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.

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.

Cushing's Syndrome and Other Causes of Insulin Resistance in Dogs.

The most common causes of insulin resistance in diabetic dogs are Cushing syndrome, diestrus, and obesity. Cushing-associated effects include insulin resistance, excessive postprandial hyperglycemia, perceived short duration of insulin action, and/or substantial within-day and/or day-to-day glycemic variability. Successful strategies to manage excessive glycemic variability include basal insulin monotherapy and combined basal-bolus insulin treatment. Ovariohysterectomy and insulin treatment can achieve diabetic remission in about 10% of cases of diestrus diabetes. Different causes of insulin resistance have an additive effect on insulin requirements and the risk of progression to clinical diabetes in dogs.

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.

Insulin glargine 300 U/ml for the treatment of feline diabetes mellitus.

OBJECTIVES: The study aimed to evaluate the efficacy and safety of insulin glargine 300 U/ml (IGla-U300) in cats with variable duration of diabetes mellitus (DM). METHODS: Thirteen client-owned cats with DM completed a prospective clinical trial. Four cats were highly suspected of hypersomatotropism and excluded from the insulin efficacy evaluation. All cats were treated with IGla-U300 SC at a starting dosage of 0.5 U/kg q12h and fed with a low carbohydrate diet. Cats were monitored for 8 weeks with a once-weekly at-home 16 h blood glucose curve (BGC) and a questionnaire evaluating the presence of DM-related clinical signs. In-clinic evaluations, including serum fructosamine measurement, were scheduled within 3 days of the first, third, sixth and eighth BGC. Glycemic variability was assessed by calculating the SD of each BGC. RESULTS: Excluding four cats suspected of hypersomatotropism, at the time of the eighth BGC, improved or absent polyuria, polydipsia, polyphagia, weight loss, lethargy and improved or normal general demeanor were reported in 8/9 (88%), 8/9 (88%), 7/9 (77%), 7/9 (77%), 7/9 (77%) and 8/9 (88%) cats, respectively. Two cats achieved remission after 29 and 53 days. Another two cats went into remission after the end of the study (days 82 and 96). All cats that achieved remission were newly diagnosed diabetics. Median (range) serum fructosamine concentration significantly decreased when comparing the time of enrollment (604 [457-683] µmol/l) with the eighth week of treatment (366 [220-738] µmol/l) (P = 0.02). In all 13 cats, biochemical hypoglycemia (blood glucose <60 mg/dl; <3.3 mmol/l) was detected in 13/104 (12.5%) BGCs, while clinical signs suggesting hypoglycemic episodes were not reported. Glycemic variability was significantly lower at the fifth BGC when comparing cats that achieved remission with cats that did not achieve remission (P = 0.02). CONCLUSIONS AND RELEVANCE: IGla-U300 seems effective and safe for the treatment of feline diabetes, but more long- term and comparative clinical trials are needed.

Mapping of Diabetes Susceptibility Loci in a Domestic Cat Breed with an Unusually High Incidence of Diabetes Mellitus.

Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with p values <0.005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes DGKG, IFG2BP2, SLC8A1, E2F6, ETV5, TRA2B and LIPH. Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats.

Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus).

Diabetes mellitus, a common endocrinopathy affecting domestic cats, shares many clinical and pathologic features with type 2 diabetes in humans. In Australia and Europe, diabetes mellitus is almost four times more common among Burmese cats than in other breeds. As a genetically isolated population, the diabetic Australian Burmese cat provides a spontaneous genetic model for studying diabetes mellitus in humans. Studying complex diseases in pedigreed breeds facilitates tighter control of confounding factors including population stratification, allelic frequencies and environmental heterogeneity. We used the feline SNV array and whole genome sequence data to undertake a genome wide-association study and runs of homozygosity analysis, of a case-control cohort of Australian and European Burmese cats. Our results identified diabetes-associated haplotypes across chromosomes A3, B1 and E1 and selective sweeps across the Burmese breed on chromosomes B1, B3, D1 and D4. The locus on chromosome B1, common to both analyses, revealed coding and splice region variants in candidate genes, ANK1, EPHX2 and LOX2, implicated in diabetes mellitus and lipid dysregulation. Mapping this condition in Burmese cats has revealed a polygenic spectrum, implicating loci linked to pancreatic beta cell dysfunction, lipid dysregulation and insulin resistance in the pathogenesis of diabetes mellitus in the Burmese cat.

Updates in Feline Diabetes Mellitus and Hypersomatotropism.

Flash glucose monitoring is a novel, noninvasive monitoring technique that is increasingly used in the management of small animal diabetes. This article provides guidance on the use of flash glucose monitoring in cats and demonstrates how this technique can be used in a range of feline diabetic cases, including those where management is proving challenging. Other aspects of complicated feline diabetic care are also discussed, including management of the sick diabetic cat, potassium depletion myopathy, and treatment options for cats with hypersomatotropism-associated diabetes mellitus. The use of insulin glargine 300 U/ml as a promising new long-acting insulin for diabetic cats is also discussed.

