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Protamine zinc insulins are generally considered to be long acting, with slow absorption from subcutaneous tissue. Protamine zinc recombinant human insulin (PZIR) may be useful to treat diabetic dogs. The purpose of this study was to describe the pharmacokinetics and pharmacodynamics of PZIR in dogs. PZIR was administered subcutaneously to 10 healthy Beagles using an incomplete crossover design, at doses of 0.3 or 0.5 U/kg (each n=5), 0.8 U/kg (n=10), or 0.8 U/kg at three separate sites (n=6). Insulin and glucose concentrations were measured over 24 h. The shapes of insulin and glucose curves were variable among dogs, and the relationship between insulin dose, concentration, and glucose-lowering effect was nonlinear. For single-site 0.8 U/kg, median (range) onset of action was 3.5 h (0.5-10 h), time to glucose nadir was 14 h (5 to >24 h), and duration of action was >24 h (16 to >24 h). Mathematical model predictions of times to 50% and 90% insulin absorption, and fraction of insulin absorbed in 24 h, were not significantly different among protocols. Results confirm the tendency toward a late onset and long duration of action for PZIR in dogs. This insulin may be an alternative treatment option for diabetic dogs., (© 2011 Blackwell Publishing Ltd.)

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.

The response to oral glucose was examined in 10 obese and 9 lean age-matched, neutered cats. In all cats, oral administration of 2g/kg glucose was followed by a prompt increase in glucose, insulin, and glucagon-like peptide (GLP)-1. There were significant differences between lean and obese cats in the areas under the curve for glucose, insulin, and GLP-1. However, the responses were variable, and a clear distinction between individual lean and obese cats was not possible. Therefore, this test cannot be recommended as a routine test to examine insulin resistance in individual cats as it is used in people. A further disadvantage for routine use is also the fact that this test requires gastric tubing for the correct administration of the glucose and associated tranquilization to minimize stress and that it was associated with development of diarrhea in 25% of the cats. GLP-1 concentrations were much lower in obese than lean cats. The low GLP-1 concentrations in obese cats might indicate a contribution of GLP-1 to the lower insulin sensitivity of obese cats, but this hypothesis needs to be further investigated., (Copyright 2010 Elsevier Inc. All rights reserved.)

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.

Simultaneous application of the euglycemic hyperinsulinemic clamp (EHC) and indirect calorimetry was used to examine heat production, fat, and glucose metabolism in lean and obese adult neutered male and female cats. The results show that in lean insulin-sensitive cats glucose oxidation predominated during fasting, whereas lipid oxidation became more prominent in obese cats. Insulin infusion during the EHC in lean cats and obese male cats led to a large increase in glucose oxidation, glycogenesis, and lipogenesis. It also led to an increase in glucose oxidation and glycogenesis in obese female cats but it was significantly less compared to lean cats and obese males. This indicates that obese females show greater metabolic inflexibility. In obese cats of either gender, insulin caused greater suppression of non-esterified fatty acids compared to lean cats suggesting that obese cats show greater fatty acid clearance than lean cats. The heat production per metabolic size was lower in obese cats than lean cats. This would perpetuate obesity unless food intake is decreased. The higher glucose oxidation rate in obese neutered male cats suggests that they are able to replete their glycogen and lipid stores at a faster rate than females in response to insulin and it implies that they gain weight more rapidly. Further studies are needed to investigate if the different response to insulin of male cats is involved in their higher risk to develop diabetes.

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.

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.

Intravenous glucose tolerance tests (IVGTTs) are used in cats and other species to assess insulin sensitivity. Several dosages have been reported but the dosage that maximally stimulates insulin secretion in cats has not been determined nor has it been compared in lean and obese animals. IVGTTs were performed in 4 lean and 4 obese spayed female cats with 5 glucose dosages: 0.3 (A), 0.5 (B), 0.8 (C), 1.0 (D). and 1.3 (E) g/kg body weight (BW). Each cat received each dosage in a random design. The glucose disposal rate was significantly different only between lean and obese cats at the highest glucose dosage. The area under the curve for insulin increased significantly among A, B, C, and D in lean and among A, B, and C in obese cats but not between D and E in lean and among C, D, and E in obese cats. Baseline insulin secretion was significantly higher (P = .03) and 1st peak insulin secretion was approximately 50% lower in obese as compared to lean cats (P = .03). Lean but not obese cats reached baseline insulin concentrations at all dosages at 120 minutes. We conclude that the glucose dosage for maximal insulin secretion is 1.0 g/ kg BW in lean and 0.8 g/kg BW in obese cats, supporting routine use of 1 g/kg BW to maximally stimulate insulin secretion regardless of body composition. Obese cats showed an abnormal insulin secretion pattern, indicating a defect in insulin secretion with obesity and insulin resistance.

