The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet β cells

FASEB J. 2014 Dec;28(12):5083-96. doi: 10.1096/fj.14-251744. Epub 2014 Aug 19.

Abstract

The aggregation of human amylin (hA) to form cytotoxic structures has been closely associated with the causation of type 2 diabetes. We sought to advance understanding of how altered expression and aggregation of hA might link β-cell degeneration with diabetes onset and progression, by comparing phenotypes between homozygous and hemizygous hA-transgenic mice. The homozygous mice displayed elevated islet hA that correlated positively with measures of oligomer formation (r=0.91; P<0.0001). They also developed hyperinsulinemia with transient insulin resistance during the prediabetes stage and then underwent rapid β-cell loss, culminating in severe juvenile-onset diabetes. The prediabetes stage was prolonged in the hemizygous mice, wherein β-cell dysfunction and extensive oligomer formation occurred in adulthood at a much later stage, when hA levels were lower (r=-0.60; P<0.0001). This is the first report to show that hA-evoked diabetes is associated with age, insulin resistance, progressive islet dysfunction, and β-cell apoptosis, which interact variably to cause the different diabetes syndromes. The various levels of hA elevation cause different extents of oligomer formation in the disease stages, thus eliciting early- or adult-onset diabetes syndromes, reminiscent of type 1 and 2 diabetes, respectively. Thus, the hA-evoked diabetes phenotypes differ substantively according to degree of amylin overproduction. These findings are relevant to the understanding of the pathogenesis and the development of experimental therapeutics for diabetes.

Keywords: apoptosis; gene–dosage effect; insulin resistance; peptide aggregation; transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Biopolymers / chemistry
  • Biopolymers / metabolism*
  • Cell Death
  • DNA Primers
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Glucose Tolerance Test
  • Insulin / blood
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Biopolymers
  • DNA Primers
  • Insulin
  • Islet Amyloid Polypeptide