Aims/hypothesis The adult non-obese Goto-Kakizaki (GK) rat model of type 2 diabetes, particularly females, carries in addition to hyperglycaemia a genetic predisposition towards dyslipidaemia, including hypercholesterolaemia. As cholesterol-induced atherosclerosis may be programmed in utero, we looked for signs of perinatal lipid alterations and islet microangiopathy. We hypothesise that such alterations contribute towards defective pancreas/islet vascularisation that might, in turn, lead to decreased beta cell mass. Accordingly, we also evaluated islet inflammation and endothelial activation in both prediabetic and diabetic animals.Methods Blood, liver and pancreas were collected from embryonic day (E)21 fetuses, 7 dayold prediabetic neonates and 2.5 month-old diabetic GK rats and Wistar controls for analysis/quantification of: (1) Results Systemic and hepatic cholesterol anomalies already exist in GK fetuses and neonates.Hyperglycaemic GK fetuses exhibit a similar percentage decrease in total pancreas and islet vascularisation and beta cell mass. Normoglycaemic GK neonates show systemic inflammation, signs of islet pre-microangiopathy, disturbed angiogenesis, collapsed vascularisation and altered pancreas development. Concomitantly, GK neonates exhibit elevated defence mechanisms.Conclusions/interpretation These data suggest an autoinflammatory disease, triggered by in utero programming of cholesterol-induced islet microangiopathy interacting with chronic hyperglycaemia in GK rats. During the perinatal period, GK rats show also a marked deficient islet vascularisation in conjunction with decreased beta cell mass.
The GK rat as a model of NIDDM. NIDDM develops as a consequence of interplay between 3-cell dysfunction, peripheral insulin resistance and elevated hepatic glucose production. However, it is unknown which is the primary abnormality and which are abnormalities secondary to elevated plasma glucose, the so-called "glucose toxicity". To delineate the primary abnormalities, it is desirable to analyse the individuals destined to become diabetic before the development of the disease. The advantage of utilizing an animal model is that the development of diabetes can be predicted and thus, it is possible to dissect the pathogenic mechanism necessary for the emergence of overt diabetes. The Goto-Kaki aki (GK) Wistar rat is especially useful in such perspective as all adult individuals in both sexes exhibit NIDDM. This spontaneous diabetes model was produced by selective breeding (with glucose intolerance as a selection index) for many generations, starting from a non-diabetic Wistar rat colony. The characteristics of GK animals bred in our colony in Paris, are close to those of the animals in the original Japanese colony: all rats have basal mild hyperglycemia and an impaired i.v. glucose tolerance. Males and females are similarly affected and their diabetic state is stable over 72 weeks of follow up. In adult GK rats, the pancreatic insulin stores and the total pancreatic 3-cell mass were decreased by 50%. Plasma insulin release in vitro in response to intravenous glucose was lacking. In vitro studies of insulin release with the isolated perfused pancreas or with perifused islets, indicate that both the early and late phases of glucose-induced insulin release are markedly affected in the adult GK rat. Concerning insulin action in adult GK rats, we have reported a decreased insulin sensitivity in the liver, in parallel to moderate insulin resistance in extrahepatic tissue, i.e. muscles and adipose tissues.Multiple defects in the -ce1l of adult GK rat with overt diabetes. The notion that in the GK b-cell, the lesion responsible for the loss of glucose-induced insulin secretion occurs before the effector system, is supported by data indicating that GK islets are duly responsive to non-nutrient secretagogues, such as sulfonylureas or a combination of barium and theophylline. It has been shown that the impaired glucose-induced insulin release in GK islets was associated with a perturbation of mitochondrial oxidative events. More specifically, it has been reported that aerobic glycolysis, but not anaerobic glycolysis, was impaired in GK islets, and it was suggested that mitochondria of GK islets exhibit a specific decrease in the activities of FAD-dependent glycerophosphate dehydrogenase and pyruvate dehydrogenase. Although this may certainly contribute to lower oxidation rates, it does not exclude other mechanisms. Indeed we have found that the 3-cells of adult GK rats had a significantly smaller mitochondrial volume and an increased number of mitochondria per unit tissue volume as compared with control 3-cells. No major delet...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.