Oophorectomy promotes islet amyloid formation in a transgenic mouse model of Type II diabetes.
OBJECTIVE
In Type II (non-insulin-dependent) diabetes mellitus, amyloid depletes islet mass. We previously found that 81% of male human islet amyloid polypeptide (IAPP) transgenic mice but only 11% of female mice developed islet amyloid, suggesting that either testosterone promotes or ovarian products protect against amyloid deposition.


METHODS
We did a bilateral oophorectomy or sham procedure in female human IAPP transgenic mice (n = 11 and n = 8, respectively) and in female non-transgenic mice (n = 7 and n = 9, respectively) at 6-8 weeks of age. Animals were followed for 1 year on a 9% fat (w/w) diet. Before we killed them we measured, fasting plasma human IAPP and did an intraperitoneal glucose tolerance test. Pancreatic content of IAPP and immunoreactive insulin (IRI) were estimated and pancreata were analysed for islet amyloid.


RESULTS
No amyloid was detected in either the sham-operated transgenic mice or, as expected, in both groups of non-transgenic mice. In strong contrast, 7 of 11 (64%) oophorectomized mice developed islet amyloid (p < 0.05). Amyloid deposition in the oophorectomized transgenic mice was not associated with any differences in incremental body weight, fasting human IAPP concentrations or glucose tolerance between the groups. Furthermore, pancreatic content of mouse IAPP, human IAPP and immunoreactive insulin did not differ between groups.


CONCLUSIONS
Oophorectomy is associated with an enhancement of islet amyloid formation in the absence of changes in glucose tolerance, circulating IAPP or pancreatic content of IRI, mouse or human IAPP. Thus, the early stages of islet amyloidogenesis seem to be independent of glucose tolerance, with ovarian products having a protective role.
Kahn
S E
SE
Department of Medicine, University of Washington and VA Puget Sound Health Care System, Seattle 98108, USA.
Andrikopoulos
S
S
Verchere
C B
CB
Wang
F
F
Hull
R L
RL
Vidal
J
J
D000682:Amyloid / Q000032:analysis / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics*; D000818:Animals; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000032:analysis; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology; D010179:Pancreas / Q000737:chemistry
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide