Hyperthyroidism in cats was virtually unknown until the late 1970s, although now it is the most common endocrine disease of cats and one of the most common diseases in older cats. Diabetes mellitus (DM) is also a commonly encountered endocrine problem in older cats, and its prevalence also has increased dramatically in the last three decades because of a large increase in the prevalence of obesity. According to Joslin (writing in 1934),1 in people, “the subject of hyperthyroidism and diabetes, as a combination of diseases, is such a small one that it permits but little to be said about,” even though diabetes not infrequently coexists with hypothyroidism and hyperthyroidism in human patients. It is not known how frequently the two diseases coexist in cats, but anecdotally, it is well known that they can occur concomitantly. One study in a tertiary care center identified only 15 cases of cats with multiple endocrine diseases between 1997 and 2008; 11 of the cases were cats with concurrent hyperthyroidism and DM.² Another study found 5.8% of 104 diabetic cats had concurrent hyperthyroidism.³ In two large studies of hyperthyroid cats, up to 5.5% were diagnosed with DM.^4,5 There are, however, no epidemiologic or pathophysiologic data demonstrating a causative link between hyperthyroidism and DM, nor is an increase in fasting blood glucose a common feature of the hyperthyroid cat.

Although the increase in both diseases has occurred during the same time span, that is, the last three decades, it does not appear that identical factors are involved in the pathogenesis except for the fact that hyperthyroidism and DM occur primarily in older cats, and most patients are over 10 years old. Hyperthyroidism and DM in young cats are extremely rare. Other risk factors for DM are body condition (obesity), sex, and reproductive status.6 At highest risk would be an old, obese, neutered male cat. A genetic predisposition appears to occur in Australian Burmese cats.

Several investigators from different continents have evaluated the risk factors for hyperthyroidism and have presented similar results despite the geographic differences.^7–9 As stated, older domestic short- and longhaired cats are more likely to develop the disease than young or purebred cats. The risk increases with increasing age. There was no difference in the risk for males versus females in one study, whereas female cats were identified at higher risk in the others. Hyperthyroid cats were more likely to have used a litter box, to be fed wet cat food from a pop-top can, or were fed all categories of table food, including high-fat dairy products. The plasticizer compounds bisphenol A and phthalates have been suspected, without proof, as a causative agent for obesity and diabetes in humans and for hyperthyroidism in cats, but no linkage has been ascertained to date. Environmental factors appear to play an important role, because hyperthyroid cats were more likely to have been exposed to smokers in their environment and to household insecticide treatments. Other risk factors include sleeping on the floor, exposure to organic fertilizers, and dental disease. Interestingly, hyperthyroidism was less likely in multicat households compared with single-cat households.

It is impossible to clearly distinguish hyperthyroidism from DM based on the clinical presentation. The most frequently seen clinical signs for hyperthyroidism and DM are the same, are similar to other chronic diseases of cats, and will worsen over time. As a result, the early recognition of hyperthyroidism in a diabetic cat and vice versa is difficult because of the shared clinical signs:

Less predictably, both conditions may present with muscle weakness, vomiting, and diarrhea. In addition, cats with severe hyperthyroidism may show agitation. The diabetic cat with acromegaly may gain, rather than lose, weight.10

Hyperthyroidism and DM are both catabolic states. Hyperthyroidism is caused by excessive secretion of thyroid hormones (TH; triiodothyronine [T₃] and thyroxine [T₄]) by hyperplastic or adenomatous thyroid glands, rarely by malignant thyroid carcinomas.11,12 Hyperthyroidism in cats is most similar to hyperthyroidism in people caused by toxic nodular goiter. Abnormalities of the G protein and 3′-5′-cyclic adenosine monophosphate (cAMP)-signaling pathway have been implicated in the pathogenesis in both species.^13,14 Although in people, antibodies against islet antigens are found with autoimmune thyroid disease, there is no evidence that a similar connection exists in hyperthyroid cats. Autoimmune processes have not been shown to play a role in either disease, and islet antigens have not been detected in diabetic cats.¹⁵

Thyroid hormones affect many aspects of metabolism and energy homeostasis, and in general terms, can be viewed as antagonists to insulin. The metabolic alterations during thyrotoxicosis represent direct effects of TH on the expression of TH-responsive genes and are mediated by binding of T₃ to TH receptors in peripheral organs.^16,17 Thyrotoxic human patients exhibit insulin resistance, that is, the effectiveness of insulin in muscle, fat, and liver is hampered.^{1,10,14,18,19} Because one of the main roles of insulin is the control of glucose homeostasis, increased insulin resistance is seen as a decrease in glucose tolerance. In a study comparing healthy with hyperthyroid cats, glucose clearance was decreased in hyperthyroid cats, and insulin secretion was increased during an intravenous glucose tolerance test.²⁰ This pattern is characteristic for peripheral insulin resistance, which causes decreased uptake of glucose into muscle and fat tissue. However, fasting blood glucose concentrations were still normal, suggesting that hepatic glucose output was normal.