Epidemiological study of dogs with diabetes mellitus attending primary care veterinary clinics in Australia.

BACKGROUND: The objectives of this study were to establish the prevalence, risk factors and comorbidities/sequelae for diabetes mellitus (DM) in Australian dogs presented to first-opinion veterinary practices. METHODS: Electronic patient records of dogs (n=134,329) attending 152 veterinary clinics during 2017 were sourced through VetCompass Australia. They included 418 dogs with DM; a prevalence of 0.36 per cent (95 per cent CI 0.33 per cent to 0.39 per cent) in Australian dogs attending these veterinary clinics. By comparing with the reference group of rarer breeds and unidentified crossbreeds, multivariable modelling was used to reveal breeds (and their crosses) with significantly higher odds of having DM. RESULTS: The results revealed that breeds (and their crosses) with significantly higher odds of having DM were Australian terriers (ORs=7.93 (95 per cent CI 2.83 to 22.27)), Siberian huskies (OR=6.24 (95 per cent CI 2.51 to 15.54)), English springer spaniels (OR=5.37 (95 per cent CI 1.48 to 19.53)), West Highland white terriers (OR=4.85 (95 per cent CI 2.55 to 9.25)), miniature schnauzers (OR=3.47 (95 per cent CI 1.16 to 10.35)), all types of poodles (OR=3.41 (95 per cent CI 2.07 to 5.61)), bichon frises (OR=3.41 (95 per cent CI 1.65 to 7.01)), schnauzers (OR=3.18 (95 per cent CI 1.42 to 7.11)) and cavalier King Charles spaniels (CKCS; OR=1.84 (95 per cent CI 1.08 to 3.13)). Breeds with lower risk were German shepherd dogs (OR=0.11 (95 per cent CI 0.01 to 0.84)), golden retrievers (OR=0.09 (95 per cent CI 0.01 to 0.68)) and boxers (no cases identified). Fisher's exact tests showed that labradoodles were diagnosed significantly more often than purebred Labradors (P=0.04) and did not differ significantly from poodles (P=0.81). Cavoodles did not differ significantly from either CKCS (p~1.00) or poodles (P=0.12). Spoodles were significantly less diagnosed than poodles (P=0.003) but did not differ from cocker spaniels (P=0.66). Desexed male dogs had a higher odds of DM than entire male (OR=0.62 (95 per cent CI 0.39 to 0.98)) and desexed female dogs (OR=0.76 (95 per cent CI 0.61 to 0.96)). Comorbidities/sequelae associated with canine DM included suspected pancreatitis (OR 10.58 (95 per cent CI 5.17 to 22.78)), cataracts (OR 9.80 (95 per cent CI 5.65 to 17.35)), hyperadrenocorticism (OR 6.21 (95 per cent CI 3.29 to 11.88)), urinary tract infection (OR 5.09 (95 per cent CI 1.97 to 13.41)) and hypothyroidism (OR 4.10 (95 per cent CI 1.08 to 15.58)). CONCLUSIONS: Breeds at most risk included Australian terriers and Siberian huskies as previously reported, as well as, for the first time, English springer spaniels. In contrast to other populations where there is female predisposition for DM, desexed male dogs in Australia were at increased risk for DM compared with both entire males and desexed females. This predisposition for desexed males to develop DM warrants further investigation.

ISFM consensus guidelines on the practical management of diabetes mellitus in cats.

PRACTICAL RELEVANCE: Diabetes mellitus (DM) is a common endocrinopathy in cats that appears to be increasing in prevalence. The prognosis for affected cats can be good when the disease is well managed, but clinical management presents challenges, both for the veterinary team and for the owner. These ISFM Guidelines have been developed by an independent, international expert panel of clinicians and academics to provide practical advice on the management of routine (uncomplicated) diabetic cats. CLINICAL CHALLENGES: Although the diagnosis of diabetes is usually straightforward, optimal management can be challenging. Clinical goals should be to limit or eliminate clinical signs of the disease using a treatment regimen suitable for the owner, and to avoid insulin-induced hypoglycaemia or other complications. Optimising bodyweight, feeding an appropriate diet and using a longer acting insulin preparation (eg, protamine zinc insulin, insulin glargine or insulin detemir) are all factors that are likely to result in improved glycaemic control in the majority of cats. There is also some evidence that improved glycaemic control and reversal of glucose toxicity may promote the chances of diabetic remission. Owner considerations and owner involvement are an important aspect of management. Provided adequate support is given, and owners are able to take an active role in monitoring blood glucose concentrations in the home environment, glycaemic control may be improved. Monitoring of other parameters is also vitally important in assessing the response to insulin. Insulin adjustments should always be made cautiously and not too frequently--unless hypoglycaemia is encountered. EVIDENCE BASE: The Panel has produced these Guidelines after careful review of the existing literature and of the quality of the published studies. They represent a consensus view on practical management of cats with DM based on available clinical data and experience. However, in many areas, substantial data are lacking and there is a need for better studies in the future to help inform and refine recommendations for the clinical management of this common disease.

