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Increased insulin resistance compounded by reduced insulin sensitivity drives the "Fat Aussie" (Alms1foz/foz) model of Alström syndrome towards obesity and type 2 diabetes mellitus
Cilia volume 1, Article number: P86 (2012)
The Fat Aussie mouse carries a spontaneous mutation (foz) resulting in a premature stop codon in exon 8 of the Alms1 gene and is a model for Alström syndrome. From 60 days of age onwards Alms1foz/foz mice exhibit a strong metabolic phenotype leading to severe obesity and type 2 diabetes mellitus (T2DM).
Investigate whether peripheral insulin resistance or a beta-cell insulin secretory defect comes first in young, non-obese pre-diabetic Alms1foz/foz mice.
Insulin tolerance tests (ITT), glucose tolerance tests (GTT), fasting and post-challenge serum insulin levels and HOMA-IR score determination were performed in age and sex-matched young lean Alms1foz/foz mice and wildtype littermates.
When compared to wildtype mice, young Alms1foz/foz mice had a significantly reduced response to insulin during ITT while no differences were observed in glucose and endogenous insulin levels during GTT. Male but not female Alms1foz/foz mice had significantly higher fasting hyperinsulinemia and HOMA-IR scores compared to wildtype littermates.
These data indicate that insulin resistance precedes obesity in young Alms1foz/foz mice at a time that beta-cell function isn’t affected. This suggests that early peripheral insulin resistance is an inherent primary consequence of the Alms1foz/foz mutation and may thereby drive the subsequent metabolic complications in this model.
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Girard, D., Petrovsky, N. Increased insulin resistance compounded by reduced insulin sensitivity drives the "Fat Aussie" (Alms1foz/foz) model of Alström syndrome towards obesity and type 2 diabetes mellitus. Cilia 1, P86 (2012). https://doi.org/10.1186/2046-2530-1-S1-P86
- Premature Stop Codon
- Serum Insulin Level
- Insulin Tolerance Test
- Increase Insulin Resistance
- Wildtype Mouse