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Compendium December 2008 (Vol 30, No 12)

Feline Diabetes Mellitus: Pathophysiology and Risk Factors

by Lori Rios, DVM, PhD, DACVIM, Cynthia R. Ward, VMD, PhD, DACVIM (Small Animal Internal Medicine)

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    The prevalence of diabetes mellitus in cats has increased over the past 30 years, making this disease a commonly encountered one in small animal practice. Many factors, including obesity, contribute to the development of diabetes in cats. Feline diabetes shares aspects of pathophysiology with diabetes in other species; however, veterinarians must remember that there are salient differences with important implications for the diagnosis and treatment of diabetes in cats.

    Diabetes mellitus is a frequently encountered disease in small animal practice. It appears to have a similar prevalence in dogs and cats.1 In humans, the number of cases of type 2 diabetes mellitus is exploding, primarily because of a rise in obesity and inactivity. As obesity and sedentary lifestyles become more prevalent in the pet population, it is likely that the incidence of diabetes in companion animals will rise accordingly. This may be a particularly relevant issue for cats, in which the prevalence of diabetes mellitus has increased over the past 30 years.2 Cats, more commonly than dogs, experience a form of diabetes most closely related to type 2 diabetes mellitus in humans. This form of the disease has been clearly linked to diet and lifestyle. Although dogs and cats share aspects of diabetes pathophysiology, diagnosis, and treatment, it is important for veterinarians to keep in mind that there are salient differences with important implications for the diagnosis and treatment of feline diabetes.

    Structure and Function of Insulin

    Diabetes mellitus is a disease of the endocrine pancreas characterized by a relative or absolute deficiency in insulin secretion. Insulin is normally secreted by the Β cells of the pancreas (approximately 70% of the endocrine cell population) in response to an influx of glucose through glucose transporters. Insulin is a polypeptide molecule composed of two chains linked together by disulfide bonds. In all species, the insulin molecule is made up of 51 amino acids; human insulin differs from canine insulin by only one amino acid and from feline insulin by four.

    In normal humans, about 50% of the total daily insulin is secreted during basal periods, serving to inhibit lipolysis, glycogenolysis, and proteolysis. Cats also secrete insulin during basal periods. The remainder of the insulin is secreted postprandially in two phases. The first phase is a rapid release of insulin from preformed granules inside Β cells. In humans, this phase occurs within a few minutes of ingestion and continues for about 10 to 15 minutes. The second phase of insulin secretion then begins and continues until normoglycemia is restored.

    Once in circulation, insulin has a half-life of about 3 to 5 minutes. It binds to insulin receptors, which are glycoprotein molecules found on many cells in the body. The receptor is a tetramer with two a and two Β subunits. The a portion of the molecule is extracellular and binds insulin. Binding to the a portion causes a conformational change that triggers autophosphorylation of tyrosine residues found on the intracellular Β subunits. This turns the receptor into an enzyme, tyrosine kinase, which mediates the effect of insulin on cellular mechanisms, specifically phosphoinositide 3-kinase, leading to diffusion of glucose into the cell (Figure 1).

    Insulin receptors exert effects on many body tissues, particularly adipose, muscle, heart, and liver tissue. In tissues other than the liver, activation of insulin receptors up-regulates intracellular vesicles. These vesicles contain a specific insulin-sensitive glucose transporter (GLUT-4). Approximately 90% of GLUT-4 transporters are sequestered intracellularly in the absence of insulin or other stimuli. When stimulated, the vesicles move to the cell membrane, fuse with it, and insert the transporter into it. This allows glucose to diffuse into the cell. When insulin activity decreases, the transporter is endocytosed and resides again in the cytoplasm until reactivated by the presence of insulin on the receptor. In humans, cells with the GLUT-4 transporter are also up-regulated in response to exercise, independent of the action of insulin. Therefore, exercise independently lowers blood glucose levels, possibly through exercise induction of nitric oxide and bradykinin.3,4

