Iapp-KO Mouse

Iapp, also known as islet amyloid polypeptide or amylin, is a 37-amino-acid peptide hormone produced by pancreatic β-cells. It activates specific multisubunit G protein-coupled receptors and is a key glucoregulatory hormone, playing an important role in energy metabolism. It also has other reported actions on systems like the cardiovascular system and bone, and functionally interacts with other hormones in the central nervous system [2].

In type 2 diabetes (T2DM), Iapp forms cytotoxic oligomers and amyloid fibrils in islets, which contribute to β-cell dysfunction, death, and islet inflammation [1,3,5]. In transgenic mice overexpressing human Iapp (hIapp), intracellular pro-apoptotic signals can be generated, and extracellular amyloidosis is directly related to β-cell apoptosis in T2DM [1]. In mice, overexpression of soluble rodent or oligomer-prone human Iapp induced changes in the islet transcriptome similar to those in prediabetes and T2DM in humans, including decreased expression of genes conferring β-cell identity and induction of islet inflammation in the case of human Iapp overexpression [4].

In conclusion, Iapp is a crucial pancreatic hormone in glucose and energy metabolism. Its abnormal aggregation in models like transgenic mice reveals its significant role in the pathogenesis of T2DM, contributing to β-cell injury, islet inflammation, and dedifferentiation. Understanding Iapp through these model-based studies provides insights into T2DM mechanisms and potential therapeutic targets [1,4].

References:

1. Raleigh, Daniel, Zhang, Xiaoxue, Hastoy, Benoît, Clark, Anne. 2017. The β-cell assassin: IAPP cytotoxicity. In Journal of molecular endocrinology, 59, R121-R140. doi:10.1530/JME-17-0105. https://pubmed.ncbi.nlm.nih.gov/28811318/

2. Hay, Debbie L, Chen, Steve, Lutz, Thomas A, Parkes, David G, Roth, Jonathan D. . Amylin: Pharmacology, Physiology, and Clinical Potential. In Pharmacological reviews, 67, 564-600. doi:10.1124/pr.115.010629. https://pubmed.ncbi.nlm.nih.gov/26071095/

3. Fernández, Marta S. 2014. Human IAPP amyloidogenic properties and pancreatic β-cell death. In Cell calcium, 56, 416-27. doi:10.1016/j.ceca.2014.08.011. https://pubmed.ncbi.nlm.nih.gov/25224501/

4. Blencowe, Montgomery, Furterer, Allison, Wang, Qing, Butler, Peter C, Gurlo, Tatyana. 2021. IAPP-induced beta cell stress recapitulates the islet transcriptome in type 2 diabetes. In Diabetologia, 65, 173-187. doi:10.1007/s00125-021-05569-2. https://pubmed.ncbi.nlm.nih.gov/34554282/

5. Montane, J, Klimek-Abercrombie, A, Potter, K J, Westwell-Roper, C, Bruce Verchere, C. . Metabolic stress, IAPP and islet amyloid. In Diabetes, obesity & metabolism, 14 Suppl 3, 68-77. doi:10.1111/j.1463-1326.2012.01657.x. https://pubmed.ncbi.nlm.nih.gov/22928566/