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Diabetes Due to a Progressive Defect in ß-Cell Mass in Rats Transgenic for Human Islet Amyloid Polypeptide (HIP Rat)

A New Model for Type 2 Diabetes

¹ Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
² Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut

The islet in type 2 diabetes is characterized by a deficit in ß-cell mass, increased ß-cell apoptosis, and impaired insulin secretion. Also, islets in type 2 diabetes often contain deposits of islet amyloid derived from islet amyloid polypeptide (IAPP), a 37–amino acid protein cosecreted with insulin by ß-cells. Several lines of evidence suggest that proteins with a capacity to develop amyloid fibrils may also form small toxic oligomers that can initiate apoptosis. The amino acid sequence of IAPP in rats and mice is identical and differs from that in humans by substitution of proline residues in the amyloidogenic sequence so that the protein no longer forms amyloid fibrils or is cytotoxic. In the present study, we report a novel rat model for type 2 diabetes: rats transgenic for human IAPP (the HIP rat). HIP rats develop diabetes between 5 and 10 months of age, characterized by an 60% deficit in ß-cell mass that is due to an increased frequency of ß-cell apoptosis. HIP rats develop islet amyloid, but the extent of amyloid was not related to the frequency of ß-cell apoptosis (r = 0.10, P = 0.65), whereas the fasting blood glucose was (r = 0.77, P < 0.001). The frequency of ß-cell apoptosis was related to the frequency of ß-cell replication (r = 0.97, P < 0.001) in support of the hypothesis that replicating cells are more vulnerable to apoptosis than nondividing cells. The HIP rat provides additional evidence in support of the potential role of IAPP oligomer formation toward the increased frequency of apoptosis in type 2 diabetes, a process that appears to be compounded by glucose toxicity when hyperglycemia supervenes.

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