    In the liver, glucose diffuses freely even in the absence of insulin. The main effect of insulin in the liver of most animals is to trap glucose within hepatic cells, increase enzyme activity that promotes glycogenesis and lipogenesis, and inhibit enzyme activity that supports glycogenolysis and gluconeogenesis. Specifically, insulin facilitates the phosphorylation of glucose to glucose-6-phosphate via the action of the enzyme glucokinase. Once phosphorylated to glucose-6-phosphate, glucose cannot diffuse out of cells into the vascular space. There is substantial evidence that cats do not have glucokinase activity in their livers and therefore cannot take up and use as much glucose as other species.5

    In addition to glucose, insulin promotes the entry of amino acids and the electrolytes potassium, magnesium, and phosphate into cells. These are considered the rapid-onset actions of insulin. Intermediate and longer-term actions of insulin include increased protein synthesis, glycogenesis, inhibition of gluconeogenesis, and increased lipogenesis. Insulin promotes fat storage by stimulating lipoprotein lipase activity and uptake of free fatty acids into adipocytes. Insulin secretion is triggered not only by glucose but also by the release of glucagon-like peptide 1 and gastric inhibitory polypeptide before glucose is absorbed in the gut. Amino acids, glucagon, and Β-adrenergic agonists, among others, are also known to influence insulin secretion. Insulin secretion is inhibited by somatostatin, a-adrenergic agonists, and Β-adrenergic antagonists.

    Pathophysiology of Insulin Resistance and β Cell Dysfunction

    Insulin resistance is defined as a condition in which a normal amount of secreted insulin produces a subnormal response. Obesity, a common cause of insulin resistance, is associated with a decreased number of insulin receptors and postreceptor failure to activate tyrosine kinase.6 Resistance to insulin not only impairs glucose uptake into insulin-sensitive cells but also stimulates hepatic cells to shift from glycolysis to gluconeogenesis, thereby further increasing plasma glucose levels. Insulin resistance is initially compensated for by an increase in insulin secretion. However, prolonged exposure to high levels of blood glucose leads to β-cell exhaustion and glucose toxicity. When the pancreas cannot secrete enough insulin to attain a level of euglycemia, a persistent state of hyperglycemia and thus diabetes ensues.

    Diabetic cats have been found to be about six times less sensitive to insulin than healthy cats.7 Much of the recent focus of research has been on the role of obesity in the development of an insulin-resistant state. In one study, cats of normal weight that were allowed to become obese demonstrated a 52% decrease in tissue sensitivity to insulin.8 In addition, normal-weight cats with initial lower insulin sensitivities have a greater risk of developing impaired glucose tolerance as they become obese.

    Recently, it has been demonstrated that GLUT-4 expression is decreased in the early stages of feline obesity and that insulin resistance may be partly due to GLUT-4 defects.9 On a molecular level, defects in insulin signaling pathways responsible for GLUT-4 translocation, such as phosphoinositide 3-kinase, or up-regulation of proteins that inhibit signaling pathways are noted in obese human subjects with insulin resistance or overt diabetes. Male cats may be more prone to diabetes than females because they are at greater risk of becoming obese and tend to have lower insulin sensitivity even at a normal weight.8 Decreased insulin sensitivity and the resultant hyperglycemia lead to excessive production of insulin and eventual β-cell exhaustion.

    The effects of hyperglycemia can be divided into three stages: glucose desensitization, β-cell exhaustion, and glucose toxicity. Initially, exposure to high levels of glucose leads to a desensitized or potentially reversible state of decreased insulin production. Prolonged exposure leads to β-cell exhaustion, whereby stores of insulin are depleted. β-cell exhaustion is considered to be potentially reversible because there are no defects in insulin synthesis. Glucose toxicity represents an irreversible state whereby cellular defects permanently impair cellular components of insulin production.10 Studies have demonstrated that the severity of glucose toxicity depends on the degree of hyperglycemia and that insulin secretion can begin to be suppressed within 2 days of persistent hyperglycemia. Histologic abnormalities associated with glucose toxicity include glycogen deposition and cell death.11

    β-cell dysfunction may play a more important role than β-cell destruction in the development of diabetes in cats and humans. The mechanisms that lead to β- cell dysfunction are complex and multifactorial, involving dyslipidemia, leptin, and cytokines as well as the direct effects of hyperglycemia. Regardless of the inciting cause, some of the markers of β-cell dysfunction have been identified. In human medicine, it is well recognized that a decrease in the first phase of postprandial insulin secretion is an early marker of β-cell dysfunction and the development of diabetes. In cats with impaired glucose tolerance, first-phase secretion has also been demonstrated to be delayed, while the second phase is both delayed and exaggerated.12 Diabetic cats appear to then progress to a loss of the first phase of secretion, with persistent abnormalities in second-phase secretion.

