Non-obese Goto-Kakizaki Rats Research Articles

Estrogen deprivation aggravates cardiac hypertrophy in nonobese Type 2 diabetic Goto-Kakizaki (GK) rats.

Both Type 2 diabetes mellitus (T2DM) and estrogen deprivation have been shown to be associated with the development of cardiovascular disease and adverse cardiac remodeling. However, the role of estrogen deprivation on adverse cardiac remodeling in nonobese T2DM rats has not been clearly elucidated. We hypothesized that estrogen-deprivation aggravates adverse cardiac remodeling in Goto–Kakizaki (GK) rats. Wild-type (WT) and GK rats at the age of 9 months old were divided into two subgroups to have either a sham operation (WTS, GKS) or a bilateral ovariectomy (WTO, GKO) (n = 6/subgroup). Four months after the operation, the rats were killed, and the heart was excised rapidly. Metabolic parameters, cardiomyocytes hypertrophy, cardiac fibrosis, and biochemical parameters were determined. GK rats had hyperglycemia with hypoinsulinemia, and estrogen deprivation did not increase the severity of T2DM. Cardiac hypertrophy, cardiac oxidative stress, and phosphor-antinuclear factor κB were higher in WTO and GKS rats than WTS rats, and they markedly increased in GKO rats compared with GKS rats. Furthermore, cardiac fibrosis, transforming growth factor-β, Bax, phosphor-p38, and peroxisome proliferator- activated receptor γ coactivator-1α expression were increased in GKS and GKO rats compared with the lean rats. However, mitochondrial dynamics proteins including dynamin-related protein 1 and mitofusin-2 were not altered by T2DM and estrogen deprivation. Although estrogen deprivation did not aggravate T2DM in GK rats, it increased the severity of cardiac hypertrophy by provoking cardiac inflammation and oxidative stress in nonobese GK rats.

Zinc와 Arachidonic Acid가 고 Fructose 식이로 유도된 인슐린 저항성에 미치는 영향

We previously demonstrated that zinc plus arachidonic acid (ZA) treatment lowered blood glucose levels in streptozotocin-induced diabetic rats, genetically diabetic obese (ob/ob) mice, and genetically diabetic, non-obese Goto-Kakizaki rats. However, plasma insulin levels did not increase with ZA treatment, suggesting that ZA lowers blood glucose levels not by stimulating pancreatic insulin secretion. However, it is unclear whether these agents lower blood glucose levels by decreasing hepatic glucose output (HGO) or by increasing glucose utilization in peripheral tissues, or both. In order to determine ZA target organ of insulin action, we divided 18 Sprague- Dawley rats weighing ~130 g into 3 groups (6 rats per group) and treated them for four weeks with: (1) Control diet (regular rat chow), (2) High fructose (60.0%) diet only, and (3) the same fructose diet plus zinc (10 mg/L) and arachidonic acid (50 mg/L) containing drinking water. After 4 weeks, insulin action was assessed using the hyperinsulinemic euglycemic clamp technique. Food intake and body weights were comparable in all three groups of rats throughout the study period. Plasma glucose and insulin concentrations, glucose uptake, and HGO in the basal state were all the same in these three rat groups. During the clamp study, fructose-treated and fructose+ZA treated rat groups did not exhibit any detectable change on insulin-mediated glucose uptake com- pared to controls. High fructose feeding impaired insulin mediated suppression of HGO, compared to controls during clamp (4.39 vs. 2.35 mg/kg/min; p<0.05). However, ZA treatment in high fructose-fed rats showed a remarkable increase in hepatic insulin sensitivity compared to high fructose-fed rats, reflected by a complete recovery in suppression of HGO during the clamp (4.39 vs. 2.18 mg/kg/min; p<0.05). This data suggests that ZA increases insulin sensitivity in liver but not glucose utilization of peripheral tissues in high fructose-fed rats.

Bone histomorphometric and biomechanical analyses in Type 2 diabetic Goto-Kakizaki rats

