Decreased gene expression of insulin signaling genes in insulin sensitive tissues of obese cats

Type 2 diabetes mellitus (DM) animal models have provided ample opportunity for investigating pathogenesis, as well as to evaluate novel treatment and prevention options for the disease. Because the domestic cat shares a similar environment with humans, it is also confronted with many similar risk factors for diabetes, such as physical inactivity and obesity. Obesity is a significant risk factor for diabetes in cats, and as such, the domestic cat may serve as an ideal model for investigating obesity induced insulin resistance. This study determined changes in insulin signaling genes within insulin sensitive tissues of obese felines. Quantitative RT-PCR was performed to determine mRNA levels of three important insulin signaling genes which have been implicated with insulin resistance: insulin receptor substrate (IRS)-1, IRS-2, and phosphatidylinositol 3’-kinase (PI3-K) p85α. Obese cats had significantly lower IRS-2 and PI3-K p85α mRNA levels in liver and skeletal muscle as compared to control cats. This down regulation of insulin signaling genes in obese cats mirrors that of obese humans and rodents suffering from insulin resistance. Interestingly, preprandial blood tests indicated that our obese cats were no different from control cats with regards to glucose tolerance and insulin resistance, thus indicating that the obese cats used in our study had a moderate level of obesity. Therefore, insulin signaling gene alterations were occurring in insulin sensitive tissues of moderately obese felines before glucose intolerance was clinically evident. As such, the monitoring of key insulin signaling genes may have some important diagnostic value to determine the risk level and degree of obesity induced insulin resistance.     

Comparison of insulin signaling gene expression in insulin sensitive tissues between cats and dogs

Diabetes mellitus (DM) is a common endocrine disease in cats and dogs with increasing prevalence. Type 1 DM appears to be the most common form of diabetes in dogs whereas Type 2 DM prevails for cats. Since insulin resistance is more frequently encountered in cats than dogs, our laboratory was interested in determining whether differences at the insulin signaling pathway level and differences in glucose and lipid metabolism could be observed between cats and dogs. Insulin resistance has been positively correlated to insulin signaling pathway abnormalities. As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85α mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. Different tissues were sampled because it is currently unknown where insulin-resistance arises from. In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. No distinct expression pattern emerged; however, differences were noted between canines and felines. In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85α mRNA expression levels which would predispose cats to develop insulin resistance. Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. Therefore, a combination of genetic and environmental factors appears to make felines more prone to suffer from insulin resistance and type 2 DM than canines.     

Comparison of time-action profiles of insulin Glargine and NPH insulin in normal and diabetic dogs

Intermediate insulin injections are commonly used for glycemic control in insulin dependent diabetic dogs acting as a replacement for natural insulin. Neutral Protamin Hagedorn (NPH) insulin and insulin glargine are two types of injectable insulin preparations commonly used in humans. In our study, we investigated the time-action profiles of both aforementioned insulin preparations in normal dogs in order to determine whether co-administration of NPH and glargine would be of benefit to insulin dependent diabetic dogs as it is for humans suffering from insulin dependent diabetes. Time-action profiles of NPH insulin and insulin glargine in normal dogs demonstrated a clear difference between both insulin preparations confirming that NPH insulin is an intermediate-acting preparation whereas insulin glargine is a long-lasting preparation. In addition, co-administration of NPH insulin and insulin glargine resulted in tight glycemic control as compared to NPH insulin alone in insulin dependent diabetic dogs. However, co-administration result in hypoglycemia at the dosages tested.     

Glucose response to exogenous insulin and kinetics of insulin metabolism in obese and lean heifers

Changes in serum concentrations of glucose and insulin after iv injection of a low (20 mU/kg) and high (200 mU/kg) dose of bovine insulin were used to quantify insulin resistance and calculate kinetic variables of injected insulin, respectively, in four obese and four lean heifers. Serum samples from jugular venous blood were collected 60, 45, 30, 15 and 1 min before and 2.5, 5, 10, 20, 30, 40, 60, 80, 100, 120, 150, 180, 210 and 240 min after each treatment. Mean (+/- SE) pretreatment concentration of insulin (microU/ml) was higher (P less than .01) in obese (50 +/- 6.6) than lean (20 +/- 1.8) heifers, even though glucose concentrations were similar in both groups (71 +/- 2.9 mg/100 ml). Concentrations of insulin after each treatment were similar in both groups and returned to pretreatment values by 60 and 120 min after injection of the low and high doses, respectively. Glucose concentrations during the first 40 min after treatment with the low dose were lower (P less than .05) in lean than obese heifers, but were similar in both groups during the first 40 to 60 min after the high dose of insulin. The high insulin dose decreased (P less than .05) glucose concentrations below those of the low dose in each group, but the difference was greater (P less than .01) in obese than lean heifers. These results indicated that obese heifers were insensitive to the glucoregulatory effects of exogenous insulin, although the maximum responses to insulin were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

Porcine somatotropin alters insulin response in growing pigs by reducing insulin sensitivity rather than changing responsiveness