    Relative or absolute insulin deficiency leads to decreased peripheral use of glucose, amino acids, and fatty acids. This contributes to increased hyperglycemia. The added contribution of glucose from hepatic gluconeogenesis only serves to worsen the situation. Hyperglycemia leads to a hyperosmotic state, dehydrating the cells. As the blood glucose level rises, the renal threshold for reabsorption of glucose is exceeded. This threshold is higher in cats (200 to 280 mg/dL) than in dogs (180 to 220 mg/dL). The loss of glucose in the urine promotes osmotic diuresis, leading to an appreciable loss of sodium and potassium as well. Polyuria is followed by polydipsia, which leads to initial clinical signs of disease.

    Histologic Features

    Insulin hypersecretion, concomitant with an increase in islet amyloid polypeptide (IAPP) secretion, can set the stage for the development of islet amyloidosis and progressive islet destruction. IAPP, a 37-amino-acid peptide that delays gastric emptying and facilitates glycogen breakdown in striated muscle, is stored and secreted with insulin. Although IAPP is secreted by many species, amyloid deposits associated with diabetes mellitus have been described only in humans, cats, and nonhuman primates. Amyloid deposition is important in the progression of feline diabetes mellitus.13

    Histologically, more than 80% of diabetic cats have been shown to have amyloid deposits from IAPP.14 Not all cats that develop islet amyloidosis have diabetes mellitus. Additional histologic features noted in diabetic cats include Histologic β-cell vacuolar degeneration, chronic pancreatitis, and reduced numbers of islets or β cells.

    Islet amyloidosis has been demonstrated to develop in histologically normal cats following a state of induced diabetes mellitus.13 Clinical diabetes mellitus was induced in previously healthy cats by partial pancreatectomy, followed by administration of growth hormone and dexamethasone. The cats were then treated with either insulin or glipizide, an insulin secretagogue used orally to treat feline diabetes. All the cats treated with glipizide developed amyloid deposits, but only one of the four insulin-treated cats had evidence of amyloid deposition.

    Islet amyloidosis is associated with β-cell destruction. IAPP has been shown in vitro to trigger apoptosis in β cells, and increasing levels of islet amyloidosis lead to progressive β-cell failure.15 Because insulin and IAPP are cosecreted, it is logical to assume that decreasing the level of insulin secretion may slow progression of amyloidosis and thus diabetes. This raises concern about the impact of oral hypoglycemic drugs, particularly those that promote insulin secretion and thus IAPP secretion.

    Comparative Physiology

    In humans, type 1 diabetes is characterized by immune-mediated destruction of the β cells and is often diagnosed in childhood or young adulthood. These patients are considered insulin dependent, and tests of insulin secretion with insulin secretagogues show markedly reduced insulin levels. The etiology of type 2 diabetes mellitus, the most common form of diabetes mellitus in humans, has genetic and behavioral components.

    Humans with type 2 diabetes are considered to have peripheral insulin resistance with some degree of insulin secretory defect. Type 2 diabetes mellitus most often occurs in adults, although the increase in childhood obesity appears to be a factor in diagnosis of type 2 diabetes in a younger population. These patients may or may not need insulin to manage their disease. Histologically, more than 90% of humans with type 2 diabetes have evidence of amyloid deposition.

    In veterinary medicine, there appears to be a shift in the literature to replace the terms type 1 and type 2 diabetes mellitus with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) as more appropriate to describe the clinical entity seen in dogs and cats.16 This classification focuses on the essential component of treatment without regard to etiologic and pathologic features. However, genetic, pathologic, and histologic features are becoming more defined in veterinary patients.

