Diabetes mellitus (DM) is defined as a group of diseases characterized by lack of insulin production, efficacy, or both. Regardless of the cause, the lack of insulin efficacy leads to a plethora of abnormalities, resulting in the clinical signs and clinicopathological features of DM. Despite the ability to carefully manage the disease process, DM remains a leading cause of death in people and an important cause of morbidity and mortality in small animal patients.
In canine medicine, DM is commonly diagnosed, with estimated reports from referral practices and insurance databases suggesting a prevalence of 0.32 to 1.33 percent (Guptill, Glickman, and Glickman, 2003, Davison, Herrtage, and Catchpole, 2005) and studies from first option practices reporting a prevalence of 0.34 to 0.36 percent (Mattin et al., 2014, Yoon et al., 2020). In our canine patients, current treatment recommendations necessitate a daily or twice daily injection of insulin alongside careful monitoring, dietary modification, and a relatively stable exercise/feeding regime. For many owners, this can prove costly (either financially or emotionally). It is suggested as many as one in 10 diabetic dogs is euthanized at diagnosis, with a further one in 10 being euthanized within a year, due to lack of success or adequate compliance (Niessen et al., 2017). To further evaluate this, a quality-of-life survey was developed highlighting the following areas of particular concern for pet owners;
- general worry;
- difficulties leaving dog with friends or family;
- worries concerning vision loss;
- boarding difficulties;
- worries regarding hypoglycemia;
- social life; and
- future care (Niessen et al., 2012).
As veterinarians, we can help address many of these concerns and, therefore, provide incentives and ideas that optimize current treatment approaches for the individual patient. For example, worries about leaving the dog with friends or family are likely to decrease if the dog is well stabilized. Concerns such as hypoglycemic crises are likely to decrease when owners are empowered to monitor blood glucose at home (Niessen et al., 2012). While not all concerns can be addressed by the veterinarian, regular visits and good control may improve quality of life and with this, survival.
Classifying diabetes
In attempting to optimize diabetic stability, it is useful to understand the disease's etiology. Traditionally, human diabetics were classified as juvenile or adult onset. Later, this was altered to describe the clinical manifestations and insulin requirement, i.e. insulin-dependent DM (IDDM) or juvenile DM, noninsulin-dependent DM (NIDDM), or mature onset and diabetes secondary to other disease (secondary DM) (Gilor et al., 2016). However, as advances were made in the understanding of the disease pathophysiology, the terminology was slowly replaced with Type I and Type II diabetes. More recently, an etiology-based classification system has been instigated. It recognizes that as DM begins, there is a subclinical phase in which euglycemia is maintained, but in which there are abnormalities in b-cell function or mass. As the disease progresses, there is acknowledgement of an initial glucose intolerance or prediabetes that inevitably progresses to DM. The different "types" are further subdivided by etiology, with Type I having both immune-mediated and idiopathic forms, and Type II being of unknown etiology (although it is recognized there is a combination of insulin secretory deficit and insulin resistance). In addition, several other forms, such as genetic defects, diseases of the exocrine pancreas, endocrinopathies that result in insulin resistance, and gestational forms, are classified separately (Gilor et al., 2016).
This classification system has been adopted, as it has been recognized that a better understanding of the disease process specific to the individual can optimize control.
In veterinary medicine the terms Type I and Type II diabetes have largely replaced the earlier terminology (IDDM and NIDDM). However, this classification is often made based on species differences, rather than specifics of the individual case (i.e. cats are presumed to have Type II or secondary DM and dogs Type I or secondary DM). Over the past decade, the paradigm for treating feline diabetes has altered, as we have developed a better understanding of the following:
- the role of glucose toxicity (structural and functional damage to the pancreatic b-cells and the target tissues of insulin caused by chronic hyperglycemia);
- optimizing hexokinase activity by feeding a low-carbohydrate diet; and
- ensuring good glycemic control, increasing the frequency of diabetic remission in this species (Nelson and Reusch, 2014).
It is perhaps this close control and good understanding of the pathophysiology in feline diabetes that has led to increased survival times and reports of higher rates of satisfaction in owners of feline DM patients, compared to owners of canine DM patients (Aptekmann et al., 2014).