Increased dietary fiber is thought to have beneficial effects on health in humans. In diabetic dogs, a beneficial effect of fiber on glycemia has been suggested, while its effect on lipid profiles in dogs has not been described. The effects of different amounts and types of fiber on glucose tolerance and lipid concentrations were evaluated and compared with those of a standard maintenance ration in 30 healthy dogs. It was concluded that increased fiber intake had no influence on glucose in healthy dogs but it may have modulated lipid homeostasis.

Changes in glycosylated hemoglobin (GHb) concentrations, K values (% disappearance of glucose/min after an intravenous injection of 1 g/kg dextrose), and blood glucose concentrations were examined in eight cats before and during the induction of diabetes, and in four of these cats after they were placed on insulin treatment. There was a statistically significant separation of GHb, K values, and fasting blood glucose concentrations between healthy and diabetic cats. Changes in GHb correlated best with the K value and single weekly fasting glucose concentrations averaged over eight periods for each cat while diabetes was induced (R = 0.80 and 0.78, respectively); however, fasting blood glucose concentrations obtained on the day of the GHb measurement were also highly correlated (R = 0.69; P < 0.001). The correlation between GHb and single weekly glucose concentrations obtained in insulin-treated cats at the time of insulin peak action and averaged over an 8-wk time period for each cat was less but still significant (R = 0.53; P < 0.001). It is concluded that GHb measurements are a simple and reliable way to monitor changes in glucose control in the diabetic cat over a prolonged period.

Prednisone was administered orally for 4 weeks at a dosage of 1.1 mg/kg of body weight/d, in divided dose every 12 hours, to a group of healthy adult dogs (n = 12). Intravenous glucose tolerance testing was performed before and after the 28-day regimen in each dog, as well as in dogs of a control group (n = 6). Glucose metabolism was evaluated by measurement of preprandial plasma insulin and glucose concentrations, total insulin secretion, and fractional clearance of glucose. Mean preprandial plasma insulin and glucose concentrations were not increased after the 4-week regimen of prednisone. Total insulin secretion in response to an IV administered glucose load was not increased in treated dogs, compared with pretreatment values or with values for control dogs. The fractional clearance of glucose was also not altered in dogs given prednisone. Results indicate that anti-inflammatory doses of prednisone, given orally for 4 weeks, probably do not alter insulin sensitivity or glucose tolerance in clinically normal dogs.

Glucose tolerance and insulin secretion after administration of a glucose load were determined in 11 clinically normal cats and 15 cats with spontaneous hyperthyroidism. In six hyperthyroid cats, a glucose tolerance test was repeated after treatment with radioactive iodine (131I). All cats had similar baseline glucose concentrations. However, the cats with hyperthyroidism had a significantly decreased glucose clearance, which was worse after treatment. Hyperthyroidism also caused a marked increase in basal and glucose-stimulated insulin secretion, which was not improved with treatment. It is concluded that hyperthyroidism in cats may lead to long-lasting alterations of glucose tolerance and insulin secretion which may not be reversed by treatment.

Intravenous glucose tolerance tests were performed in eight adult cats before and after a 4-week treatment with thyroxine. The untreated cats had a mean fasting blood glucose concentration of 7.7 +/- 0.3 mmol/l and a mean fasting insulin concentration of 88 +/- 31 pmol/l which were not significantly different from mean fasting glucose and insulin concentrations after 4 weeks of thyroxine administration (6.9 +/- 0.2 mmol/l and 101 +/- 28 pmol/l respectively). At 120 min after glucose injection, the glucose concentration in untreated cats returned to baseline concentrations as did the insulin concentration. However, in the hyperthyroid cats both glucose and insulin concentrations were significantly (P less than 0.001) higher (13.6 +/- 0.8 mmol/l and 245 +/- 17 pmol/l respectively) in comparison with the baseline and untreated cats. The t1/2 for glucose disappearance was significantly higher in the cats rendered hyperthyroid, and the glucose disposal rate constant (K) was significantly lower in this group. It is concluded that hyperthyroidism in cats leads to impairment of glucose tolerance possibly due to peripheral insulin resistance.