Role of Insulin Resistance in the Pathogenesis and Development of Type 2 Diabetes in WBN/Kob-<i>Lepr^fa</i> Rats

Abstract

WBN/Kob-Leprfa (fa/fa) rats have been identified as a new animal model of type 2 diabetes (T2DM), as they are characterized by impaired pancreatic insulin secretion and severe insulin resistance. Our previous study demonstrated impaired insulin secretion and its involvement in hyperglycemia in fa/fa rats. The present study was aimed at elucidating the role of insulin resistance in the development and progression of diabetes in these animals. Troglitazone (TGZ) was used as an insulin sensitizer. Insulin resistance and insulin secretory capacity were measured by a homeostasis model assessment of insulin resistance and the area under the blood concentration–time curve for plasma insulin levels after intravenous glucose tolerance testing, respectively. The fa/fa rats exhibited marked insulin resistance between 5 and 11 weeks of age, compared with age-matched Wistar rats. The insulin secretory capacity of fa/fa rats was higher than that of Wistar rats at 5 weeks of age, but decreased by 50% between 9 and 11 weeks of age. The fa/fa rats were fed a standard diet, with or without 0.2% w/w TGZ, for 4 weeks. Treatment with TGZ significantly improved insulin resistance, hyperglycemia and hypertriglyceridemia in both prophylactic and therapeutic study groups. These results suggest that insulin resistance is markedly involved in the development and progression of T2DM in fa/fa rats.

Effects of oleuropein in rats with simultaneous type 2 diabetes and renal hypertension: a study of antihypertensive mechanisms

“…The value of blood glucose obtained in the present study (183.8^7.1 mg/dl) is in the range of other models of type 2 diabetes including STZ-NA induced (210^10 mg/ dl) [16], Goto-Kakizaki (175^10 mg/dl) [17], WNB-Kob-Lepr fa (175^10 mg/dl) [18], low STZ-high fat-induced Figure 3. PE concentration-response curves (n ¼ 7 each) in the absence (-) and presence (þ) of L-NAME in aortic rings from control group (A), simultaneous type 2 diabetes and renal hypertensive group receiving vehicle (DM2 þ HTN-Veh) (B), and simultaneous diabetes and renal hypertensive groups receiving oleuropein at 20 mg/kg/day (DM2 þ HTN-Ole20) (C), 40 mg/kg/day (DM2 þ HTN-Ole40) (D), or 60 mg/kg/day (DM2 þ HTN-Ole60) (E) after 4 weeks of treatment.…”

Correlations of microRNA-124a and microRNA-30d with clinicopathological features of breast cancer patients with type 2 diabetes mellitus

“…It was well-known that T2DM is characterized by insulin resistance and impaired insulin secretion caused by insufficiency of pancreatic beta-cells (Mizokami-Stout et al 2012; Okuno et al 2013). Additionally, HbA1c may capture the glucose exposure that may relevant to cancer risk and higher HbA1c level may be correlated with a higher risk of cancer incidence and cancer-related mortality (Joshu et al 2012; Li et al 2014).…”

Syphacia muris infection delays the onset of hyperglycemia in WBN/Kob-Lepr fa rats, a new type 2 diabetes mellitus model

“…A typical phenotype encountered in fa/fa rats is characterized by obesity resulting from hyperphagia. Younger fa/fa rats exhibit euglycemia accompanied by marked hyperinsulinemia, indicating that severe insulin resistance is compensated by increased insulin secretion in these animals (Okuno et al, 2013). These authors also reported that hyperglycemia thereafter develops in association with a marked decline in plasma insulin levels.…”

“…Conversely, Zucker fatty rats are obese and have hyperinsulinemia over their lifetime (Shiota and Printz, 2012). Previous reports showed that fa/fa rats have severe insulin resistance and develop hyperglycemia at 7−9 weeks of age (Akimoto et al, 2008;Kaji et al, 2012;Okuno et al, 2013;Nagakubo et al 2014) and that pancreatitis with inflammatory infiltration is observed prior to the onset of hyperglycemia (Kaji et al 2012;Okuno et al, 2013;Nagakubo et al, 2014). These features make the fa/fa rat a useful novel model for evaluating the course of the obese T2DM.…”