Objective To characterize the bone metabolism in Goto-Kakizaki(GK) rats,a spontaneous type 2 diabetic model.Methods Ten six-month old male GK rats were enrolled,with ten age-and sex-matched nondiabetic Wistar rats as controls.Blood samples were collected from the carotid artery for analysis of calcium,phosphate,osteocalcin and tartrate-resistant acid phosphatase activity.Bone mineral density was assessed by a dual energy X-ray absorptiometry at the femur and the fifth vertebral body,respectively,followed by biomechanical studies.The metaphyseal tibiae were embedded in methylmethacrylate to obtain undecalcified sections.Histomorphometric analysis was performed with an analysis software for multimedia pathological image.Results The body weight was much lower in the GK rats than that in the healthy Wistar rats(P0.01).Compared with the controls,the GK rats had significantly lower serum osteocalcin concentration [(4.97±0.49,6.75±0.71) μg/mL] and higher tartrate-resistant acid phosphatase activity [(17.92±5.23,8.31±2.69) U/L],both were P0.01.Bone density at the femur and lumbar vertebra was significantly deceased in the diabetic rats [(0.16±0.01,0.22±0.02;0.12±0.01,0.16±0.02) g/cm~2, P0.01].Bone morphologic analysis showed that the lengths of femur and lumbar were reduced by 10.3% and 9.5%,respectively,in the GK rats(P0.01),while no significant difference was seen in the values of cross-sectional area at both sites(P0.05).Histomorphometrical study showed significantly decreased trabecular bone volume,trabecular thickness,osteoid surface and thickness in GK rats [(15.72±1.18,19.13±1.13)%,(61.91± 4.54, 74.43 ± 3.63) μm,(18.18±1.25,19.63±1.07)%,(3.68±0.48,4.34±0.35) μm,P0.01 or 0.05],respectively.Further,the mineralizing surface,mineral apposition rate and bone formation rate were also decreased in the GK rats compared with those in the controls [(17.77±1.54,19.56±2.07)%,(1.07±0.22,1.35±0.16;0.20±0.03,0.26±0.04) μm/day,P0.05 or P0.01],along with an increase in mineralization lag time (2.66±0.56,2.12±0.35,P0.05).Conclusion Nonobese GK rats develop bone mass loss with increased risk of bone fracture.Type 2 diabetes mellitus per se may induce disequilibrium of bone remodelling by interfering with the function and activity of osteoblasts.

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

The inability of insulin to stimulate glucose metabolism in skeletal muscle fibres is a classic characteristic of type 2 diabetes. Using the non-obese Goto–Kakizaki rat as an established animal model of this type of diabetes, sucrose gradient centrifugation studies were performed and confirmed the abnormal subcellular location of the glucose transporter GLUT4. In addition, this analysis revealed an unexpected drastic reduction in the surface membrane marker β-dystroglycan, a dystrophin-associated glycoprotein. Based on this finding, a comprehensive immunoblotting survey was conducted which showed a dramatic decrease in the Dp427 isoform of dystrophin and the α/ β-dystroglycan subcomplex, but not in laminin, sarcoglycans, dystrobrevin, and excitation–contraction–relaxation cycle elements. Thus, the backbone of the trans-sarcolemmal linkage between the extracellular matrix and the actin membrane cytoskeleton might be structurally impaired in diabetic fibres. Immunohistochemical studies revealed that the reduction in the dystrophin–dystroglycan complex does not induce obvious signs of muscle pathology, and is neither universal in all fibres, nor fibre-type specific. Most importantly, the expression of α-syntrophin and the syntrophin-associated neuronal isoform of nitric oxide synthase, nNOS, was demonstrated to be severely reduced in diabetic fibres. The loss of the dystrophin–dystroglycan complex and the syntrophin–nNOS complex in selected fibres suggests a weakening of the sarcolemma, abnormal signalling and probably a decreased cytoprotective mechanism in diabetes. Impaired anchoring of the cortical actin cytoskeleton via dystrophin might interfere with the proper recruitment of the glucose transporter to the surface membrane, following stimulation by insulin or muscle contraction. This may, at least partially, be responsible for the insulin resistance in diabetic skeletal muscles.

Genetic Modifiers ofLeprfaAssociated with Variability in Insulin Production and Susceptibility to NIDDM

In an attempt to identify the genetic basis for susceptibility to non-insulin-dependent diabetes mellitus within the context of obesity, we generated 401 genetically obeseLeprfa/LeprfaF2 WKY13M intercross rats that demonstrated wide variation in multiple phenotypic measures related to diabetes, including plasma glucose concentration, percentage of glycosylated hemoglobin, plasma insulin concentration, and pancreatic islet morphology. Using selective genotyping genome scanning approaches, we have identified three quantitative trait loci (QTLs) on Chr. 1 (LOD 7.1 for pancreatic morpholology), Chr. 12 (LOD 5.1 for body mass index and LOD 3.4 for plasma glucose concentration), and Chr. 16 (P< 0.001 for genotype effect on plasma glucose concentration). The obese F2 progeny demonstrated sexual dimorphism for these traits, with increased diabetes susceptibility in the males appearing at approximately 6 weeks of age, as sexual maturation occurred. For each of the QTLs, the linked phenotypes demonstrated sexual dimorphism (more severe affection in males). The QTL on Chr. 1 maps to a region vicinal to that previously linked to adiposity in studies of diabetes susceptibility in the nonobese Goto–Kakizaki rat, which is genetically closely related to the Wistar counterstrain we employed. Several candidate genes, including tubby (tub), multigenic obesity 1 (Mob1), adult obesity and diabetes (Ad), and insulin-like growth factor-2 (Igf2), map to murine regions homologous to the QTL region identified on rat Chr. 1.