Novel insight into streptozotocin-induced diabetic rats from the protein misfolding perspective

Abstract

Protein folding is a process of self-assembly defined by the sequence of the amino acids of the protein involved. Additionally, proteins tend to unfold, misfold and aggregate due to both intrinsic and extrinsic causes. Human islet amyloid polypeptide (hIAPP) aggregation is an early step in diabetes mellitus. However, the aggregation of rat IAPP (rIAPP) remains an open question. Adult female Sprague-Dawley rats weighing 150–250 g were divided into two groups. The experimental group (streptozotocin [STZ]) (n = 21) received an intraperitoneal injection of a single dose of 40 mg/kg STZ. We used the mouse anti-IAPP antibody and the anti-amyloid oligomer antibody to study the temporal course of rIAPP oligomerization during STZ-induced diabetes using a wide array of methods, strategies and ideas derived from biochemistry, cell biology, and proteomic medicine. Here, we demonstrated the tendency of rIAPP to aggregate and trigger cooperative processes of self-association or hetero-assembly that lead to the formation of amyloid oligomers (trimers and hexamers). Our results are the first to demonstrate the role of rIAPP amyloid oligomers in the development of STZ-induced diabetes in rats. The IAPP amyloid oligomers are biomarkers of the onset and progression of diabetes and could play a role as therapeutic targets.

Zinc restriction promotes β-cell hyper-hormonemia and endocrine pancreas degeneration in mice

“…Toxic oligomers in pancreatic islets can be found in non-transgenic mice [41]. Similarly, Leyva-García and colleagues found responsive material to antibody anti oligomer-like immunoreactive material (“anti-amyloid oligomer”, A11 antibody) on streptozotocin-induced mice [42]. These findings corroborate with previous identification of aggregated amylin on diabetic and elder nondiabetic individuals [43].…”

Amyloid Biomarkers in Conformational Diseases at Face Value: A Systematic Review

“…Sometimes these results can cause confusion in the results’ reading ( Figure 3 and Figure 4 , Table 2 ). In our group we have demonstrated that the rat IAPP hexamers are diagnostic biomarkers of the onset and progression of diabetes mellitus and play a role as therapeutic targets [ 20 , 22 ].…”

“…For instance, we now know that the soluble amyloid oligomers—the most cytotoxic and the cause of death of target cells (in the brain, pancreas, etc. )—of conformational diseases are characterized by [ 11 , 15 ]: Low Molecular weight (trimers (10–15 kDa), hexamers (24–30 kDa) [ 20 ]. Contain β-sheet-rich structures [ 6 , 11 ].…”

“…CDs have a common pathophysiological basis—an alteration at protein level, whether in size, shape, folding or conformation. Consequently, the resulting cytotoxicity produces a deficiency of functional proteins [ 1 , 5 , 6 , 7 , 11 , 19 , 20 ].…”

Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

“…Moreover, proteins tend to unfold, misfold and aggregate due to intrinsic and extrinsic causes [ 1 , 2 , 3 ]. Unfolding and aggregation of proteins gives way to what is known as “conformational diseases (CDs)”: One of the most challenging CDs is diabetes [ 1 , 4 , 5 , 6 , 7 , 8 ]. The prevalence of diabetes is increasing rapidly: 29.1 million people or 9.3% of the population of the USA has diabetes resulting in a total cost of $245 billion [ 9 ].…”