5 than on day 1 (mean reduction 1.3 [0–2.7] units/kg/injection, P = .003, paired t‐test). The product of insulin dose and area under the BGC was lower on day 5 than day 1 (difference of means: 1,912; SD, 1523; u × mg/dL × hours, P = .001; paired t‐test). No clinically relevant adverse effects were encountered. Conclusions Short‐acting pasireotide rapidly decreased IGF‐1 in cats with HST and insulin‐dependent diabetes. The decrease in IGF‐1 was associated with increased insulin sensitivity.

Screening diabetic cats for hypersomatotropism: performance of an enzyme-linked immunosorbent assay for insulin-like growth factor 1

Screening diabetic cats for feline hypersomatotropism (HS) is currently dependent on using a radioimmunoassay (RIA) for measurement of growth hormone or insulin-like growth factor 1 (IGF-1), both of which require radioactivity, are costly and have limited availability. Performance of an enzyme-linked immunosorbent assay (ELISA) using anti-human IGF-1 antibodies was assessed. Total IGF-1 was determined in diabetic cat samples across a wide range of IGF-concentrations using a previously validated RIA (serum: 92 cats; plasma: 31 cats). Repeat IGF-1 measurement was then performed using the ELISA-system. Mean IGF-1 recovery after serial dilution proved satisfactory with a correlation coefficient of 0.96 (serum) and 0.97 (plasma). Appropriate precision was established [intra-assay coefficient of variation (CV) 9.5 ± 2% (serum) and 13.6 ± 7% (plasma); inter-assay CV 11.4 ± 4% (serum) and 7.6 ± 6% (plasma)] and significant effect of hyperlipidaemia, haemoglobinaemia, bilirubinaemia and storage was excluded, with the exception of an increase in serum IGF-1 when left at room temperature for more than 24 h. ELISA concentrations correlated significantly with RIA concentrations (serum Pearson r2: 0.75; plasma: 0.83, P <0.001). Receiver operating characteristics analysis showed an area under the curve of 0.99 (serum) and 0.96 (plasma), and indicated high diagnostic accuracy for categorising a diabetic cat correctly as suspicious for HS at a serum IGF-1 cut-off of 997 ng/ml (sensitivity, 100%; specificity, 88.1%). The current study is the first to validate an easy-to-use and economical IGF-1 ELISA for the screening for HS among diabetic cats, which is important given the suspected significant prevalence of HS-induced diabetes mellitus.

Pasireotide Long-Acting Release Treatment for Diabetic Cats with Underlying Hypersomatotropism

Background Long‐term medical management of hypersomatotropism (HS) in cats has proved unrewarding. Pasireotide, a novel somatostatin analogue, decreases serum insulin‐like growth factor 1 (IGF‐1) and improves insulin sensitivity in cats with HS when administered as a short‐acting preparation. Objectives Assess once‐monthly administration of long‐acting pasireotide (pasireotide LAR) for treatment of cats with HS. Animals Fourteen cats with HS, diagnosed based on diabetes mellitus, pituitary enlargement, and serum IGF‐1 > 1000 ng/mL. Methods Uncontrolled, prospective cohort study. Cats received pasireotide LAR (6–8 mg/kg SC) once monthly for 6 months. Fructosamine and IGF‐1 concentrations, and 12‐hour blood glucose curves (BGCs) were assessed at baseline and then monthly. Product of fructosamine concentration and insulin dose was calculated as an indicator of insulin resistance (Insulin Resistance Index). Linear mixed‐effects modeling assessed for significant change in fructosamine, IGF‐1, mean blood glucose (MBG) of BGCs, insulin dose (U/kg) and Insulin Resistance Index. Results Eight cats completed the trial. Three cats entered diabetic remission. Median IGF‐1 (baseline: 1962 ng/mL [range 1051–2000 ng/mL]; month 6: 1253 ng/mL [524–1987 ng/mL]; P < .001) and median Insulin Resistance Index (baseline: 812 μmolU/L kg [173–3565 μmolU/L kg]; month 6: 135 μmolU/L kg [0–443 μmolU/L kg]; P = .001) decreased significantly. No significant change was found in mean fructosamine (baseline: 494 ± 127 μmol/L; month 6: 319 ± 113.3 μmol/L; P = .07) or MBG (baseline: 347.7 ± 111.0 mg/dL; month 6: 319.5 ± 113.3 mg/dL; P = .11), despite a significant decrease in median insulin dose (baseline: 1.5 [0.4–5.2] U/kg; 6 months: 0.3 [0.0–1.4] U/kg; P < .001). Adverse events included diarrhea (n = 11), hypoglycemia (n = 5), and worsening polyphagia (n = 2). Conclusions and Clinical Importance Pasireotide LAR is the first drug to show potential as a long‐term management option for cats with HS.

