Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/islet amyloid polypeptide transgenic mice.
OBJECTIVE
Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble beta-sheet-containing oligomers is linked to islet beta-cell degeneration and the pathogenesis of type 2 diabetes. Here, we used tetracycline, which modifies hA/hIAPP oligomerization, to probe mechanisms whereby hA/hIAPP causes diabetes in hemizygous hA/hIAPP-transgenic mice.


METHODS
We chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival.


RESULTS
Homozygous mice developed severe spontaneous diabetes due to islet beta-cell loss. Hemizygous transgenic animals also developed spontaneous diabetes, although severity was less and progression rates slower. Pathogenesis was characterized by initial islet beta-cell dysfunction followed by progressive beta-cell loss. Islet amyloid was absent from hemizygous animals with early-onset diabetes and correlated positively with longevity. Some long-lived nondiabetic hemizygous animals also had large islet-amyloid areas, showing that amyloid itself was not intrinsically cytotoxic. Administration of tetracycline dose-dependently ameliorated hyperglycemia and polydipsia, delayed rates of diabetes initiation and progression, and increased longevity compared with water-treated controls.


CONCLUSIONS
This is the first report to show that treating hA/hIAPP transgenic mice with a modifier of hA/hIAPP misfolding can ameliorate their diabetic phenotype. Fibrillar amyloid was neither necessary nor sufficient to cause diabetes and indeed was positively correlated with longevity therein, whereas early- to mid-stage diabetes was associated with islet beta-cell dysfunction followed by beta-cell loss. Interventions capable of suppressing misfolding in soluble hA/hIAPP oligomers rather than mature fibrils may have potential for treating or preventing type 2 diabetes.
School of Biological Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Jacqueline F
JF
Aitken
Kerry M
KM
Loomes
David W
DW
Scott
Shivanand
S
Reddy
Anthony R J
AR
Phillips
Gordana
G
Prijic
Chathurini
C
Fernando
Shaoping
S
Zhang
Ric
R
Broadhurst
Phil
P
L'Huillier
Garth J S
GJ
Cooper
D000284:Administration, Oral; D000682:Amyloid / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000517:prevention & control*; D018450:Disease Progression; D005951:Glucose Tolerance Test; D006720:Homozygote; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D013752:Tetracycline / Q000008:administration & dosage / Q000627:therapeutic use*
D000682:Amyloid; D001786:Blood Glucose; D017931:DNA Primers; D058228:Islet Amyloid Polypeptide; D011500:Protein Synthesis Inhibitors; D013752:Tetracycline