B6.129(C)-Ank2^tm3.1Bnt/J

Stock number: 027915
Product name: Ankb^R1788W
Strain synonyms: B6.129(C)-Ank2^{tm3.1(R1788W)Bnt}/J
Research areas: Diabetes and Obesity Research

Description

Ankb^R1788W (Ank2) knock-in mice develop a metabolic syndrome characterized by early-onset pancreatic ß cell dysfunction and age- or diet-dependent increases in adiposity and insulin resistance. Tissue-specific ANK2 deficiency is also observed.

Detailed description

Ankyrin-B (Ank2; AnkB) is a member of the ankyrin family of membrane adaptors that contributes to the assembly of diverse specialized plasma membrane domains. In humans, the p.R1788W variant, located in the unstructured C-terminal regulatory domain, is present in 0.3% of North Americans of mixed European descent and is associated with type 2 diabetes (T2D).

These knock-in mice carry the R1788W mutation in the Ank2 gene. Homozygotes develop a metabolic syndrome characterized by early-onset pancreatic β cell dysfunction and age- or diet-dependent increases in adiposity and insulin resistance. Tissue-specific ANK2 deficiency is also observed.

Homozygous mice are born at the expected Mendelian ratios and exhibit no differences in mRNA levels, as assessed by qPCR. Protein levels in homozygotes, however, are reduced significantly in a subset of tissues, including fat, liver, skeletal muscle, pancreatic β cells, and heart. Primary mouse embryonic fibroblast (MEF) cultures also show reduced protein expression. No change in protein expression is detected in the brain.

Similar to heterozygous Ank2 knockout mice (see Stock No. 027916), homozygous Ank2^R1788W mutant mice exhibit over 50% reduction in glucose-stimulated insulin secretion (normalized to total insulin content). In contrast to Ank2^R1788W mutant animals, islets isolated from homozygous Ank2^L1622I mutant animals (see Stock No. 027914) respond normally to glucose stimulation.

While fasting serum glucose levels are unaltered in both Ank2^R1788W and Ank2^L1622I homozygous mice, oral administration of glucose (2 g/kg body weight) during an oral glucose tolerance test leads to both an increased level of blood glucose at 30 minutes as well as a delay in glucose clearance. The areas under the blood glucose response curves are significantly increased by 2- and 1.7 fold in homozygous Ank2^R1788W and Ank2^L1622I knock-in mice, respectively. Heterozygotes demonstrate 1.8- and 1.4-fold increases, respectively.

Both 3-month-old and 10-month-old Ank2^R1788W and Ank2^L1622I homozygous mice show overall similar average rates of food intake, energy source utilization, and activity compared with littermate controls during both light and dark cycles.

Both Ank2^R1788W and Ank2^L1622I homozygous mutant mice exhibit significant adipocyte hypertrophy (54% increase in adipocyte diameter in Ank2^R1788W and 38% in Ank2^L1622I mice) which is accompanied by elevated levels of circulating nonesterified fatty acids. The increase in body fat is more prominent than the overall changes in total body weight.

Development

An R1788W (C to T) mutation in exon 22 and loxP-flanked neomycin cassette were knocked into the mouse Ank2 gene through homologous recombination in 129-derived embryonic stem cells. Resultant chimeric mice were bred with C57BL/6J animals. The floxed neomycin cassette was excised though crosses with CMV-Cre mice (see Stock No. 006054). This strain was backcrossed to full C57BL/6J congenicity via speed congenic services at The Jackson Laboratory.