It is known that hyperthyroidism by itself causes increased hepatic glucose production and a dramatic increase in Krebs cycle flux.^21–23 One might therefore expect excess glucose production in thyrotoxicosis. However, it has been shown in cats that pyruvate cycling flux, a futile cycle, is also stimulated by TH, thereby negating an effect on gluconeogenesis.¹⁸ It is conceivable that in hyperthyroid cats, gluconeogenesis is kept low and fasting blood glucose is kept in the normal range through enhancement of this futile cycle. It has been shown in hyperthyroid rats that gluconeogenesis was only increased 20%, because pyruvate cycling decreased gluconeogenesis by more than two-thirds compared with what would be seen were pyruvate cycling not operative. This suggests pyruvate cycling plays a functional role in protecting against overproduction of glucose in the liver.²⁴ Hyperglycemia is therefore not a feature of hyperthyroidism. Contrary to popular belief, there is no evidence that hyperthyroidism increases intestinal glucose absorption in cats, and data from other species are highly controversial.^25,26

In contrast to the effect of hyperthyroidism on hepatic glucose regulation, the diabetic cat has lost the ability to regulate glucose output from the liver and shows high fasting blood glucose concentrations. Although it is possible that hyperthyroidism beneficially affects gluconeogenesis in diabetic cats to some degree, it does not overcome the detrimental effects of absolute or relative insulin deficiency. It is certainly conceivable that in the long term, hyperthyroidism could lead to DM, because it causes insulin resistance, and insulin resistance is a risk factor for DM, but this needs to be investigated in a well-controlled study. To date, there is no evidence for such a link. The deciding factor would be β-cell mass. As long as a cat has a relatively large β-cell mass, it will be able to withstand the insult of insulin resistance.

Obesity is the most common nutritional disorder, and diabetes mellitus (DM) is one of the most common endocrine diseases in cats. The prevalence for both has increased dramatically in the last three decades. Obesity has been reported to occur in 10% to 40% and DM in about 0.2% to 1.2% of the cat population.1–4 Environmental factors, such as unrestricted food intake and reduced physical activity, are largely responsible for the modern epidemic of obesity. Obesity and DM are tightly linked to each other in cats, as they are in people. It is thought that feline obesity increases the risk of developing DM three- to fivefold. Other risk factors for DM are gonadectomy and sex. Obese male neutered cats have been thought to have the highest risk to develop the disease,⁵ although in a more recent study in England, sex was not significantly associated with DM.⁶ Antibodies to islet antigens do not seem to play a role in the pathogenesis of DM in cats.⁷

Unlike in people, a diagnosis of DM in cats is usually made only when the animal exhibits obvious clinical signs of hyperglycemia. In people, an oral glucose tolerance test (OGTT) is frequently used to document DM but is rarely performed in pets. The OGTT has been described in cats;8 however, as in dogs, this test is associated with highly variable results and is not recommended as a routine clinical diagnostic test. The intravenous glucose tolerance test (IVGTT), although associated with less variability, is labor intensive and not suited for use in clinical practice. Therefore, early recognition of cats at risk of developing DM is difficult, and no clear pattern of easily measurable parameters has yet emerged that would indicate development or progression of the disease process.

Obesity occurs when energy intake exceeds energy output. There are subjective as well as objective methods to measure increases in body mass. Two body condition scoring systems (5- and 9-point scales) are frequently used in clinical practice. Although subjective, they can be easily performed by one person. Longitudinal assessment (i.e., repeated over time) of animals should preferably be performed by the same person to decrease the variability of results. A score of 3/5 or 5/9 indicates the cat is well proportioned, that is, of normal weight, while a body condition score of 5/5 or 9/9 indicates the cat is obese and has heavy deposits of fat. Values in between indicate increasing fat deposits as the numbers rise. Girth circumference may be measured behind the last rib and is a good objective indicator of obesity. Similar to body condition scoring, it can also be performed by one person. The results correlate very well with fat measurements using more sophisticated methods, such as dual-energy x-ray absorptiometry (DEXA).9 Because normal girth values are not available for different cat breeds, at this time, this method should only be used to follow the body condition in an individual animal over time. Plain radiographs may also be helpful in assessing condition by evaluating falciform and paralumbar fat deposits. Other objective methods, such as body mass index, DEXA scanning, or magnetic resonance imaging have also been performed in cats, but not usually in clinical practice. Because normal ranges for those techniques are not available for different breeds, these tests are also valuable only when performed over time in the same cat.

Obesity and DM are characterized by quantitative and qualitative alterations of insulin secretion. Normally, insulin is secreted from β-cells in a biphasic manner in response to high glucose during an IVGTT. In the cat, as in people, other fuels such as amino acids potentiate the secretion of insulin in the presence of glucose. Characteristic changes that are seen in obese compared to lean cats are a marked increase in the second or maintenance phase of insulin release. The amount of insulin secreted during the second phase is primarily an indicator of glucose uptake into peripheral tissues. Because of the change in glucose transport and the delayed clearance of glucose in obese cats (described later), higher insulin concentrations are needed in obese cats to produce a normal insulin response from cells. This is known as insulin resistance. Insulin resistance is classically measured with a method called the euglycemic hyperinsulinemic clamp. Simply explained, this is a technique in which a constant amount of insulin is infused. Glucose is also infused in the amount necessary to keep blood glucose concentrations in the euglycemic range. The more sensitive a cat is to the effect of insulin, the more glucose must be infused. It has been shown in cats that every kilogram in weight gain leads to a 15% to 30% loss in sensitivity to insulin.10,11 It is important to note that insulin resistance induced by obesity is reversible with weight loss.¹²

The insulin resistance of obesity has been associated not only with total fat mass, but also with the distribution of triglycerides within the body and within tissues. In people, a loss of insulin sensitivity has been associated particularly with triglyceride deposition in the abdomen (abdominal subcutaneous and intra-abdominal), muscle, and liver. In obese cats, the response to insulin is tissue dependent, and even in long-term obese cats, insulin resistance is only seen in adipose and muscle tissue, not in the liver. In muscle and fat, the following changes are seen in cats with obesity-induced insulin resistance:

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