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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

Background

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).

Objective

Investigate whether peripheral insulin resistance or a beta-cell insulin secretory defect comes first in young, non-obese pre-diabetic Alms1foz/foz mice.

Methods

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.

Results

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.

Conclusions

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.

Author information

Correspondence to D Girard.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Premature Stop Codon
  • Serum Insulin Level
  • Insulin Tolerance Test
  • Increase Insulin Resistance
  • Wildtype Mouse