Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction.
Islet amyloid derived from islet amyloid polypeptide (IAPP) is a well-recognized feature of type II diabetes. However, the mechanism of islet amyloidogenesis is unknown. In vitro studies suggest that amino acid residues 20-29 in human, but not mouse, IAPP confer amyloidogenicity consistent with the absence of spontaneous islet amyloidosis in mice. Several clinical and in vitro studies suggest that increased synthetic rates of IAPP predispose to IAPP-amyloidosis. In the present study, we sought to test the hypothesis that pharmacological induction of insulin resistance in a mouse transgenic (TG) for human IAPP would induce islet amyloid and beta-cell dysfunction. TG and non-transgenic (N-TG) control mice were treated with both rat growth hormone (12 micrograms/day) and dexamethasone (0.24 mg/day) (dex/GH) or received no treatment for 4 weeks, after which animals were killed to examine islet morphology. Treatment with dex/GH caused hyperglycemia (7.3 +/- 0.4 vs. 5.2 +/- 0.1 mmol/l, TG vs. N-TG, P < 0.001) associated with a decreased plasma insulin concentration (595 +/- 51 vs. 996 +/- 100 pmol/l, TG vs. N-TG, P < 0.05) in TG versus control mice. Islet amyloid was induced in treated TG mice but not in control mice. Islet amyloid was identified in both intra- and extracellular deposits, the former being associated with evidence of beta-cell degeneration. We conclude that dex/GH treatment in mice TG for human IAPP induces IAPP-derived islet amyloid, hyperglycemia, and islet dysfunction. The present model recapitulates the islet morphology and phenotype of type II diabetes.
Couce
M
M
Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, USA.
Kane
L A
LA
O'Brien
T D
TD
Charlesworth
J
J
Soeller
W
W
McNeish
J
J
Kreutter
D
D
Roche
P
P
Butler
P C
PC
D000682:Amyloid / Q000502:physiology*; D000686:Amyloidosis / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics
D000682:Amyloid; D017931:DNA Primers; D058228:Islet Amyloid Polypeptide; D012333:RNA, Messenger; D003907:Dexamethasone; D013006:Growth Hormone