However, dogs are not big cats. DM in dogs is typically characterized by permanent hypoinsulinemia, with no increase in C-peptide in response to insulin secretagogues and, therefore, an absolute requirement for exogenous insulin administration (Gilor et al., 2016). This combination is classic for Type I DM, but can be present in other forms of disease, depending on the stage of disease and degree of glucotoxicity. Type I DM in people is subdivided into autoimmune destruction and idiopathic forms. Canine studies that assessed whether or not there was cell-mediated immune destruction of b-cells in diabetic dogs demonstrated mixed results, with some reporting autoimmune destruction in up to 50 percent of cases (Hoenig and Dawe, 1992, Davison, Herrtage, and Catchpole, 2011). Others have found no evidence of autoimmune destruction (Gepts and Toussaint, 1967, Ahlgren et al., 2014, Shields et al., 2015). Several studies have demonstrated an absence of, or decreased number of, islets with degeneration and vacuolization, but overall, there appears to be little or no inflammation associated with these changes (Gepts and Toussaint, 1967, Ling G.V. et al., 1977, Shields et al., 2015). There does exist a genetic predisposition to DM in several breeds; dog leukocyte antigen (DLA) haplotypes have been identified with a greater prevalence in some breeds that are at an increased risk of DM, such as the Tibetan terrier, Cairn terrier, and Samoyed (Catchpole et al., 2013, Ahlgren et al., 2014, Holder et al., 2015, Kim et al., 2016). However, the association between the DLA locus, other immune system genes, and the risk of DM in dogs remains unclear to date. In addition, anti-insulin antibodies (AIA) have been identified in diabetic dogs, and appear to be more common in treated than untreated dogs (Holder et al., 2015, Kim et al., 2016). Pancreatic b-cell presentation of insulin peptides by major histocompatibility complex (MHC) Class II molecules encoded by DLA genes would be required for an immunoglobulin G (IgG) antibody response to occur. DLA genes vary markedly from breed to breed; of the breeds studied, the Dachshund, Carin terrier, miniature schnauzer, and Tibetan terrier are more likely to develop AIA (Holder et al., 2015).
In comparison to cats, Type II DM appears to be rare in dogs. Canine obesity has been shown to cause a degree of insulin resistance; however, studies suggest that in dogs, compensatory increases in insulin secretion prevent the development of Type II DM (Gilor et al., 2016). However, a recent study assessing risk factors in the development of DM found that overweight dogs were at a significantly increased risk. Therefore, the role of obesity in canine DM is an area in which further research is required (Pöppl et al., 2017).
Secondary diabetes is DM that occurs as a consequence of another condition. Some breeds that have been found to be an increased risk of DM are also recognized as being more prone to developing pancreatitis (i.e. Yorkshire terrier, fox terrier, and miniature schnauzers), and some have hypothesized pancreatitis could lead to a secondary DM (Gilor et al., 2016, Yoon et al., 2020). Studies investigating a potential link between pancreatitis and DM in dogs have, to date, demonstrated variable results. Some of these studies indicate between 33 percent and 61 percent of DM cases showed histopathological features of chronic or acute pancreatitis, whereas others have suggested histopathological evidence of pancreatitis is rare or not evident in canine DM cases (Gepts and Toussaint, 1967, Ling G.V. et al., 1977, Alejandro et al., 1988, Shields et al., 2015). Other causes of secondary diabetes in dogs include excessive growth hormone production (during gestation, diestrus, or as a consequence of exogenous administration of progestins) and exposure to excessive cortisol (either from administration of glucocorticoids or naturally occurring hypercortisolism).
Understanding insulin
There are a range of issues that can arise from insulin administration—a specific compound may have an inappropriate duration of action, or the individual dog could make antibodies against a particular type. There are several insulin formulations available in both veterinary and human medicine (Thompson et al., 2015). Porcine insulin has the same amino acid sequence as canine insulin; therefore, porcine lente insulin zinc suspension has traditionally been considered a rational choice for use in dogs (Behrend et al., 2018). This has an intermediate duration of action. In addition, a human recombinant protamine zinc insulin with longer duration of action compared to lente insulins (Maggiore et al., 2012) is now available as a veterinary formulation for dogs. Unlicensed products that are used include other human insulins. Neutral protamine Hagedorn (NPH) is a recombinant human insulin made by nonpathogenic bacteria (with different preparations using vairous strains of bacteria) (Thompson et al., 2015). These forms of insulin have an intermediate duration of action compared with the long-acting insulins glargine and detemir (Fracassi et al., 2012, Hess and Drobatz, 2013, Fracassi et al., 2015). Glargine is a long-acting recombinant insulin analogue that forms subcutaneous microprecipitates, allowing for slow absorption and a prolonged duration of action. While glargine is described as "peakless" in humans, studies in dogs have demonstrated variable results, with one suggesting a similar peakless action, while the other found an unpredictable nadir (the inclusion of a diet high in soluble fiber in the earlier study may have contributed to the more stable blood glucose measurements in that study) (Fracassi et al., 2012, Hess and Drobatz, 2013). It has been reported AIA is seen more frequently in dogs treated with bovine insulin (52 percent) compared to those treated with porcine insulin (12 percent) (Holder et al., 2015). In addition, studies have demonstrated anti-insulin antibodies and insulin-reactive T-cells are detectable in a subset of diabetic dogs on insulin therapy (dogs in this study were receiving porcine or human [NPH or PZI] insulins) (Kim et al., 2016).
