Medical management of feline diabetes can be a challenging under any circumstances but can be extremely frustrating when the diabetic cat also requires immunosuppressive therapy. This aim of this lecture is to review useful strategies for the clinical management of diabetic cats that also receive immunosuppressive therapy for a concurrent disorder.
Most cats are middle aged or older when diabetes develops. The same age group is also at risk for other medical disorders, some of which may require immunosuppressive drug therapy. Diabetes and the need for immunosuppressive therapy occur in two different scenarios in cats. In the first scenario, a cat with established diabetes develops an unrelated disorder, such as lymphoma, that requires immunosuppressive therapy. In the second scenario, a cat with a non-diabetic condition that requires immunosuppression therapy develops diabetes as a consequence of drug therapy. It is important to appreciate that even though the clinical manifestations of diabetes are the same, the etiology of diabetes may be subtly different in each scenario. In particular, insulin resistance may play a large role in the development of drug-induced diabetes and the diabetic state may be reversible if insulin resistance can be addressed.
Immunosuppressive Drugs
The drugs most commonly used to induce immunosuppression in cats are glucocorticoid preparations and cyclosporine. Chlorambucil, cyclophosphamide, gold salts and the newer agents, mycophenolate mofetil and tacrolimus have also been used in cats. Among the drugs used for immunosuppression in cats, glucocorticoids have the greatest potential to negatively impact diabetes management. Glucocorticoids cause insulin resistance by antagonizing the effects of insulin on target tissues, such as muscle and adipose tissue. Glucocorticoids cause glucose intolerance through several mechanisms, which can lead to overt diabetes under some circumstances. Glucocorticoid use in diabetic cats leads to unregulated glucose homeostasis and complicates effective diabetes management.
An association between cyclosporine therapy and diabetes has been established in humans but is not well studied in cats. Cyclosporin (and the related drug tacrolimus) is a calcineurin inhibitor that inhibits insulin secretion in vitro (Paty, et al., 2002). Abnormal glucose metabolism is observed in non-diabetic people receiving cyclosporine (Hjelmesaeth, et al., 2007). Post transplantation diabetes is an unfortunate complication after organ transplant in people receiving immunosuppression therapy with cyclosporine or tacrolimus (Mora PF, 2005). In people, the diabetogenic potential of cyclosporine appears to be less than tacrolimus. A possible role for cyclosporine in the onset of feline diabetes is suggested by a recent study that showed a much higher risk for diabetes in cats that had received a renal transplant when compared with non-transplanted controls (Case, et al., 2007). The diabetogenicity of other immunosuppressive drugs has received little attention in human and veterinary medicine. A few studies have examined the effect of mycophenolate mofetil on beta cell function and glucose homeostasis but these studies have yielded conflicting results. Based on a few studies, the diabetogenic effect of MMF appears to be less than either glucocorticoids or cyclosporine A (Penfornis and Kury-Paulin, 2006).
Clinical Approach to the Diabetic Cat That Needs Immunosuppressive Therapy
Choosing an Immunosuppressive Agent
Be sure that immunosuppression is needed:
Ideally, a firm diagnosis and a clear indication for immunosuppression is preferred prior to initiating therapy. However, it is not always the case that the need for therapy is well documented. In our referral clinic, we occasionally encounter diabetic cats that have habitually received glucocorticoids for months or years prior to the onset of diabetes with little or no medical evidence to conclude the therapy is warranted. In all cases, it is recommended that an appropriate diagnostic work-up be completed to ensure the diagnosis is accurate before instituting immunosuppression.
Select the appropriate drug for immunosuppression:
Selection of the appropriate drug to induce and maintain immunosuppression depends on many factors including the immune disorder that is being treated, the presence of concurrent medical disorders, indications / contraindications for a specific drug, the comparative cost of treatments, and the owner's ability to comply with the veterinarian's recommendations. Glucocorticoids are frequently used as a first line immunosuppressant in cats due to the low cost, relative lack of adverse effects, and the wide availability of oral and parenteral products. However, of the immunosuppressive agents used in cats, glucocorticoids are also the most likely to cause diabetes. Cyclosporin is gaining favor as an immunosuppressive agent in cats due to its efficacy and relatively low toxicity, although expense remains a problem for some owners. Although experimental and clinical evidence in humans implicates cyclosporine as a cause of diabetes, it is unclear whether the same situation exists in cats. Given the current level of knowledge, cyclosporine is the drug of choice for cats with established diabetes that subsequently require immunosuppression for an unrelated disorder. Several options can be considered for those cats that develop glucocorticoid-induced diabetes. The easiest option is to reduce the glucocorticoid dose in an attempt to ameliorate diabetes. If dose reduction is impossible (because clinical signs of immune disease return) or ineffective (because diabetes persists), cyclosporine is an excellent substitute. Bear in mind, however, that cyclosporine may not be an effective substitute for glucocorticoid in all circumstances. Mycophenolate mofetil is another potential substitute for glucocorticoid or cyclosporine therapy. Additional research is needed, however, before mycophenolate can be routinely recommended for use in cats. Tacrolimus has been used successfully as an immunosuppressant in dogs and cats. Whether it is a suitable substitute for glucocorticoid or cyclosporine is not established. However, given that it is more diabetogenic than cyclosporine in people, its use in diabetic cats should be approached with caution.
