IAPP-induced beta cell stress recapitulates the islet transcriptome in type 2 diabetes

Montgomery Blencowe; Allison Furterer; Qing Wang; Fuying Gao; Madeline Rosenberger; Lina Pei; Hiroshi Nomoto; Alex M Mawla; Mark O Huising; Giovanni Coppola; Xia Yang; Peter C Butler; Tatyana Gurlo

doi:10.1007/s00125-021-05569-2

IAPP-induced beta cell stress recapitulates the islet transcriptome in type 2 diabetes

Diabetologia. 2022 Jan;65(1):173-187. doi: 10.1007/s00125-021-05569-2. Epub 2021 Sep 23.

Authors

Montgomery Blencowe^{1

2}, Allison Furterer^{3

4}, Qing Wang³, Fuying Gao³, Madeline Rosenberger⁴, Lina Pei⁴, Hiroshi Nomoto⁴, Alex M Mawla⁵, Mark O Huising⁵, Giovanni Coppola^{3

6}, Xia Yang^{1

2}, Peter C Butler⁴, Tatyana Gurlo⁷

Affiliations

¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
² Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
³ Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
⁴ Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
⁵ Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA.
⁶ Department of Neurology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
⁷ Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA. tgurlo@mednet.ucla.edu.

Abstract

Aims/hypothesis: Type 2 diabetes is characterised by islet amyloid and toxic oligomers of islet amyloid polypeptide (IAPP). We posed the questions, (1) does IAPP toxicity induce an islet response comparable to that in humans with type 2 diabetes, and if so, (2) what are the key transcriptional drivers of this response?

Methods: The islet transcriptome was evaluated in five groups of mice: beta cell specific transgenic for (1) human IAPP, (2) rodent IAPP, (3) human calpastatin, (4) human calpastatin and human IAPP, and (5) wild-type mice. RNA sequencing data was analysed by differential expression analysis and gene co-expression network analysis to establish the islet response to adaptation to an increased beta cell workload of soluble rodent IAPP, the islet response to increased expression of oligomeric human IAPP, and the extent to which the latter was rescued by suppression of calpain hyperactivation by calpastatin. Rank-rank hypergeometric overlap analysis was used to compare the transcriptome of islets from human or rodent IAPP transgenic mice vs humans with prediabetes or type 2 diabetes.

Results: The islet transcriptomes in humans with prediabetes and type 2 diabetes are remarkably similar. Beta cell overexpression of soluble rodent or oligomer-prone human IAPP induced changes in islet transcriptome present in prediabetes and type 2 diabetes, including decreased expression of genes that confer beta cell identity. Increased expression of human IAPP, but not rodent IAPP, induced islet inflammation present in prediabetes and type 2 diabetes in humans. Key mediators of the injury responses in islets transgenic for human IAPP or those from individuals with type 2 diabetes include STAT3, NF-κB, ESR1 and CTNNB1 by transcription factor analysis and COL3A1, NID1 and ZNF800 by gene regulatory network analysis.

Conclusions/interpretation: Beta cell injury mediated by IAPP is a plausible mechanism to contribute to islet inflammation and dedifferentiation in type 2 diabetes. Inhibition of IAPP toxicity is a potential therapeutic target in type 2 diabetes.

Keywords: Beta cell; Cell cycle; Dedifferentiation; Inflammation; Islet amyloid polypeptide; Prediabetes; Protein misfolding; Type 2 diabetes; Unfolded protein response.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid / metabolism
Animals
Diabetes Mellitus, Type 2* / genetics
Diabetes Mellitus, Type 2* / metabolism
Insulin-Secreting Cells* / metabolism
Islet Amyloid Polypeptide / genetics
Islet Amyloid Polypeptide / metabolism
Islets of Langerhans* / metabolism
Mice
Mice, Transgenic
Transcriptome / genetics

Substances

Amyloid
Islet Amyloid Polypeptide

Abstract

Publication types

MeSH terms

Substances

Grants and funding