Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein (TXNIP)

Abstract

Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein (TXNIP), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in TXNIP expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.

Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice

“…NZO mice are a well-established model to study type II diabetes and obesity [ 18 ]. A number of different feeding strategies are known to induce an obesity-related phenotype in this mouse strain, even though these mice already gain weight on a standard diet (SD).…”

“…NZO mice gain weight on a standard diet compared to wildtype B6 mice, exhibit obesity and develop insulin resistance when fed a HFD. However, if challenged with nutritional carbohydrates, a progressive loss of beta-cells can be observed [ 18 , 20 , 21 , 22 , 23 , 24 ]. In our experiments 22w NZO SD mice already showed a higher increase in body and liver weight as well as plin2 content, compared to 22w B6 on SD.…”

“…All animal procedures were performed in accordance with the guidelines of the German Law on the Protection of Animals and the experimental protocol was reviewed and approved by the local authorities (Landesamt für Arbeitsschutz, Verbraucherschutz und Gesundheit Brandenburg, Germany, Brandenburg, approval number: V3-2347-21-2015). The animal experiments are partially described in [ 18 ]. Briefly, male C57Bl/6J and male NZO mice (C57Bl/6J (B6) and NZO/HIBomDIfE, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany) were housed in open cages of 4–5 animals in a controlled environment (20 ± 2 °C, 12/12 h light/dark cycle) with ad libitum access to diet and water.…”