Exogenous porcine somatotropin (pST) treatment consistently improves growth performance and reduces fat deposition in pigs, and it is hypothesized that one component of the mechanism is through altering the sensitivity and/or responsiveness to insulin. Therefore, a study was conducted to investigate the effect of pST treatment on whole-body glucose metabolism in response to varying doses of insulin. Eight barrows were surgically prepared with indwelling catheters and randomly assigned to one of two treatment groups (0 or 120 μg pST/kg BW · d) for 13 d. Whole-body glucose kinetics were measured during infusion of [6-(3)H]-glucose under basal conditions and during hyperinsulinemic-euglycemic clamps at various insulin infusion rates (7, 28, and 140, and 14, 70, and 280 ng insulin/kg BW · min) and alterations in the dose-response parameters were calculated with nonlinear regression. Treatment with pST increased basal plasma concentrations of glucose (36%; P = 0.005), insulin (276%; P = 0.001), and NEFAs (177%; P = 0.01) and decreased the rate of glucose disappearance (-59%; P = 0.001). The responsiveness (maximum response) for steady state glucose infusion rate to maintain glycemia was not altered by pST (112 vs 106 μmol/min · kg; P = 0.78), whereas the sensitivity (effective dose at 50% of maximum response) was increased almost 7-fold (1.3 vs 8.7 ng/mL; P = 0.027). Similar responses were observed for rate of glucose disappearance and insulin-dependent glucose utilization. Therefore, pST-induced insulin resistance with regard to whole-body glucose uptake is due to a reduced sensitivity to insulin, rather than a change in responsiveness.     

The diagnosis of equine insulin dysregulation

Insulin dysregulation is the hallmark of equine metabolic syndrome and has received attention because of its direct association with laminitis. In the absence of an adequate treatment for laminitis, a focus on prophylaxis is needed, making early detection of individuals at risk of developing laminitis one of the main challenges in equine endocrinology. Recent studies have shown that insulin dysregulation goes beyond tissue insulin resistance and it is now demonstrated that the equine enteroinsular axis plays a major role in insulin secretion and equine hyperinsulinaemia. In this review, we discuss the different tests currently available to diagnose insulin dysregulation in horses: the ones investigating tissue insulin resistance and those investigating the enteroinsular axis, detailing their goals, practicalities and limitations. This review supports the contention that the diagnosis of equine insulin dysregulation should now be based on the investigation of both tissue insulin resistance and the equine enteroinsular axis. Regardless of the tests used many factors of variation, such as breed, diet, fasting state or season, have been identified and could potentially confound the results of a specific test. Therefore, careful interpretation of the results of a given test in each individual situation is required to optimise the detection of horses at risk of laminitis.     

Pancreatic insulin secretory response and insulin action in heat-exposed sheep given a concentrate or roughage diet

The effects of heat exposure and type of diet on the insulin secretory response to glucose and glucose disposal in response to insulin action in female sheep were investigated employing hyperglycemic and euglycemic clamp techniques. Animals were divided into concentrate and roughage diet groups, and were maintained at the same intake levels of metabolizable energy and crude protein in both diets. Each diet group was subjected to either thermoneutral (20°C, 70% RH) or hot (30°C, 70% RH) environment, followed by glucose clamp experiments.

Heat-exposed sheep showed significant increases in respiration rates (P<.001) and rectal temperature (P<.05). Plasma glucose concentrations in the basal conditions were lower (P<.01) in the hot environment than in the thermoneutral environment, but there was no significant difference in basal levels of plasma insulin between the environmental treatments. In the hyperglycemic clamp experiment, mean plasma insulin increments increased (P<.05) during the heat exposure period across diet treatments. The ratio of mean plasma insulin increment to glucose infusion rate tended to be higher (P<.07) in the hot environment than in the thermoneutral environment, but diet treatment did not affect the ratio of mean plasma insulin increment to glucose infusion rate. The euglycemic clamp technique showed that glucose infusion rates remained unchanged among treatments. Insulin secretion response to glucose could be stimulated in the hot environment.     

Basal plasma insulin and homeostasis model assessment (HOMA) are indicators of insulin sensitivity in cats

The objective of this study was to compare simpler indices of insulin sensitivity with the minimal model-derived insulin sensitivity index to identify a simple and reliable alternative method for assessing insulin sensitivity in cats. In addition, we aimed to determine whether this simpler measure or measures showed consistency of association across differing body weights and glucose tolerance levels. Data from glucose tolerance and insulin sensitivity tests performed in 32 cats with varying body weights (underweight to obese), including seven cats with impaired glucose tolerance, were used to assess the relationship between Bergman's minimal model-derived insulin sensitivity index (S(I)), and various simpler measures of insulin sensitivity. The most useful overall predictors of insulin sensitivity were basal plasma insulin concentrations and the homeostasis model assessment (HOMA), which is the product of basal glucose and insulin concentrations divided by 22.5. It is concluded that measurement of plasma insulin concentrations in cats with food withheld for 24 h, in conjunction with HOMA, could be used in clinical research projects and by practicing veterinarians to screen for reduced insulin sensitivity in cats. Such cats may be at increased risk of developing impaired glucose tolerance and type 2 diabetes mellitus. Early detection of these cats would enable preventative intervention programs such as weight reduction, increased physical activity and dietary modifications to be instigated.     

The effect of xylazine and xylazine followed by insulin on blood glucose and insulin in the dairy cow

The effect of xylazine and xylazine followed 20 minutes later by insulin upon glucose metabolism and plasma insulin concentrations was examined in three cows. After doses of 0.18 mg per kg xylazine given intramuscularly (IM) or 0.15 mg per kg given intravenously (IV) hepatic glucose production increased, plasma insulin concentrations decreased to 25 to 33 per cent of control values, and there was a prolonged hyperglycaemia. When 200 units of soluble insulin were given 20 minutes after similar doses of xylazine there was a rapid fall in blood glucose and a reduction in the rate of glucose production by the liver. Xylazine-induced hyperglycaemia arose from a combination of increased hepatic glucose production and reduced plasma insulin concentrations. Peripheral tissues were still responsive to insulin and when adequate insulin was available blood glucose concentrations rapidly decreased.