Glucose Intolerance in Spontaneously Hypertensive and Wistar-Kyoto Rats: Enhanced Gene Expression and Synthesis of Skeletal Muscle Glucose Transporter 4.

Abstract

To clarify the relationship between blood pressure and insulin resistance, we studied the role of glucose transporter 4 (GLUT4) in skeletal muscle and the effect of angiotensin-converting enzyme inhibitor on insulin resistance. Blood pressure and plasma glucose and plasma insulin responses to glucose loading (2 glkg, ip) were measured in spontaneously hypertensive rats (SHRs), Wistar-Kyoto rats (WKYs), and Wistar rats at 8, 12, and 20 wk of age. GLUT4 gene expression and plasma membrane protein content were also determined in the gastrocnemius muscle. SHRs and WKYs at the age of 8 wk had significantly higher plasma glucose levels than did age-matched control Wistar rats. Insulin response also tended to be higher. Glucose intolerance was also present in 12-wk-old SHRs, but normalized at the age of 20 wk. In contrast, WKYs were glucose intolerant at 12 and 20 wk. Gene expression and plasma membrane content of GLUT4 were augmented in both 8-wk-old SHRs and WKYs, indicating a compensatory increase in these variables. Effects of captopril (20-30 mg/kg/d from 8 to 20 wk) on GLUT4 were also investigated in these three strains. Captopril improved steady state plasma glucose levels in association with 1.2-to 2.5-fold higher GLUT4 gene expression and a 1.4-fold increase in skeletal muscle GLUT4 protein in SHRs and WKYs. Our results suggest that (1) not only SHRs but also WKYs may have glucose intolerance and hence insulin resistance; (2) gene expression and protein synthesis of skeletal muscle GLUT4 are probably increased compensatorily, indicating that abnormalities in GLUT4 do not have a pivotal role in the development of insulin resistance in SHRs and WKYs; and (3) captopril stimulates skeletal muscle gene expression and synthesis of GLUT4, providing further evidence of its beneficial effect on glucose metabolism. (Hypertens Res 1997; 20: 279-286)

Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats

“…In addition to being glucose intolerant, the ACI is the only strain to exhibit increased fasting glucose levels, a known predictor of T2D (51,52). In contrast to the ACI, the WKY strain shows elevated fasting insulin and an increased insulin response to a glucose challenge, as previously demonstrated (35,63). We show that the WKY has relatively low QUICKI levels, implying decreased insulin sensitivity, and that their IGI levels are ) and the scale of the effects, such that, e.g., for an otherwise average body weight, diplotype substitutions could push the phenotype anywhere from 296 to 374 g. The transformed value of the phenotypes, as described in METHODS, is used.…”

“…Although none of the inbred founder strains of the HS rat colony are overtly diabetic, we have demonstrated that at least two of the HS founder strains, WKY and ACI, exhibit glucose intolerance (64). Previous studies have found that the WKY rat also has higher plasma insulin levels than other strains both at fasting (75) and in response to a glucose challenge (35,63). In addition, when made genetically obese by mutating the leptin receptor, the WKY rat (fatty WKY) shows decreased insulin sensitivity relative to Zucker rats (27).…”

Clinical Characteristics Influencing the Effectiveness of Metformin on Japanese Type 2 Diabetes Receiving Sulfonylureas

“…Numerous studies have reported that a defect of insulin action in skeletal muscle was observed in spontaneously hypertensive rats [23][24][25]. On the other hand, it has been previouly reported that an antidiabetic action of metformin was observed predominantly in liver but that it was less effective in skeletal muscle [26].…”

“…So the reason why the hypoglycemic effect of metformin decreases in patients with hypertension may be due to the inability of this drug sufficiently improve insulin sensitivity in skeletal muscle, a phenomenon which is often observed in hypertensive patients. While antihypertensive drugs including inhibitors of angiotensin converting enzyme [24,25,27] and calcium antagonists [28,29] partially improve the insulin sensitivity in skeletal muscle, metformin may efficiently ameliorate glycemic control via improvement of insulin sensitivity in liver. The reason why there was no difference in hypoglycemic effects of metformin between IM and NIM groups, although mean systolic pressure of NIM group was significantly higher than that of the IM group, may be due to the prescription of larger numbers of antihypertensive drugs and higher ratios of inhibitors of angiotensin converting enzyme.…”

Fine-mapping a locus for glucose tolerance using heterogeneous stock rats

“…These studies indicate that diabetes susceptibility alleles will segregate within the HS rat colony. While the WKY rat has previously been found to exhibit hyperglycemia and glucose intolerance (17,21), no information is currently available regarding glucose regulation in the ACI rat.…”