Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/islet amyloid polypeptide transgenic mice

Diabetes. 2010 Jan;59(1):161-71. doi: 10.2337/db09-0548. Epub 2009 Sep 30.


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.

Research design and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Amyloid / genetics*
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Blotting, Northern
  • DNA Primers
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Disease Progression
  • Glucose Tolerance Test
  • Homozygote
  • Humans
  • Insulin-Secreting Cells / pathology
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Transgenic
  • Polymerase Chain Reaction
  • Protein Synthesis Inhibitors / administration & dosage
  • Protein Synthesis Inhibitors / therapeutic use*
  • Tetracycline / administration & dosage
  • Tetracycline / therapeutic use*


  • Amyloid
  • Blood Glucose
  • DNA Primers
  • Islet Amyloid Polypeptide
  • Protein Synthesis Inhibitors
  • Tetracycline