    Feline Diabetes Mellitus

    The development of feline diabetes can be associated with age, weight, sex, genetic predisposition, preexisting disease, and, undoubtedly, numerous other factors.17 A significant number of cats, like dogs, require insulin to regulate their blood glucose level and thus are classified as having IDDM. However, a large proportion of cats are considered to have NIDDM.16 Recent studies have demonstrated that between 30% and 83% of diabetic cats can become non-insulin dependent with a period of initial insulin administration and diet therapy.18,19 However, it is very difficult to initially differentiate insulin-dependent from non"insulin-dependent cats, and often, a diagnosis of IDDM or NIDDM can be made only after the initiation of therapy and evaluation of the response to treatment. Intravenous glucose tolerance tests used to differentiate between NIDDM and IDDM in humans have not proven reliable for use in cats. Both NIDDM and IDDM cats have been shown to have low baseline insulin concentrations and lack of response to a glucose challenge.20

    The difference between NIDDM cats and IDDM cats is not clear, although it may represent a matter of degree of loss of β cells and reversibility of insulin resistance. There appears to be a continuum of histopathologic lesions that correlate with the likelihood that a cat is insulin dependent, rather than a distinct etiologic or pathophysiologic distinction. In comparison to human and canine diabetes, there is little evidence for an immune-mediated process leading to autoantibody destruction of β cells. A study of 26 newly diagnosed diabetic cats failed to find any evidence of autoantibodies.21 Therefore, investigation has not yet demonstrated a feline analog to the type 1 diabetes found in people or dogs.

    Researchers believe that feline diabetes more closely mirrors type 2 diabetes in humans, although, clinically, a greater proportion of feline patients may be dependent on insulin for treatment than human patients. The course of the disease, risk factors, and histologic features of feline diabetes are similar to those of type 2 human diabetes. The typical diabetic cat is middle-aged or older, with most diabetic cats being more than 6 years of age at presentation.20 Neutered and male cats have a higher incidence of the disease. With the exception of Burmese cats, there does not appear to be a breed predisposition. Obesity is a known risk factor for cats and is thought to increase the risk of disease three- to fivefold.22

    Diet may also be a factor in the development of feline diabetes because persistent hyperglycemia in the absence of obesity also leads to glucose intolerance. Many commercial cat foods contain high levels of carbohydrates, and diets containing a high level of carbohydrates have been shown to decrease insulin sensitivity.13 In addition, diets higher in protein have been shown to decrease the insulin dosage needed in diabetic cats.23

    Regardless of whether a cat needs insulin to regulate blood glucose, the key feature of feline diabetes mellitus is a combination of increased peripheral insulin resistance and decreased insulin secretion. The interplay of insulin resistance and β-cell dysfunction leads to a self-perpetuating cycle that ultimately culminates in diabetes mellitus. The relative importance of each factor, the inciting events, and the nature of β-cell dysfunction are all controversial.

    Secondary Diabetes Mellitus

    Many cats develop diabetes in association with other diseases or predisposing states. In humans, this form of diabetes falls into the "other," or type 3, category. Diseases or drugs that cause insulin resistance and diseases that cause pancreatic destruction can lead to secondary diabetes mellitus in both humans and cats (Table 1). For example, concurrent endocrinopathy, such as hyperthyroidism, hyperadrenocorticism, and acromegaly, and exogenous steroid hormone administration are known to cause insulin resistance in peripheral tissues.20,24 The reversibility of diabetes secondary to other disease states likely depends on the ability to successfully treat the primary disease and the extent of β-cell destruction at the time of diagnosis.

    Transient Diabetes Mellitus

    An estimated 20% of diabetic cats are transiently diabetic.20 These cats present with clinical and laboratory findings of diabetes, but their clinical signs and blood glucose levels return to normal about 4 to 6 weeks after initiation of treatment. Some of these cats may be able to permanently discontinue treatment, while others may redevelop clinical signs and require future treatment. It is theorized that transiently diabetic cats have subclinical disease and become clinically affected when a predisposing factor places additional demand on the pancreas.20 Stress or diseases causing insulin resistance can lead to hyperglycemia and subsequent β-cell exhaustion or glucose toxicity. Once good glycemic control is attained, β cells can take weeks to recover from moderate exhaustion. Severe exhaustion may lead to glucose toxicity and become irreversible.11 The possibility of a transient diabetic state underlies the importance of ruling out predisposing factors that lead to disease as well as closely monitoring for significant improvement in disease once treatment is initiated.

