Diabetic GK Rats Research Articles

Salivary Peptide P-C Potentiates Insulin Release and Inhibits Glucagon Release from Isolated Perfused Pancreas of the Diabetic GK Rat

We investigated the effects of the salivary peptide P-C (P-C), a saliva-derived peptide, on glucose (8.3 mM)- and arginine (10 mM)-induced insulin release and arginine (10 mM)-induced glucagon release using the perfused pancreas of spontaneously diabetic GK rats. Both its potentiating effect on insulin release and its inhibitory effect on glucagon release were concentration-dependent in diabetic GK rats. The ratio of insulin release obtained with P-C (194 nM) to that without P-C in GK rats was the same as ratio in normal Wistar rats. The ratio (0.40) of glucagon release obtained with P-C (194 nM) to that without P-C was smaller in diabetic GK rats than that (0.75) in normal Wistar rats. These results indicate that P-C inhibits arginine-induced glucagon release in diabetic GK rat pancreas more effectively than in normal Wistar rat pancreas.

Altered conditioned taste aversion and glucose utilization in related brain nuclei of diabetic GK rats

The impact of diabetes and especially hyperglycemia on brain glucose utilization and insulin binding are still not clear. This is probably due to the fact that most studies have been performed in streptozotocin treated rats that are highly hyperglycemia and that could have an effect per se on the brain. The aim of the present work was to measure, in vivo, glucose utilization and insulin binding in different areas of the brain of the spontaneously diabetic GK rats that present a moderate hyperglycemia. Brain insulin receptors number was not changed in the brain of GK rats. By contrast, an increased glucose utilization was present in the external plexiform and the intergranular layers of the olfactory bulbs, as well as in the amygdaloid of the GK rats. These structures are involved in conditioned taste aversion, which was found to be greatly altered in the diabetic rats. These results sustain the hypothesis of impaired neuropsychological functions in diabetic patients particularly in term of learning and memory.

Diabetic GK Rat Plasma but Not Normal Wistar Rat Plasma Induces Insulin-Stimulated DNA Synthesis in Primary Cultured Smooth Muscle Cells in GK Rat Aorta

We investigated the effect of diabetic plasma on insulin-stimulated DNA synthesis in primary cultured aortic smooth muscle cells (SMC) of the GK rat, a model of non-insulin-dependent diabetes mellitus, and compared it with that of Wistar normal rat plasma. We measured the incorporation of 3H-thymidine into cultured SMC. The diabetic plasma (3%) of GK rat, but neither the plasma (3%) of Wistar normal rat nor the plasma (3%) (not containing both insulin-like growth factor-I (IGF-I) and corticosterone) of Wistar hypophysectomized rat induced insulin-stimulated DNA synthesis in GK rat SMC. The responsiveness of SMC to insulin, not to IGF-I, was decreased remarkably by the diabetic state. The diabetic plasma of GK rat remarkably enhanced and the plasma of Wistar hypophysectomized rat weakly enhanced insulin-stimulated DNA synthesis in Wistar normal rat SMC. Corticosterone (20 nM) increased insulin-stimulated DNA synthesis in GK rat SMC but decreased it in Wistar normal rat SMC, using the plasma of Wistar hypophysectomized rat. Corticosterone levels were lower in GK rat plasma than in normal Wistar rat plasma. These results demonstrate that the enhancement of insulin-stimulated DNA synthesis in diabetic SMC by the diabetic plasma of GK rat may be due to neither IGF-I nor corticosterone but due to other factors.

O-41 - Angiogenic effects of macrophage-derived cytokines containing platelet-derived growth factor and interleukin-1 a in spontaneously diabetic GK rat.

O-41 - Angiogenic effects of macrophage-derived cytokines containing platelet-derived growth factor and interleukin-1 a in spontaneously diabetic GK rat.