Update on insulin treatment for dogs and cats: insulin dosing pens and more.

Insulin therapy is still the primary therapy for all diabetic dogs and cats. Several insulin options are available for each species, including veterinary registered products and human insulin preparations. The insulin chosen depends on the individual patient's requirements. Intermediate-acting insulin is usually the first choice for dogs, and longer-acting insulin is the first choice for cats. Once the insulin type is chosen, the best method of insulin administration should be considered. Traditionally, insulin vials and syringes have been used, but insulin pen devices have recently entered the veterinary market. Pens have different handling requirements when compared with standard insulin vials including: storage out of the refrigerator for some insulin preparations once pen cartridges are in use; priming of the pen to ensure a full dose of insulin is administered; and holding the pen device in place for several seconds during the injection. Many different types of pen devices are available, with features such as half-unit dosing, large dials for visually impaired people, and memory that can display the last time and dose of insulin administered. Insulin pens come in both reusable and disposable options. Pens have several benefits over syringes, including improved dose accuracy, especially for low insulin doses.

Faecal microbiota of cats with insulin-treated diabetes mellitus.

Microorganisms within the gastrointestinal tract significantly influence metabolic processes within their mammalian host, and recently several groups have sought to characterise the gastrointestinal microbiota of individuals affected by metabolic disease. Differences in the composition of the gastrointestinal microbiota have been reported in mouse models of type 2 diabetes mellitus, as well as in human patients. Diabetes mellitus in cats has many similarities to type 2 diabetes in humans. No studies of the gastrointestinal microbiota of diabetic cats have been previously published. The objectives of this study were to compare the composition of the faecal microbiota of diabetic and non-diabetic cats, and secondarily to determine if host signalment and dietary factors influence the composition of the faecal microbiota in cats. Faecal samples were collected from insulin-treated diabetic and non-diabetic cats, and Illumina sequencing of the 16S rRNA gene and quantitative PCR were performed on each sample. ANOSIM based on the unweighted UniFrac distance metric identified no difference in the composition of the faecal microbiota between diabetic and non-diabetic cats, and no significant differences in the proportions of dominant bacteria by phylum, class, order, family or genus as determined by 16S rRNA gene sequencing were identified between diabetic and non-diabetic cats. qPCR identified a decrease in Faecalibacterium spp. in cats aged over ten years. Cat breed or gender, dietary carbohydrate, protein or fat content, and dietary formulation (wet versus dry food) did not affect the composition of the faecal microbiota. In conclusion, the composition of the faecal microbiota was not altered by the presence of diabetes mellitus in cats. Additional studies that compare the functional products of the microbiota in diabetic and non-diabetic cats are warranted to further investigate the potential impact of the gastrointestinal microbiota on metabolic diseases such as diabetes mellitus in cats.

Continuous glucose monitoring in small animals.

The use of continuous glucose monitoring systems in veterinary patients is summarized and discussed. The current clinical uses in veterinary medicine, including monitoring of hospitalized/sick diabetic patients, long-term monitoring of stable diabetic patients, anesthetized patients, and other patients with altered blood glucose homeostasis are presented. The most important advantage of these systems over intermittent blood glucose measurements is that they facilitate detection of brief periods of hypoglycemia and provide information overnight. The accuracy and advantages/disadvantages compared with traditional monitoring are addressed. The technology involved in the currently available monitoring systems is also discussed.

Adiponectin profiles are affected by chronic and acute changes in carbohydrate intake in healthy cats.

Adiponectin is a key adipokine that regulates carbohydrate and lipid metabolism. It circulates in stable low (LMW) and high molecular weight (HMW) forms. The aims of this study were to characterize baseline adiponectin profiles (total, LMW and HMW multimers) in healthy cats and to assess the effects of varying dietary carbohydrate content on adiponectin profiles. Cats were maintained on a diet with moderate carbohydrate content (37% metabolisable energy [ME]) for 4 weeks and then randomly allocated to either a low carbohydrate (19% ME) or high carbohydrate (52% ME) diet for 4 weeks. Fasting and postprandial plasma adiponectin profiles were measured by ELISA and sucrose gradient/Western blot. After consuming the moderate carbohydrate diet for 4 weeks, fasting total, HMW and LMW plasma adiponectin concentrations were 5.0±0.6, 2.5±0.5 and 2.6±0.2 µg/mL, respectively. After changing to the low carbohydrate diet, fasting total adiponectin was unchanged but HMW adiponectin increased and LMW adiponectin decreased. No significant postprandial changes were observed. Cats consuming the high carbohydrate diet had increased fasting total and LMW adiponectin with no change in HMW adiponectin. In the postprandial state total adiponectin was reduced and there was a trend towards a decrease in HMW (p=0.086) but not LMW multimers. These data indicate that feline adiponectin multimer profiles are similar to those reported in other species and demonstrate that changes in plasma adiponectin occur in response to chronic and acute carbohydrate intake and these reflect differential changes in adiponectin multimers.