Type 2 Diabetes as a Protein Misfolding Disease | Amprion
Prions

Type 2 Diabetes as a Protein Misfolding Disease

By March 30, 2018 No Comments

Originally Posted on Cell Press | July 2015

Scientist researching on Type 2 Diabetes as a Protein Misfolding Disease

Type 2 diabetes (T2D) is a highly prevalent and chronic metabolic disorder, considered as a protein misfolding disease. Recent evidence suggests that formation of toxic aggregates of the islet amyloid polypeptide (IAPP) might contribute to b-cell dysfunction and disease. However, the mechanism of protein aggregation and associated toxicity remains unclear.

Misfolding, aggregation, and accumulation of diverse proteins in various organs is the hallmark of the group of protein misfolding disorders (PMDs), including highly prevalent illnesses affecting the central nervous system (CNS) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

In this review we discuss the current understanding of the mechanisms implicated in the formation of protein aggregates in the endocrine pancreas and associated toxicity in the light of the long-standing knowledge from neurodegenerative diseases associated with misfolded proteins.

Protein Misfolding Disease

PMDs are diseases where at least one protein or peptide has been shown to misfold, aggregate, and accumulate in tissues where the disease-specific damage occurs. There are at least 30 different PMDs, including several neurode-generative disorders such as AD, PD, Huntington disease (HD), transmissible spongiform encephalopathies (TSEs), and amyotrophic lateral sclerosis (ALS), as well as diverse systemic disorders such as familial amyloid polyneuropa-thy, T2D, secondary amyloidosis, and dialysis-related amyloidosis.

The first line of evidence that linked protein misfolding and aggregation with disease came from post-mortem histopathological studies showing that a typical feature of each disease is the accumulation of protein deposits comprising a different protein, such as amyloid-b (Ab) and tau in AD, a-synuclein in PD, poly-Q extended huntingtin in HD, IAPP in T2D and prion protein (PrP) in TSEs.

Perhaps the most compelling evidence for the key role of misfolded proteins came from genetic studies. Mutations in the genes encoding the proteins that predominantly comprise the aggregates have been genetically associated with inherited transmission of many PMDs Inheritance of these mutations resulted in earlier onset and increased severity of the disease than in sporadic cases and were associated with a more extensive burden of protein aggregates.

Furthermore, transgenic expression of disease-specific human genes harboring the associated mutations in animal models reproduced several phenotypic and pathological characteristics of PMDs, supporting the key contribution of protein aggregates in these diseases. In the case of TSEs, the prominent role for misfolded protein aggregates is well supported by the fact that these diseases can be transmitted from individual to individual by the sole administration of misfolded prion protein aggregates.

Although T2D is often considered a PMD, few studies have investigated the involvement of protein misfolding in the disease pathogenesis. The subject has been mostly neglected in the diabetes field despite the fact that the evidence implicating the accumulation of misfolded protein aggregates in T2D pathogenesis are comparable with other diseases such as AD or PD. Here we review the literature and discuss the role of protein misfolding and aggregation in T2D.

Related Articles Posts on Misfolded Protein Diseases: