Feline comorbidities: Pathophysiology and management of the obese diabetic cat.

PRACTICAL RELEVANCE: Up to 40% of the domestic feline population is overweight or obese. Obesity in cats leads to insulin resistance via multiple mechanisms, with each excess kilogram of body weight resulting in a 30% decline in insulin sensitivity. Obese, insulin-resistant cats with concurrent beta-cell dysfunction are at risk of progression to overt diabetes mellitus. APPROACH TO MANAGEMENT: In cats that develop diabetes, appropriate treatment includes dietary modification to achieve ideal body condition (for reduction of insulin resistance), and optimization of diet composition and insulin therapy (for glycemic control and the chance of diabetic remission). Initially, as many obese cats that become diabetic will have lost a significant amount of weight and muscle mass by the time of presentation, some degree of diabetic control should be attempted with insulin before initiating any caloric restriction. Once body weight has stabilized, if further weight loss is needed, a diet with ≤ 12-15% carbohydrate metabolizable energy (ME) and >40% protein ME should be fed at 80% of resting energy requirement for ideal weight, with the goal of 0.5-1% weight loss per week. Other approaches may be necessary in some cats that need either substantial caloric restriction or do not find low carbohydrate diets palatable. Long-acting insulins are preferred as initial choices and oral antidiabetic drugs can be used in combination with diet if owners are unable or unwilling to give insulin injections. Glucagon-like peptide-1 (GLP-1) agonists have recently been investigated for use as adjunctive treatment in diabetic cats and sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently being evaluated in clinical trials. EVIDENCE BASE: The information in this review is drawn from: epidemiological studies on obesity prevalence; prospective longitudinal studies of development of insulin resistance with obesity; randomized controlled studies; and expert opinion regarding the effect of diet on diabetes management in cats.

Effect of sensor location in dogs on performance of an interstitial glucose monitor.

OBJECTIVE To identify variations in glucose values concurrently obtained by use of a continuous glucose monitoring system (CGMS) at the same site, reliability of results for each site, lag time for each site, and influence of site thickness on CGMS accuracy. ANIMALS 8 random-source research dogs. PROCEDURES In experiment 1, 8 CGMS sensors were implanted bilaterally at 1 site (4 sensors/side) in 4 dogs. In experiment 2, 2 CGMS sensors were implanted bilaterally at each of 4 sites (1 sensor/side) in 8 dogs; 4 of those 8 dogs then were subjected to a glycemic clamp technique. The CGMS results were compared among sensors and with criterion-referenced results during periods of euglycemia for all 8 dogs and during hyperglycemia and hypoglycemia for 4 dogs during the glycemic clamp procedure. RESULTS Differences (median, -7 mg/dL; interquartile range [IQR], -18.75 to 3 mg/dL) between CGMS and criterion-referenced glucose concentrations differed significantly among dogs and sites; during euglycemia, they were not different from the expected normal variation between multiple sensors concurrently implanted at the same site. Differences (median, -35 mg/dL; IQR, -74 to -15 mg/dL) between CGMS and criterion-referenced concentrations were greater during changes in glucose concentrations. Thoracic sensors were most accurate but had the shortest mean functional life. CONCLUSIONS AND CLINICAL RELEVANCE Significant differences were detected between CGMS and criterion-referenced glucose concentrations. Overall clinical utility of CGMS was acceptable at all sites, with most of the values from all sensors, sites, and dogs meeting guidelines for point-of-care glucometers.

Metabolic Effects of Obesity and Its Interaction with Endocrine Diseases.

Obesity in pet dogs and cats is a significant problem in developed countries, and seems to be increasing in prevalence. Excess body fat has adverse metabolic consequences, including insulin resistance, altered adipokine secretion, changes in metabolic rate, abnormal lipid metabolism, and fat accumulation in visceral organs. Obese cats are predisposed to endocrine and metabolic disorders such as diabetes and hepatic lipidosis. A connection likely also exists between obesity and diabetes mellitus in dogs. No system has been developed to identify obese pets at greatest risk for development of obesity-associated metabolic diseases, and further study in this area is needed.

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.

Carbohydrate metabolism and pathogenesis of diabetes mellitus in dogs and cats.

Diabetes mellitus (DM) is a common disease in dogs and cats and its prevalence is increasing in both species, probably due to an increase in obesity, although only in cats has obesity been clearly identified as a major risk factor for diabetes. While the classification of diabetes in dogs and cats has been modeled after that of humans, many aspects are different. Autoimmune destruction of beta cells, a feature of type 1 DM in people, is common in dogs; however, in contrast to what is seen in people, the disease occurs in older dogs. Diabetes also occurs in older cats but islet pathology in those species is characterized by the presence of amyloid, the hallmark of type 2 DM. Despite being overweight or obese, most naive diabetic cats, contrary to type 2 diabetic humans, present with low insulin concentrations. The physiology of carbohydrate metabolism and pathogenesis of diabetes, including histopathologic findings, in dogs and cats are discussed in this chapter.

Evaluation of routine hematology profile results and fructosamine, thyroxine, insulin, and proinsulin concentrations in lean, overweight, obese, and diabetic cats.

OBJECTIVE: To compare results of hematologic testing in nondiabetic and diabetic cats to identify possible indicators of alterations in long-term glucose control. DESIGN: Cross-sectional study. ANIMALS: 117 client-owned cats (76 nondiabetic cats [25 with normal body condition, 27 overweight, and 24 obese] and 41 naïve [n = 21] and treated [20] diabetic cats). PROCEDURES: Signalment and medical history, including data on feeding practices, were collected. A body condition score was assigned, and feline body mass index was calculated. Complete blood counts and serum biochemical analyses, including determination of fructosamine, thyroxine, insulin, and proinsulin concentrations, were performed. Urine samples were obtained and analyzed. RESULTS: Glucose and fructosamine concentrations were significantly higher in the naïve and treated diabetic cats than in the nondiabetic cats. Insulin and proinsulin concentrations were highest in the obese cats but had great individual variation. Few other variables were significantly different among cat groups. Most cats, even when obese or diabetic, had unlimited access to food. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that cats at risk of developing diabetes (ie, overweight and obese cats) could not be distinguished from cats with a normal body condition on the basis of results of isolated hematologic testing. A longitudinal study is indicated to follow nondiabetic cats over a period of several years to identify those that eventually develop diabetes. Findings also suggested that dietary education of cat owners might be inadequate.

Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity.

OBJECTIVES: Obese cats show many similarities to obese people, including insulin resistance and an increased diabetes risk. However, atherosclerosis and cardiovascular disease are not seen in cats. In people, they are associated with the development of an inflammatory response, which, we hypothesized, does not occur in cats. DESIGN AND METHODS: Twenty neutered cats of equal gender distribution were allowed to gain weight by offering food ad libitum and were examined before and at 10, 30, 60, and 100% weight gain. All cats reached 60% of weight gain, 12 cats gained 100% in 12 months. RESULTS: Fat was equally distributed between subcutaneous and visceral depots. Insulin-independent glucose uptake increased and insulin sensitivity decreased with increasing adiposity. However, baseline glucose concentrations were unchanged suggesting a decrease in EGP. Inflammatory cytokines (Il-1, IL-6, TNFa) and catalase, superoxide dismutase, glutathione peroxidase did not change. Insulin, proinsulin, and leptin were positively and adiponectin negatively correlated with adiposity. Heat production increased with obesity, but became less when body weight gain was > 60%. CONCLUSIONS: This indicates that metabolism adapts more appropriately to the higher intake of calories in the initial phase of obesity but slows at higher body fat content. This likely contributes to the difficulty to lose weight.

The cat as a model for human obesity and diabetes.

Obesity is the most common nutritional disorder of cats and is a risk factor for diabetes. Similar to developments in obese people, obese cats show peripheral tissue insulin resistance and may demonstrate glucose intolerance when challenged with pharmacological amounts of glucose. However, they compensate well for the insulin resistance and do not show elevated glucose concentrations when monitored during their regular daily routine, including postprandial periods. This is possible because obese cats in the fasted and postprandial state are able to maintain hepatic insulin sensitivity and decrease endogenous glucose production, which allows them to maintain normoglycemia. Also dissimilar to what is seen in many obese humans, cats do not develop atherosclerosis and clinical hypertension. The time course for progression to overt diabetes of obese cats is unknown. One might speculate that diabetes develops when the liver finally becomes insulin resistant and/or insulin secretion becomes too low to overcome increased glucose production. In addition, amyloid, demonstrated to be deposited in islet of chronically obese cats, may contribute to a reduction in insulin secretion by reducing functional ß-cell mass.

Evaluation of long-term glucose homeostasis in lean and obese cats by use of continuous glucose monitoring.

OBJECTIVE: To evaluate intraday and interday variations in glucose concentrations in cats and to test the utility of a continuous glucose monitoring system (CGMS). ANIMALS: 6 lean and 8 long-term (> 5 years) obese cats. PROCEDURES: Blood glucose concentrations were measured during the course of 156 hours by use of a laboratory hexokinase-based reference method and a handheld glucometer. Interstitial glucose concentrations were evaluated with a CGMS. RESULTS: Paired measures of glucose concentrations obtained with the CGMS typically were marginally higher than concentrations for the reference method and less biased than concentrations obtained with the glucometer. This was partially confirmed by the concordance correlation coefficients of the concentration for the CGMS or glucometer versus the concentration for the reference method, although the correlation coefficients were not significantly different. Mean ± SD area under the curve for the glucose concentration (AUCG) did not differ significantly between lean (14.0 ± 0.5 g/dL•h) and obese (15.2 + 0.5 g/dL•h) cats during the 156-hour period, but one of the obese cats had a much higher AUCG. Within-day glucose variability was small in both lean and obese cats. CONCLUSIONS AND CLINICAL RELEVANCE: Glucose homeostasis was maintained, even in long-term obese cats, and intraday glucose fluctuations were small. One obese cat might have been classified as prediabetic on the basis of the AUCG, which was approximately 25% higher than that of the other obese and lean cats. The CGMS can be useful in the evaluation of long-term effects of drugs or diet on glucose homeostasis in cats.

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats.

Obesity and age are risk factors for feline diabetes. This study aimed to test the hypothesis that age, long-term obesity, and dietary composition would lead to peripheral and hepatorenal insulin resistance, indicated by higher endogenous glucose production (EGP) in the fasted and postprandial state, higher blood glucose and insulin, and higher leptin, free thyroxine, and lower adiponectin concentrations. Using triple tracer-(2)H(2)O, [U-(13)C(3)] propionate, and [3,4-(13)C(2)] glucose infusion, and indirect calorimetry-we investigated carbohydrate and fat metabolic pathways in overnight-fasted neutered cats (13 young lean, 12 old lean, and 12 old obese), each fed three different diets (high protein with and without polyunsaturated fatty acids, and high carbohydrate) in a crossover design. EGP was lowest in fasted and postprandial obese cats despite peripheral insulin resistance, indicated by hyperinsulinemia. Gluconeogenesis was the most important pathway for EGP in all groups, but glycogen contributed significantly. Insulin and leptin concentrations were higher in old than in young lean cats; adiponectin was lowest in obese cats but surprisingly highest in lean old cats. Diet had little effect on metabolic parameters. We conclude that hepatorenal insulin resistance does not develop in the fasted or postprandial state, even in long-term obese cats, allowing the maintenance of euglycemia through lowering EGP. Glycogen plays a major role in EGP, especially in lean fasted cats, and in the postprandial state. Aging may predispose to insulin resistance, which is a risk factor for diabetes in cats. Mechanisms underlying the high adiponectin of healthy old lean cats need to be further explored.

The impact of obesity, sex, and diet on hepatic glucose production in cats.

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using (2)H(2)O, [U-(13)C(3)]propionate, and [3,4-(13)C(2)]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had approximately 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

The effects of obesity and fatty acids on the feline immune system.

Obesity is a rising problem in cats. It is a risk factor for several diseases and has been linked to impaired immunity. The goal of this study was to determine the effect of body composition and effects of diet on immune function in cats. Twenty-eight short-term obese and 12 lean cats with equal gender distribution were evenly and randomly divided into two groups which were either fed a diet containing saturated (SFA) or long-chain n-3 polyunsaturated fatty acids (3-PUFA) for a period of 6 months prior to testing. Blood was collected by venipuncture from the jugular vein. Blood samples were analyzed in a double blind fashion. A complete blood count was performed and lymphocyte distribution was examined by flow cytometric analysis with specific fluorescein-conjugated subset markers. Immune function was measured as follows: the proliferative activity of different cellular fractions was tested with polyclonal mitogens such as lipopolysaccharide (LPS), phytohaemagglutinin (PHA), phorbol 12-myristate 13-acetate (PMA), Ca ionophore, and concanavalin A. Innate immune functions assessed were phagocytosis and natural killer cell (NK) cytotoxicity. A similar immune innate and adaptive immune response was elicited regardless of diet or body condition. However, there was no correlation between body condition, diet, and any of the quantitative and qualitative functional responses of the immune system. We conclude that short-term obesity and the fatty acid composition of the diet do not alter immune responses in cats.

The cat as a model for human nutrition and disease.

PURPOSE OF REVIEW: Obesity is a new pandemic in humans associated with increased morbidity and mortality. A similar sharp increase has occurred in the number of obese cats in recent years. There are many reasons for this increase in both species; for cats, the main problems are unlimited access to a nutrient-dense diet and sedentary life style. Obesity is a major risk factor for diabetes whose prevalence has increased concomitantly. Cats develop a form of diabetes that is similar to type 2 in humans, characterized by islet amyloid and loss of beta-cell mass. The energy metabolism of cats and the pathophysiology of obesity and diabetes are being characterized in order to identify similarities and differences from humans and to recognize causative and protective factors for adverse sequelae to obesity and diabetes. RECENT FINDINGS: New approaches to the study of lipid and glucose metabolism in cats show that glucose metabolism is not as dissimilar and lipid metabolism is not as similar to that of humans as previously thought, perhaps explaining why cats do not develop the classic metabolic syndrome. SUMMARY: The cat is an excellent model for examining the pathophysiology and complications of obesity and diabetes.

Evaluation of transdermal application of glipizide in a pluronic lecithin gel to healthy cats.

OBJECTIVE: To evaluate plasma glipizide concentration and its relationship to plasma glucose and serum insulin concentrations in healthy cats administered glipizide orally or transdermally. ANIMALS-15 healthy adult laboratory-raised cats. PROCEDURE: Cats were randomly assigned to 2 treatment groups (5 mg of glipizide, PO or transdermally) and a control group. Blood samples were collected 0, 10, 20, 30, 45, 60, 90, and 120 minutes and 4, 6, 10, 14, 18, and 24 hours after administration to determine concentrations of insulin, glucose, and glipizide. RESULTS: Glipizide was detected in all treated cats. Mean +/- SD transdermal absorption was 20 +/- 14% of oral absorption. Mean maximum glipizide concentration was reached 5.0 +/- 3.5 hours after oral and 16.0 +/- 4.5 hours after transdermal administration. Elimination half-life was variable (16.8 +/- 12 hours orally and 15.5 +/- 15.3 hours transdermally). Plasma glucose concentrations decreased in all treated cats, compared with concentrations in control cats. Plasma glucose concentrations were significantly lower 2 to 6 hours after oral administration, compared with after transdermal application; concentrations were similar between treatment groups and significantly lower than for control cats 10 to 24 hours after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Transdermal absorption of glipizide was low and inconsistent, but analysis of our results indicated that it did affect plasma glucose concentrations. Transdermal administration of glipizide is not equivalent to oral administration. Formulation, absorption, and stability studies are required before clinical analysis can be performed. Transdermal administration of glipizide cannot be recommended for clinical use at this time.

Assessment of the influence of fatty acids on indices of insulin sensitivity and myocellular lipid content by use of magnetic resonance spectroscopy in cats.

OBJECTIVE: To determine whether dietary fatty acids affect indicators of insulin sensitivity, plasma insulin and lipid concentrations, and lipid accumulation in muscle cells in lean and obese cats. ANIMALS: 28 neutered adult cats. PROCEDURE: IV glucose tolerance tests and magnetic resonance imaging were performed before (lean phase) and after 21 weeks of ad libitum intake of either a diet high in omega-3 polyunsaturated fatty acids (3-PUFAs; n = 14) or high in saturated fatty acids (SFAs; 14). RESULTS: Compared with the lean phase, ad libitum food intake resulted in increased weight, body mass index, girth, and percentage fat in both groups. Baseline plasma glucose or insulin concentrations and glucose area under the curve (AUC) were unaffected by diet. Insulin AUC values for obese and lean cats fed 3-PUFAs did not differ, but values were higher in obese cats fed SFAs, compared with values for lean cats fed SFAs and obese cats fed 3-PUFAs. Nineteen cats that became glucose intolerant when obese had altered insulin secretion and decreased glucose clearance when lean. Plasma cholesterol, triglyceride, and non-esterified fatty acid concentrations were unaffected by diet. Ad libitum intake of either diet resulted in an increase in both intra- and extramyocellular lipid. Obese cats fed SFAs had higher glycosylated hemoglobin concentration than obese cats fed 3-PUFAs. CONCLUSION AND CLINICAL RELEVANCE: In obese cats, a diet high in 3-PUFAs appeared to improve long-term glucose control and decrease plasma insulin concentration. Obesity resulted in intra- and extramyocellular lipid accumulations (regardless of diet) that likely modulate insulin sensitivity.

Effect of darglitazone on glucose clearance and lipid metabolism in obese cats.

OBJECTIVE: To examine the effect of darglitazone, a compound of the thiazolidinedione class, on glucose clearance and lipid metabolism in obese cats. ANIMALS: 18 obese and 4 lean adult neutered female cats. PROCEDURE: IV glucose tolerance tests with measurements of glucose, insulin, and nonesterified fatty acid (NEFA) concentrations were performed before and 42 days after daily administration of darglitazone (9 obese cats) or placebo (9 obese and 4 lean cats). Additionally, cholesterol, triglyceride, leptin, and glycosylated hemoglobin concentrations were measured. RESULTS: Darglitazone-treated cats had significantly lower cholesterol, triglyceride, and leptin concentrations, compared with placebo-treated obese cats. A significant decrease in the area under the curve for NEFAs, glucose, and insulin during an i.v. glucose tolerance test was seen in darglitazone-treated cats. The drug was well tolerated. CONCLUSION AND CLINICAL RELEVANCE: The response of obese cats to darglitazone was similar to the response to thiazolidinediones in obese humans and rodents Darglitazone was effective in improving insulin sensitivity and glucose and lipid metabolism in obese cats.

Effects of obesity on lipid profiles in neutered male and female cats.

OBJECTIVE: To examine whether obese cats, compared with lean cats, have alterations in lipoprotein metabolism that might lead to a decrease in glucose metabolism and insulin secretion. ANIMALS: 10 lean and 10 obese adults cats (5 neutered males and 5 neutered females each). PROCEDURE: Intravenous glucose tolerance tests with measurements of serum glucose, insulin, and nonesterified fatty acid (NEFA) concentrations were performed. Lipoprotein fractions were examined in serum by isopycnic density gradient ultracentrifugation. RESULTS: Obese cats had insulin resistance. Plasma triglyceride and cholesterol concentrations were significantly increased in obese cats, compared with lean cats. Very low density lipoprotein (VLDL) concentrations were increased in obese cats, compared with lean cats; however, the composition of various fractions remained unchanged between obese and lean cats, indicating greater synthesis and catabolism of VLDL in obese cats. Serum high density lipoprotein (HDL) cholesterol concentrations were increased in obese cats, compared with lean cats. Serum NEFA concentrations were only significantly different between obese and lean cats when separated by sex; obese male cats had higher baseline serum NEFA concentrations and greater NEFA suppression in response to insulin, compared with lean male cats. CONCLUSIONS AND CLINICAL RELEVANCE: Lipid metabolism changes in obese cats, compared with lean cats. The increase in VLDL turnover in obese cats might contribute to insulin resistance of glucose metabolism, whereas the increase in serum HDL cholesterol concentration might reflect a protective effect against atherosclerosis in obese cats.

Effects of neutering on hormonal concentrations and energy requirements in male and female cats.

OBJECTIVE: To determine whether changes in concentrations of hormones involved in glucose and fatty acid homeostasis are responsible for the increased probability that neutered cats will develop obesity and diabetes mellitus. ANIMALS: 10 male and 10 female weight-maintained adult cats. PROCEDURE: Results of glucose tolerance tests and concentrations of hormones and nonesterified fatty acids (NEFA) were examined before and 4, 8, and 16 weeks after neutering. RESULTS: Caloric requirements for weight maintenance were significantly decreased 8 and 16 weeks after neutering in females. Glucose concentrations during a glucose tolerance test did not change in neutered females or males. The area under the curve (AUC) for insulin was significantly higher in males, compared with females, before neutering. However, the AUC for insulin increased and was significantly higher 4 and 8 weeks after neutering in females. The AUC for insulin did not change in neutered male cats. Leptin concentrations did not change in females but increased significantly in males 8 and 16 weeks after neutering. Thyroxine concentrations did not change after neutering; however, free thyroxine concentration was significantly higher in females than males before neutering. Baseline concentrations of NEFA were significantly higher in female than male cats before but not after neutering. Suppression of NEFA concentrations after glucose administration decreased successively in male cats after neutering, suggesting decreased insulin sensitivity. CONCLUSIONS AND CLINICAL RELEVANCE: Changes in NEFA suppression, caloric intake, and leptin concentrations may be indicators of, and possible risk factors for, the development of obesity in cats after neutering.