Characterization of the Prediabetic State in a Novel Rat Model of Type 2 Diabetes, the ZFDM Rat

Abstract

We recently established a novel animal model of obese type 2 diabetes (T2D), the Zucker fatty diabetes mellitus (ZFDM) rat strain harboring the fatty mutation (fa) in the leptin receptor gene. Here we performed a phenotypic characterization of the strain, focusing mainly on the prediabetic state. At 6–8 weeks of age, fa/fa male rats exhibited mild glucose intolerance and severe insulin resistance. Although basal insulin secretion was remarkably high in the isolated pancreatic islets, the responses to both glucose stimulation and the incretin GLP-1 were retained. At 10–12 weeks of age, fa/fa male rats exhibited marked glucose intolerance as well as severe insulin resistance similar to that at the earlier age. In the pancreatic islets, the insulin secretory response to glucose stimulation was maintained but the response to the incretin was diminished. In nondiabetic Zucker fatty (ZF) rats, the insulin secretory responses to both glucose stimulation and the incretin in the pancreatic islets were similar to those of ZFDM rats. As islet architecture was destroyed with age in ZFDM rats, a combination of severe insulin resistance, diminished insulin secretory response to incretin, and intrinsic fragility of the islets may cause the development of T2D in this strain.

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET

“…Apart from that, the age of the investigated ZDF rats is of utmost importance: analogous to our study, Welch et al . studied ZDF rats at week 12, which is considered to be consistent with the metabolic alterations occurring at an early stage of type 2 DM in human subjects 31 , 32 . To further strengthen our preliminary findings, we also investigated 18 F-FDG under hyperinsulinemic-euglycemic clamp conditions: This strategy is known to provide an excellent image quality and is superior to other conventional techniques to enhance cardiac activity, such as glucose load and/or insulin bolus prior to image acquisition 33 – 35 .…”

Alterations of voltage‐dependent K+ channels in the mesenteric artery during the early and chronic phases of diabetes

“…Several type 1 diabetic disease models including diabetes‐prone (DP) BB rats and streptozotocin (STZ)‐induced diabetic models have been used to study type 1 diabetes . Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models . Among these, the OLETF rat is a useful animal model for type II diabetes .…”

“…21,22 Type 2 diabetes is characterized by insulin resistance, for which db/db mice, OLETF rats, and ZFDM rats serve as experimental animal models. [23][24][25][26][27][28][29] Among these, the OLETF rat is a useful animal model for type II diabetes. [24][25][26][27] OLETF rats have a disease similar to human diabetes because the onset of diabetes is relatively slow (after 18 weeks of age), blood sugar levels increase gradually, disease occurs more frequently in males, and diabetes is accompanied by mild obesity.…”

Antagonistic interaction between Nodal and insulin modulates pancreatic β-cell proliferation and survival

“…Mice lacking active Akt in the β-cells showed inability of β-cell mass compensation and increased susceptibility to experimental diabetes [ 8 ]. Conversely, enhanced Akt activity is found to be associated with increased β-cell proliferation and β-cell mass in the Zucker fatty rats [ 18 ], which spontaneously develop obese and insulin resistance but not diabetes [ 19 ]. It is presumably that the Akt-mediated β-cell mass compensatory response represents an important mechanism allowing these obese rats remained in euglycemia despite insulin resistance [ 1 ].…”