db/dbMice Exhibit Features of Human Type 2 Diabetes That Are Not Present in Weight-Matched C57BL/6J Mice Fed a Western Diet

Abstract

To understand features of human obesity and type 2 diabetes mellitus (T2D) that can be recapitulated in the mouse, we compared C57BL/6J mice fed a Western-style diet (WD) to weight-matched genetically obese leptin receptor-deficient mice (db/db). All mice were monitored for changes in body composition, glycemia, and total body mass. To objectively compare diet-induced and genetic models of obesity, tissue analyses were conducted using mice with similar body mass. We found that adipose tissue inflammation was present in both models of obesity. In addition, distinct alterations in metabolic flexibility were evident between WD-fed mice and db/db mice. Circulating insulin levels are elevated in each model of obesity, while glucagon was increased only in the db/db mice. Although both WD-fed and db/db mice exhibited adaptive increases in islet size, the db/db mice also displayed augmented islet expression of the dedifferentiation marker Aldh1a3 and reduced nuclear presence of the transcription factor Nkx6.1. Based on the collective results put forth herein, we conclude that db/db mice capture key features of human T2D that do not occur in WD-fed C57BL/6J mice of comparable body mass.

Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation

“…Islets were also isolated from 8-week-old male db /+ and db/db mice (B6.BKS(D)-Leprdb/J; stock number 00697) acquired from the Jackson Laboratories. Extraction of RNA, cDNA synthesis, and transcript analysis have been described in detail previously [7] , [39] .…”

“…Nkx6.1 is important for suppression of the glucagon gene and together MafA and Nkx6.1 support glucose-stimulated insulin secretion [4] , [5] . Several of these TFs are either reduced in abundance or in nuclear presence in mouse models of obesity and in humans with obesity and T2D [6] , [7] , [8] . In addition, Aldh1a3 has recently been associated with de-differentiation of β-cells, helping to explain reduced insulin secretion in both rodents and humans [9] , [10] .…”

Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation

“…We administered MSCs to db/db mice, a well-established mouse model of hT2DM [37] and b cell dedifferentiation [38]. Two doses of MSCs were administered to db/db mice at the age of 7 weeks and 9 weeks using a tail vein injection and equal volume of PBS as a control treatment (Fig.…”

Gelidium elegans Extract Ameliorates Type 2 Diabetes via Regulation of MAPK and PI3K/Akt Signaling

“…We hypothesized that this may be achieved through the modulation of GLUT4 expression, insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K), and MAPK pathways. We tested this possibility using the leptin receptor-deficient db/db mouse, a model of T2D, which exhibits a number of the typical metabolic defects seen in patients, including hyperglycemia and hyperinsulinemia [ 36 , 37 ], and shares many of the clinical characteristics of human T2D [ 37 , 38 ]. Thus, the present study investigated the effect of GEE on glucose metabolism in db/db mice by analyzing its effects on the PI3K/Akt and MAPK signaling pathways.…”