    A companion article on diagnosis, treatment, and monitoring of feline diabetes mellitus was printed in the December 2008 issue and is available here.

    Downloadable PDF

    Dr. Ward discloses that she has received financial support from Morris Animal Foundation and Nestlé Purina PetCare Company.

    1. Panciera DL, Thomas C, Eiker S, et al. Epizootiologic patterns of diabetes mellitus in cats: 333 cases (1980-1986). JAVMA 1990;197(11):1504-1508.

    2. Prahl A, Glickman L, Guptill L, et al. Time trends and risk factors for diabetes mellitus in cats (abstract). J Vet Intern Med 2003;17(3):434.

    3. McGee S, Hargreaves M. Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol 2006;33(4):395-399.

    4. Shepherd PR, Kahn BB. Glucose transporters and insulin action, implication for insulin resistance and diabetes mellitus. N Engl J Med 1999;341(4):248-257.

    5. Tanaka A, Inoue A, Washizu T, et al. Comparison of expression of glucokinase gene and activities of enzymes related to glucose metabolism in livers between dogs and cats. Vet Res Commun 2005;29:477-485.

    6. Olefsky JM, Kolterman OG. Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes. Am J Med 1981;51:151-168.

    7. Feldhahan JR, Rand JS, Martin J. Insulin sensitivity in normal and diabetic cats. J Feline Med Surg 1999;1:107-115.

    8. Appleton DJ, Rand JS, Sunvold GD. Insulin sensitivity decreases with obesity, and lean cats with low insulin sensitivity are at greatest risk of glucose intolerance with weight gain. J Feline Med Surg 2001;3:211-228.

    9. Brennan CL, Heonig M, Ferguson DC. GLUT4 but not GLUT1 expression decreases early in the development of feline obesity. Domest Anim Endocrinol 2004;26:291-301.

    10. Robertson RP, Harmon J, Tran PO, et al. Glucose toxicity in β-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 2003;52:581-587.

    11. Link KRJ, Rand JS. Glucose toxicity in cats. J Vet Intern Med 1996a;10:185.

    12. Rand J. Current understanding of feline diabetes: part 1, pathogenesis. J Feline Med Surg 1993;1:143-153.

    13. Hoenig M, Hall G, Ferguson D, et al. A feline model of experimentally induced islet amyloidosis. Am J Pathol 2000;157:2143-2150.

    14. Johnson KH, O'Brien TD, Betsholtz C, et al. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989;321(8):513-518.

    15. O'Brien TD, Butler PC, Kreutter DK, et al. Intracellular amyloid associated with cytotoxicity in COS-1 cells expressing human amyloid polypeptide. Am J Pathol 1995;147:609-616.

    16. Nelson RW. Diabetes mellitus. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. St. Louis, Elsevier: Saunders; 2005:1563-1591.

    17. Rand JS, Bobbermien LM, Hendrikz JK, et al. Over representation of Burmese cats with diabetes mellitus. Aust Vet J 1997;75(6):402-405.

    18. Marshall RD, Rand JS. Treatment with glargine results in higher remission rates than lente or protamine zinc insulins in newly diagnosed diabetic cats (abstract). J Vet Intern Med 2005;19(3):425.

    19. Weaver KE, Rozanski EA, Mahony OM, et al. Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med 2006;20:234-238.

    20. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. St. Louis: Saunders; 2004.

    21. Hoenig M, Reusch C, Peterson ME. β cell and insulin antibodies in treated and untreated diabetic cats. Vet Immunol Immunopathol 2000;77:93-102.

    22. Scarlett JM, Donoghue S. Associations between body condition and disease in cats. JAVMA 1998;212(11):1725-1731.

    23. Frank G, Anderson W, Pazak K, et al. Use of a high-protein diet in the management of feline diabetes mellitus. Vet Ther 2002;2(3):238-246.

    24. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990;4:192-201.

    References »

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