Diabetes Evaluation and Treatment
Clinical and laboratory evaluation for all diabetic cats should minimally consist of a physical examination, complete blood count, serum biochemistry analysis, urinalysis and urine culture. Appropriate testing for viral, protozoal, and other infectious agents may be warranted in some cases. The initiation of insulin therapy does not entail any special considerations when the cat is concurrently receiving immunosuppressive therapy. In diabetic cats already being treated with insulin when immunosuppressive therapy is initiated, the insulin therapy is adjusted as needed to maintain glycemic control. For those cats that develop diabetes as a result of immunosuppressive therapy, the author's initial approach is similar to that used for routine diabetics. The insulin product and dose chosen are those that are best suited for the cat being evaluated. Therapeutic decisions about insulin therapy are made without regard for the possible antagonistic effects of immunosuppressive drugs.
Once diabetes therapy is established, the monitoring protocol for cats receiving immunosuppressive therapy is similar that used for routine feline diabetic monitoring. Typically, a feline diabetic monitoring program entails observation at home, urine testing, glucose curves, and periodic recheck examinations.
Owner Education
Owner education is an important part of managing diabetic cats receiving immunosuppressive therapy. The education provided varies slightly depending on the scenario in which diabetes is recognized. Cats with established diabetes (i.e., they are already receiving treatment for diabetes) that begin immunosuppressive therapy may experience loss of diabetic control. In these patients, it is ideal to optimize glucose control prior to initiating immunosuppressive therapy if possible. A monitoring program should be discussed with the owner so that any changes in the cat's diabetes status can be detected as early as possible. The approach to cats that develop diabetes while on immunosuppressive therapy is slightly different. In these cats, the onset of diabetes is unpredictable and the owner may not immediately notice or appreciate the meaning of the clinical signs. Educating the owner about possible complications, including diabetes, at the time immunosuppressive therapy is instituted is helpful for raising awareness about the significance of changes in the cat's status during immunosuppressive treatment.
Define Therapeutic Goals
If administration of immunosuppressive therapy is unavoidable, it is important to work with the owner to define the goals and expectations of combined diabetic and immunosuppressive therapy for the patient. If both the immune disorder and diabetes are readily controlled, so much the better but it is not always possible to optimize both sides of the equation. At one end of the spectrum, insufficient immunosuppressive therapy may result in uncontrolled immunologic disease, which may represent a poor trade-off for well-regulated diabetes. At other end of the spectrum, immunosuppression at a level needed to abolish immune-mediated signs may mean that diabetes is difficult or impossible to regulate. In most cases, a balance must be struck between the two treatment modalities as no management protocol will address all of the patient's problems. When a 'best option' approach is selected, the point on the spectrum that the patient occupies is determined by patient factors (severity of disease, complications of diabetes, etc.), owner factors (compliance, finances, long term expectations, etc), and the degree to which the patient's quality of life can be maintained.
References
1. Paty BW, Harmon JS, Marsh CL, Robertson RP. Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation. 2002; 73(3):353-7.).
2. Hjelmesaeth J, Hagen LT, Asberg A, Midtvedt K, Størset O, Halvorsen CE, Mørkrid L, Hartmann A, Jenssen T. The impact of short-term ciclosporin A treatment on insulin secretion and insulin sensitivity in man. Nephrol Dial Transplant. 2007; 22(6):1743-9.
3. Mora PF. Post-transplantation diabetes mellitus. Am J Med Sci. 2005; 329(2):86-94.
4. Case JB, Kyles AE, Nelson RW, Aronson L, Kass PH, Klose TC, Bailiff NL, Gregory CR. Incidence of and risk factors for diabetes mellitus in cats that have undergone renal transplantation: 187 cases (1986-2005). J Am Vet Med Assoc. 2007; 230(6):880-4.
5. Penfornis A, Kury-Paulin S. Diabetes Metab. 2006; 32(5 Pt 2):539-46.