Expression of wild-type and mutant S20G hIAPP in physiologic knock-in mouse models fails to induce islet amyloid formation, but induces mild glucose intolerance.
Aims/Introduction:  Human islet polypeptide S20G mutation (hIAPP(S20G)) is associated with earlier onset type 2 diabetes and increased amyloidogenicity and cytotoxicity in vitro vs wild-type hIAPP (hIAPP(WT)), suggesting that amyloidogenesis may be pathogenic for type 2 diabetes. We compared the contributions of hIAPP(S20G) and hIAPP(WT) toward intra islet amyloid formation and development of type 2 diabetes in a unique physiologic knock-in mouse model.


METHODS
We replaced the mouse IAPP gene (M allele) with hIAPP(WT) (W allele) and hIAPP(S20G) (G allele) via homologous recombination and backbred transgenic mice against C57Bl/6 strain 5 generations to minimize genetic variation. Mice (3 month old) were maintained on control (CD) or high fat diet (HFD) for 15 months and studied at 3 month intervals by oral glucose tolerance testing (OGTT) and pancreas histology to assess glucose homeostastis, amyloidogeneisis, islet mass, β cell replication, and apoptosis.


RESULTS
IAPP blood levels were indistinguishable in all mice. WW and GW mice maintained on both diets lacked intraislet amyloid at all ages. On both diets relative to MM controls WW and GW mice exhibit glucose intolerance (P < 0.008) with no differences in insulin secretion. However, GW mice secreted significantly more insulin (P < 0.03 that WW mice on both diets throughout the study. By 12 months on the high fat diet all mice increased their β cell mass about 3-fold and were indistinguishable.


CONCLUSIONS
Physiologic expression of hIAPP(WT) and hIAPP(S20G) in C57Bl/6 mice produces mild glucose intolerance with inappropriately normal insulin secretion that is independent of intraislet amyloid formation. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00166.x, 2011).
Department of Medicine/Divisions of Endocrinology.
Henry J
HJ
Hiddinga
The First Department of Medicine, Wakayama University of Medical Science.
Setsuya
S
Sakagashira
The First Department of Medicine, Wakayama University of Medical Science.
Masayuki
M
Ishigame
Department of Medicine/Divisions of Endocrinology.
Pranathi
P
Madde
Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan.
Tokio
T
Sanke
The First Department of Medicine, Wakayama University of Medical Science.
Kishio
K
Nanjo
Department of Medicine/Divisions of Endocrinology ; Human Cellular Therapy Laboratory, Mayo Clinic Rochester, Rochester, MN.
Yogish C
YC
Kudva
Department of Biochemistry/Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, AZ, USA.
James J
JJ
Lee
Pediatrics ; Biochemistry/Molecular Biology.
Jan
J
van Deursen
Department of Medicine/Divisions of Endocrinology ; Biochemistry/Molecular Biology.
Norman L
NL
Eberhardt
Islet amyloid polypeptide; Transgenic mice; Type 2 diabetes