Monitoring diabetes
If all dogs presenting with DM are presumed to have irreversible diabetes, and treatment is aimed at decreasing clinical signs rather than achieving good glycemic control, no dogs will ever achieve remission. However, careful assessment of the individual can aid in identification of the underlying disease type and in some cases remission can be achieved. This raises the question, should we improve glycemic control? To decrease the chance of hyperglycemia-associated organ damage, lower glucose toxicity, and improve quality of life, the patient's blood glucose should be maintained below the renal threshold (approximately 200 mg/dL in dogs), but remain high enough to prevent hypoglycemia (Behrend et al., 2018).
American Animal Hospital Association (AAHA) guidelines recommend consultations every seven to 10 days after diagnosis with a blood glucose curve until clinical signs are controlled (Behrend et al., 2018). However, when the monitoring and stability of diabetic dogs treated within primary care practice was evaluated, one study reported only 18 of 40 dogs were stabilized within 12 weeks of diagnosis, and that the median number of consultations performed in the first month was three, decreasing to one every 19 days thereafter (Cartwright, Cobb and Dunning, 2018). In this study, dogs achieving remission within the first 12 weeks demonstrated a median survival time of 20.5 months, whereas those that did not had a median survival time of 2.5 months (Cartwright, Cobb, and Dunning, 2018). In comparison, a 2018 study performed in a referral population demonstrated a median survival time of 964 days (Tardo et al., 2019). While these two studies cannot be compared directly, it is likely that owners of pets presenting to a referral center are highly motivated and committed to long-term follow-up. Studies such as this highlight the need for regular veterinary visits and monitoring of glycemic control.
There is an increasing number of ways in which a diabetic patient can be monitored. However, with the realization that one of the greatest concerns for the owners of diabetic dogs is fear of hypoglycemic events, home-monitoring using either glucose curves or implantable glucometers has become increasingly popular (Niessen et al., 2012). Commonly, the ear, gum, non-weight-bearing accessory foot pad or elbow callus can be used to obtain a capillary sample that can be analyzed on a portable glucometer (Borin-Crivellenti, Crivellenti, and Tinucci-Costa, 2012, Cook, 2012). Veterinary glucometers are ideal as they provide an accurate measurement with a minimal volume of blood. However, blood glucose curves should always be interpreted in light of the clinical signs. Further, owners should be encouraged to keep a log of daily food and water intake, energy levels, exercise routine, and general wellness for practitioners to interpret alongside a blood glucose curve. Recently, implantable glucometers have become widely available. Initially, use of these was generally reserved for the unstable patient, and home-monitoring could only be performed in cases where the owner was able to collect capillary samples for glucometer evaluation to calibrate the device (Fleeman, 2011, Cook, 2012, Surman and Linda Fleeman, 2013). This is no longer the case, thanks to flash systems that are pre-calibrated and can simply be placed by the veterinarian to provide a continuous assessment of blood glucose for up to 14 days (Corradini et al., 2016). Careful monitoring of blood glucose not only allows for better insulin regulation, but can reassure owners who are worried their dog is at risk of a hypoglycemic event.
Even when monitoring is ideal, there are some dogs that can prove difficult to stabilize. In such cases, it can be useful to first assess the dog's lifestyle and routine. For example, is the dog on a suitable diet and exercise regimen? Studies have suggested a high-fiber diet is ideal for many diabetics (Kimmel et al., 2000). However, this may be influenced by the underlying disease process; if secondary diabetes is suspected, a diet suitable for treating the underlying condition may be considered (Teixeira et al., 2018). In unstable cases where adequate monitoring, appropriate insulin-dosing, and lifestyle measures have been made, consideration should be given to other diseases that can lead to insulin resistance, such as hypercortisolism, increased growth hormone production, or urinary tract infections (UTIs).
Kerry Rolph, BVM&S, CertVC, PhD, FANZCVS (feline chapter), DipECVIM-Ca, FRCVS, is an associate professor of small animal internal medicine at Ross University School of Veterinary Medicine (RUSVM). She graduated from Edinburgh University and worked in small animal practice for two years before returning to Edinburgh to study for her PhD. Dr. Rolph gained both her certificate in veterinary cardiology and PhD in 2004. In 2010, she passed the Feline Medicine Australian College of Veterinary Scientists Fellowship examinations. Four years later, Rolph gained her European diploma in companion animal medicine and became a European specialist in companion animal medicine. She then worked at a private referral hospital in Bristol, England, for three years before joining RUSVM in January 2019. Rolph can be contacted via email at KRolph@rossvet.edu.kn.
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