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

Abstract

The islet in type 2 diabetes is characterized by a deficit in ␤-cell mass, increased ␤-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 ␤-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 ϳ60% deficit in ␤-cell mass that is due to an increased frequency of ␤-cell apoptosis. HIP rats develop islet amyloid, but the extent of amyloid was not related to the frequency of ␤-cell apoptosis (r ‫؍‬ 0.10, P ‫؍‬ 0.65), whereas the fasting blood glucose was (r ‫؍‬ 0.77, P < 0.001). The frequency of ␤-cell apoptosis was related to the frequency of ␤-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. Diabetes 53: 1509 -1516, 2004

No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes

“…On the other hand, most mechanisms that have been suggested to underlie a putative progressive beta cell damage in T2D may not be relevant for the clinical situation or have been difficult to show in vivo, e.g. glucotoxicity due to uncontrolled diabetes and cytotoxicity by islet amyloid polypeptide (IAPP) [21,22] [23]. Mechanistically, it has also been discussed whether chronic hyperglycemia and different genetic variants of the insulin receptor may affect the clinical course of diabetes [24][25][26].…”

Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic β-cells: protective role of p62-positive cytoplasmic inclusions

“…The generation of h-IAPP transgenic rats (HIP rats) has been described in detail previously. 10 In this study, we used 4-to 6-month-old WT (n ¼ 6) and pre-diabetic HIP rats (n ¼ 6) (fasting glucose ¼ 87 ± 4 mg per 100 ml).…”

“…Transgenic expression of h-IAPP in b-cells of rodents at rates present in insulin resistance leads to the development of diabetes because of ER stress-induced b-cell apoptosis with formation of membrane-damaging intracellular IAPP oligomers comparable to those present in humans with T2DM. 3,5,[10][11][12] Conserved mechanisms protect long-lived cells with a high protein synthetic burden (such as b-cells) from accumulation of intracellular protein aggregates and the adverse consequences termed proteotoxicity. 9 A quality control system in the ER recognizes misfolded proteins and targets them for degradation by the ubiquitin/proteasome system.…”

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

“…This raises the interesting possibility that interactions of soluble forms of A␤ with dysfunctional IR and IGF-1R might play a "gain-of-function" role in A␤ oligomerization, actively promoting protein misfolding and/or mis-assembly. Precedent that interactions between fibrillogenic proteins and cell surfaces can alter the nature of oligomerization was recently reported for human amylin oligomers, formation of which is linked to diabetes (58,81).…”