Prospective evaluation of a protocol for transitioning porcine lente insulin-treated diabetic cats to human recombinant protamine zinc insulin:

Objectives The objective was to evaluate a nadir-led protocol for transitioning porcine lente insulin suspension (PLIS)-treated diabetic cats onto human recombinant protamine zinc insulin (PZIR). Methods Recently diagnosed (<5 months) diabetic cats, treated with PLIS q12h for ⩾6 weeks, were recruited. Fructosamine, 24 h blood glucose curve (BGC), quality of life assessment (DIAQoL-pet score) and Diabetic Clinical Score (DCS) were assessed at enrolment (PLIS-treated) and 2, 4 and 12 weeks after transitioning to PZIR (starting dose 0.2–0.7 U/kg q12h). Short duration of insulin action was defined as <9 h. Linear mixed effects modelling assessed for change in fructosamine, mean blood glucose (MBG) during BGCs, DIAQoL-pet score, DCS and q12h insulin dose. McNemar’s tests compared the proportion of cats with hypoglycaemia at week 0 (PLIS-treated) and week 4 (PZIR-treated). Results Twenty-two cats were recruited. Median PLIS dose at enrolment was 0.5 U/kg (interquartile range 0.3–0.7 U/kg) q12h, equalling median PZIR starting dose (0.5 U/kg; interquartile range 0.3–0.7 U/kg q12h). Transitioning was followed by significant decreases in fructosamine (P = 0.00007), insulin dose (P = 0.02), DCS (P = 8.1 × 10−8) and DIAQoL-pet score (P = 0.003), indicating improved quality of life. MBG did not alter significantly (P = 0.1). Five cats (22.7%) achieved remission. Hypoglycaemia was recorded in 30/190 12 h BGCs (15.8%) and five cats experienced clinical hypoglycaemia. The proportion of cats with hypoglycaemia did not differ between PLIS (week 0) and PZIR (week 4) (P = 1.0). Duration of action was analysed in 19 cats. Six cats (31.6%) showed short duration of action on PLIS, compared with two cats (10.5%) after 4 weeks on PZIR. All six cats with short PLIS duration showed duration of ⩾9 h on PZIR. Conclusions and relevance Used alongside a low-carbohydrate diet, transitioning to PZIR was associated with significantly improved clinical signs and quality of life, with some cats achieving remission. Transition to PZIR should be considered for cats with short duration of action on PLIS.

Evaluation and Diagnostic Potential of Serum Ghrelin in Feline Hypersomatotropism and Diabetes Mellitus

Background Ghrelin is a growth hormone secretagogue. It is a potent regulator of energy homeostasis. Ghrelin concentration is down‐regulated in humans with hypersomatotropism (HS) and increases after successful treatment. Additionally, ghrelin secretion seems impaired in human diabetes mellitus (DM). Hypothesis Serum ghrelin concentration is down‐regulated in cats with HS‐induced DM (HSDM) compared to healthy control cats or cats with DM unrelated to HS and increases after radiotherapy. Animals Cats with DM (n = 20) and with HSDM (n = 32), 13 of which underwent radiotherapy (RT‐group); age‐matched controls (n = 20). Methods Retrospective cross‐sectional study. Analytical performance of a serum total ghrelin ELISA was assessed and validated for use in cats. Differences in serum ghrelin, fructosamine, IGF‐1 and insulin were evaluated. Results Ghrelin was significantly higher (P < .001) in control cats (mean ± SD: 12.9 ± 6.8 ng/mL) compared to HSDM‐ (7.9 ± 3.3 ng/mL) and DM‐cats (6.7 ± 2.3 ng/mL), although not different between the HSDM‐ and DM‐cats. After RT ghrelin increased significantly (P = .003) in HSDM‐cats undergoing RT (from 6.6 ± 1.9 ng/mL to 9.0 ± 2.2 ng/mL) and the after RT ghrelin concentrations of HSDM cats were no longer significantly different from the serum ghrelin concentration of control cats. Serum IGF‐1 did not significantly change in HSDM‐cats after RT, despite significant decreases in fructosamine and insulin dose. Conclusion and Clinical Importance Ghrelin appears suppressed in cats with DM and HSDM, although increases after RT in HSDM, suggesting possible presence of a direct or indirect negative feedback system between growth hormone and ghrelin. Serum ghrelin might therefore represent a marker of treatment effect.

Associations between single nucleotide polymorphisms in the calcium sensing receptor and chronic kidney disease-mineral and bone disorder in cats

Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD. Client owned cats (≥9years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n=192) (125 with azotaemic CKD and 66 healthy), Persians (n=40) and Burmese (n=25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression. Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (<6%) for all SNPs. Allele frequencies varied between breeds. In non-pedigree cats, one synonymous SNP CaSR:c.1269G>A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P=0.031). Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats.