title: Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice.
abstract: Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and beta-cell dysfunction. Islet amyloid is associated with reduced beta-cell mass and function and develops in the majority of our C57BL/6J x DBA/2J (F(1)) 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 F(1) 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%, F(1): 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 +/- 3%, F(1): 44 +/- 8%, DBA2: 49 +/- 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 +/- 0.01%, F(1): 9.2 +/- 2.9%, DBA2: 5.7 +/- 2.3%, p < or = 0.01) were significantly lower in BL6 than F(1) and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F(1) (r(2) = 0.75, P < 0.001) and DBA2 (r(2) = 0.87, P < 0.001) mice but not BL6 mice (r(2) = 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 (F(1) and DBA2 mice) being more susceptible to amyloid deposition that replaces beta-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.
authors.affiliation: Division of Metabolism, Endocrinology, and Nutrition, Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA 98108, USA. rhull@u.washington.edu
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hull
authors.forename: Melissah R
authors.initials: MR
authors.lastname: Watts
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kodama
authors.forename: Zhen-ping
authors.initials: ZP
authors.lastname: Shen
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Utzschneider
authors.forename: Darcy B
authors.initials: DB
authors.lastname: Carr
authors.forename: Josep
authors.initials: J
authors.lastname: Vidal
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000682:Amyloid / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D011994:Recombinant Proteins