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) p85alpha. Obese cats had significantly lower IRS-2 and PI3-K p85alpha 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.
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-85alpha 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-85alpha 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.
Dietary therapy is an important treatment component for diabetes mellitus (DM). In this study, the impact of three different commercially available diet regiments (1 general use and 2 aimed for treating obesity and DM) on short-term post-prandial serum glucose and insulin concentrations of five healthy cats to better understand what impact each of these diets may have for diabetic cats. The diet regiments used in this study were as follows: C/D dry (General Use- Low protein, High fat, High carbohydrate, and Low fiber), M/D dry (DM- High protein, High fat, Low carbohydrate, and High Fiber), and W/D dry (DM- Low Protein, Low Fat, High Carbohydrate, and High Fiber). No significant difference in post-prandial serum glucose levels were observed with the C/D (84.6 +/- 1.5 mg/dl) and W/D (83.8 +/- 1.4 mg/dl) dry diets when compared to pre-prandial fasting levels (83.9 +/- 1.4 mg/dl). However, a significant reduction was observed with the M/D diet (78.9 +/- 0.8 mg/dl) which had 50-60% less carbohydrates than either C/D or W/D diet. Unlike what was observed with post-prandial glucose levels, an interesting pattern emerged with post-prandial insulin levels, which were increasing with W/D, C/D, and M/D diets in that order (1.1 +/- 0.2, 1.7 +/- 0.2, and 2.3 +/- 0.2 ng/ml respectively). Most surprising, though, was the fact that the W/D diet did not seem to stimulate insulin secretion as compared to pre-prandial levels (1.1 +/- 0.1 ng/ml) in healthy cats. Interestingly, the W/D diet had high levels of carbohydrate and low levels of protein. Coincidentally, the only diet (M/D) which had a significant reduction in post-prandial glucose also showed the highest increase in post-prandial insulin in healthy cats. Therefore, dietary amounts of carbohydrate, fat, protein and fiber can all have an individual impact on post-prandial glycemia and subsequent insulin requirement levels. Just as concepts regarding dietary management of people with DM are evolving, investigators are reassessing what constitutes the ideal diet for the diabetic feline. As such, having a better understanding for each dietary component, may lead us to better understand how we can synergize certain dietary components to aid in DM management.
In order to evaluate the immune state of dogs suffering from pituitary-dependent hyperadrenocorticism (PDH), peripheral lymphocyte subsets were examined. Twenty seven PDH dogs and eight healthy control dogs were used in the current study. Eight healthy dogs served as the control group. Twenty seven PDH dogs were categorized into 4 groups based on their post serum cortisol concentrations by ACTH stimulation test: 2-5, excellent control (n = 8); 5-20, fair control (n = 7); >20, poor control (n = 4); and untreated (n = 8). Cell counts were executed with white blood cells (WBC), lymphocytes, CD3(+) (T lymphocytes), CD4(+) (Helper T lymphocytes), CD8(+) (Cytotoxic T lymphocytes), CD21(+) (B lymphocytes) cells in addition to calculating CD4(+)/CD8(+) ratio. Results indicated a significant difference in lymphocyte numbers and lymphocyte subset populations (CD3(+), CD4(+), CD8(+), and CD21(+) cells) between PDH and control dogs. Moreover, comparison of the PDH groups (excellent control; fair control; poor control; untreated) demonstrated that all groups had a significant decrease in lymphocytes numbers (CD3(+), CD4(+) and CD21(+) cell counts) as compared to control group. Meanwhile, no significant differences were observed in WBC counts and CD4(+)/CD8(+) ratio between groups. Furthermore, lymphocyte subset distribution in excellent control PDH dogs without concurrent disease (n = 4) better resembled that of control dogs as compared to PDH dogs with concurrent disease (n = 4). PDH dogs may be suffering from an immuno-depressed state as evidenced by significant differences in lymphocyte subset populations. Furthermore, treatment of both PDH and concurrent disease might improve lymphocyte subset distribution.
Measurements of serum fructosamine, glycated hemoglobin, and glycated albumin (GA) complement serum glucose concentration for better management of diabetes mellitus (DM). Especially, the serum fructosamine test has long been used for diagnosing and monitoring the effect of treatment of DM in dogs. However, fructosamine tests are currently not performed in veterinary medicine in Japan. GA and fructoasmine levels have been shown to strongly correlate. However, the clinical implications of using GA remain to be elucidated. Therefore, the purpose of the current study was threefold: 1) Determine whether GA% is altered by acute hyperglycemia in normal dogs, simulating stress induced hyperglycemia; 2) Demonstrate that GA% does not dynamically change with diurnal variation of blood glucose concentration in diabetic dogs; and 3) Investigate whether GA% is capable of providing an index of glycemic control for 1-3 weeks in diabetic dogs as is the case with diabetic human patients. Our study demonstrated that serum GA% remains very stable and unaltered under acute hyperglycemic conditions (intravenous glucose injection) and in spite of diurnal variation of blood glucose concentration. Furthermore, serum GA% can reflect long-term changes (almost 1-3 weeks) in blood glucose concentration and the effect of injected insulin in diabetic dogs.
Circulating levels of monosaccharides can act as a reflection of systemic glucose/ energy metabolism. Characteristic changes observed in these levels can be seen in patients with diabetes and other metabolic disorders. There have been a few reports describing the significance of mannose metabolism as an energy source under physiological and pathological conditions. However, the relationship between circulating levels of mannose and the pathophysiology of diabetes mellitus are unknown in dogs. This study examined circulating levels of mannose between healthy control and diabetic dogs and evaluated the clinical significance of mannose levels in dogs. Diabetic dogs demonstrated a higher circulating level of mannose in comparison to normal healthy control dogs. Plasma mannose was positively correlated with plasma glucose and fructosamine, respectively. Interestingly, plasma mannose levels were affected by plasma insulin levels. In the context of feeding and glucose tolerance tests, plasma mannose levels responded to changes in circulating insulin levels. Circulating plasma mannose levels decreased after feeding in both control and diabetic animals in spite of observed insulin level differences. However, when glucose tolerance tests were given, a positive correlation between mannose levels and insulin levels was observed. Therefore, plasma mannose levels obtained via glucose tolerance testing may be used as a new diagnostic method for evaluating insulin resistance or deficiency in diabetic dogs.
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