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Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice

¹Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle; and ²Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington

Submitted 5 October 2004 ; accepted in final form 11 May 2005

Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and -cell dysfunction. Islet amyloid is associated with reduced -cell mass and function and develops in the majority of our C57BL/6J x DBA/2J (F₁) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J x DBA/2J F₁ mice (n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F₁: 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 ± 3%, F₁: 44 ± 8%, DBA2: 49 ± 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 ± 0.01%, F₁: 9.2 ± 2.9%, DBA2: 5.7 ± 2.3%, p 0.01) were significantly lower in BL6 than F₁ and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F₁ (r² = 0.75, P < 0.001) and DBA2 (r² = 0.87, P < 0.001) mice but not BL6 mice (r² = 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F₁ and DBA2 mice) being more susceptible to amyloid deposition that replaces -cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.

islet amyloid; islet amyloid polypeptide; genetic background; -cell mass; -cell dysfunction; insulin secretion

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