Diabetes Mellitus-Induced Enhancement of Prostaglandin F2α-Responses Is Inhibitedby Lipoxygenase- but Not Cyclooxygenase-Inhibitors in Mesenteric Veins and Arteries of Mouse and Rat

The mechanisms responsible for diabetes mellitus-induced enhancement of prostaglandin (PG) F2 alpha response were investigated in vascular smooth muscles isolated from diabetic mice and rats. Streptozocin (150 mg/kg, i.v. bolus, 6 week-elapsed)-ddY mice and (60 mg/kg, i.v. bolus)-Wistar rats and genetically diabetic GK-rats were used. The responses to PGF2 alpha were enhanced in small blood vessels such as mesenteric arteries (diabetic rats) and veins (diabetic mice) and they were reduced in large blood vessels such as the aorta and vena cava (diabetic rats). The enhanced response to PGF2 alpha in diabetic blood vessels was significantly inhibited by nordihydroguaiaretic acid (NDGA) (0.03 mM) and phenidone (0.05 mM), lipoxygenase inhibitors, cycloheximide (1 mg/kg, i.v.), a protein synthesis inhibitor and actinomycin D (2.8 mg/kg, i.v.), a RNA polymerase inhibitor, but neither inhibited by cyclooxygenase inhibitors, a thromboxane antagonist, nor Ca2+ antagonists. The PGF2 alpha response was also enhanced with aging alone, whereas the extent of enhancement was less than that with diabetes mellitus, and not significantly blocked by NDGA. These results demonstrate that diabetes mellitus-induced imbalance in the regulation of the eicosanoid metabolic pathways (suppressed cyclooxygenase and accelerated lipoxygenase) may cause the enhancement of PGF2 alpha-induced responses in small blood vessels.

Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.

Spontaneously diabetic nonobese GK rats exhibit high basal plasma glucose and insulin levels and a poor insulin secretory response to glucose. We studied insulin biosynthesis, insulin release, and glucose metabolism in freshly isolated islets from GK rats and control Wistar rats. In GK rats, islet insulin content was decreased when expressed per islet but normal when related to DNA content. In the presence of a low concentration (2.8 mM) of glucose both (pro)insulin and total protein biosynthesis was doubled in islets from GK rats. As judged from the (pro)insulin/total protein synthesis ratio, (pro)insulin biosynthesis was normally stimulated by 16.7 mM glucose. In islets from diabetic rats both basal and glucose-stimulated insulin release were dramatically decreased. A reduced secretory response to 10 mM leucine or 10 mM leucine plus 10 mM glutamine and a lack of response to 10 mM monomethylsuccinate were observed. By contrast the insulinotropic capacity of nonnutrient secretagogues such as 62 microM gliclazide or the combination of 2 mM Ba2+ and 1.4 mM theophylline in the absence of extracellular Ca2+ remained normal. Glucose oxidation (estimated as the production of 14CO2 from D-[6-14C]glucose) was severely impaired, whereas no major alteration of glycolytic flux (as judged from the conversion of D-[5-3H]glucose to 3H2O) could be detected. Accordingly, the D-[6-14C]glucose oxidation/D-[5-3H]glucose use ratio was less markedly increased in response to a rise in glucose concentration in islets from GK rats than in islets from control rats. Thus, in islets from diabetic GK rats, glucose-induced insulin release but not insulin biosynthesis was impaired. This defect is associated with, and probably at least in part due to, a deficient oxidative metabolism of glucose in islet mitochondria.

Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes

Spontaneously diabetic nonobese GK rats exhibit high basal plasma glucose and insulin levels and a poor insulin secretory response to glucose. We studied insulin biosynthesis, insulin release, and glucose metabolism in freshly isolated islets from GK rats and control Wistar rats. In GK rats, islet insulin content was decreased when expressed per islet but normal when related to DNA content. In the presence of a low concentration (2.8 mM) of glucose both (pro)insulin and total protein biosynthesis was doubled in islets from GK rats. As judged from the (pro)insulin/total protein synthesis ratio, (pro)insulin biosynthesis was normally stimulated by 16.7 mM glucose. In islets from diabetic rats both basal and glucose-stimulated insulin release were dramatically decreased. A reduced secretory response to 10 mM leucine or 10 mM leucine plus 10 mM glutamine and a lack of response to 10 mM monomethylsuccinate were observed. By contrast the insulinotropic capacity of nonnutrient secretagogues such as 62 microM gliclazide or the combination of 2 mM Ba2+ and 1.4 mM theophylline in the absence of extracellular Ca2+ remained normal. Glucose oxidation (estimated as the production of 14CO2 from D-[6-14C]glucose) was severely impaired, whereas no major alteration of glycolytic flux (as judged from the conversion of D-[5-3H]glucose to 3H2O) could be detected. Accordingly, the D-[6-14C]glucose oxidation/D-[5-3H]glucose use ratio was less markedly increased in response to a rise in glucose concentration in islets from GK rats than in islets from control rats. Thus, in islets from diabetic GK rats, glucose-induced insulin release but not insulin biosynthesis was impaired. This defect is associated with, and probably at least in part due to, a deficient oxidative metabolism of glucose in islet mitochondria.

Effect of Manidipine on Balloon Catheter-Induced Arterial Smooth Muscle Cell Proliferation in Spontaneously Diabetic GK Rats

The inhibitory effect of manidipine, a long acting calcium channel blocker, on vascular smooth muscle cell proliferation was investigated in spontaneously diabetic GK rats with balloon catheter-induced denudation of the carotid artery. Treatment with manidipine at doses of 4.6 and 15.1 mg/kg/day inhibited thickening of the neo-intima in the balloon catheter-injured artery without any effect on blood pressure and lowered the ratio of intima to wall areas and wall to total vascular areas in a dose-dependent fashion. These results suggest that manidipine inhibits an abnormal proliferation of the intima in the carotid artery of spontaneously diabetic rats.

Effect of Pioglitazone on Sucrose-Deteriorated Diabetic States in Spontaneously Diabetic GK Rats

Effect of Pioglitazone on Sucrose-Deteriorated Diabetic States in Spontaneously Diabetic GK Rats

Spontaneously-developed Diabetic GK Rat—Pathogenesis and Diabetic Complications

Spontaneously diabetic GK rats were produced from rats of Wistar strain by repeating the selective breeding using glucose tolerance as a selection indicator. Of 211 normal rats 18 were selected by oral glucose tolerance test (GTT) and by the breeding 162 first generation rats were obtained. This procedure was repeated in each generation. The mean glucose tolerance curve became more diabetic with advance of generation and all of 9th generation rats had a diabetic character. The diabetic rats are not obese and there is no sex difference as regards occurrence of severity of the diabetic state. Significantly lower insulin secretion in GTT was observed in GK rats as compared with Wistar rats. Pancreas perfusion studies revealed that GK rats lacked the first response and then showed delayed and low insulin secretion. In addition, there was significantly reduced insulin secretion in isolated GK islets as compared to Wistar rats. Histological studies showed severe deformity, atrophy and fibrosis of GK islets. These histological abnormalities progressed with age. Immunohistochemistry to insulin and glucagon displayed reduced number of B cells and malorientation of A cells within GK islets. Glycolytic pathway enzyme activities in GK livers showed significantly higher than those of Wistar rats. Insulin insensitivity in GK livers may probably suggest the existence of insulin resistance. GK rats have the perilphera neuropathy and the thickening of glomerular basement membranes. GK rat is a promising model of non-insulin dependent diabetes mellitus and a good model of diabetic complications, as well.

Role of Hepatic Insulin Sensitivity in Development of Hyperglycemia of Spontaneously Diabetic GK Rats

Role of Hepatic Insulin Sensitivity in Development of Hyperglycemia of Spontaneously Diabetic GK Rats