Genes with Epigenetic Alterations in Human Pancreatic Islets Impact Mitochondrial Function, Insulin Secretion, and Type 2 Diabetes

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Dec 12

PMID 38086799

Authors

Tina Ronn

Jones K Ofori

Alexander Perfilyev

Alexander Hamilton

Karolina Pircs

Fabian Eichelmann

Sonia Garcia-Calzon

Alexandros Karagiannopoulos

Hans Stenlund

Anna Wendt

Petr Volkov

Matthias B Schulze

Hindrik Mulder

Lena Eliasson

Sabrina Ruhrmann

Karl Bacos

Charlotte Ling

Affiliations

Soon will be listed here.

Abstract

Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.

Citing Articles

DNA methylation in the association between pesticide exposures and type 2 diabetes.

Zheng G, Fang Z, Zhou B, Zuo L, Chen X, Liu M World J Diabetes. 2025; 16(2):99200.

PMID: 39959275 PMC: 11718482. DOI: 10.4239/wjd.v16.i2.99200.

Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure.

Zhang Y, Hu S, Han S, Liu C, Liang X, Li Y Cell Discov. 2025; 11(1):14.

PMID: 39934105 PMC: 11814079. DOI: 10.1038/s41421-025-00769-1.

Unveiling mitochondrial mysteries: Exploring novel tRNA variants in type 2 diabetes mellitus.

Cheng C, Hao W, Cheng T World J Diabetes. 2025; 16(1):98798.

PMID: 39817212 PMC: 11718450. DOI: 10.4239/wjd.v16.i1.98798.

Mitochondrial Dysfunction in Diabetic Periodontitis: Mechanisms and Therapeutic Potential.

Meng L, Wen W J Inflamm Res. 2025; 18():115-126.

PMID: 39810976 PMC: 11730282. DOI: 10.2147/JIR.S492041.

Blood-Based Epigenetic Biomarkers Associated With Incident Chronic Kidney Disease in Individuals With Type 2 Diabetes.

Marchiori M, Maguolo A, Perfilyev A, Maziarz M, Martinell M, Gomez M Diabetes. 2024; 74(3):439-450.

PMID: 39715581 PMC: 11842608. DOI: 10.2337/db24-0483.

References

Rovira-Llopis S, Banuls C, Diaz-Morales N, Hernandez-Mijares A, Rocha M, Victor V . Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications. Redox Biol. 2017; 11:637-645. PMC: 5284490. DOI: 10.1016/j.redox.2017.01.013. View

Baltrusch S . Mitochondrial network regulation and its potential interference with inflammatory signals in pancreatic beta cells. Diabetologia. 2016; 59(4):683-7. DOI: 10.1007/s00125-016-3891-x. View

Volkmar M, Dedeurwaerder S, Cunha D, Ndlovu M, Defrance M, Deplus R . DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J. 2012; 31(6):1405-26. PMC: 3321176. DOI: 10.1038/emboj.2011.503. View

Olsson A, Volkov P, Bacos K, Dayeh T, Hall E, Nilsson E . Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets. PLoS Genet. 2014; 10(11):e1004735. PMC: 4222689. DOI: 10.1371/journal.pgen.1004735. View

Yang B, Dayeh T, Kirkpatrick C, Taneera J, Kumar R, Groop L . Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets. Diabetologia. 2010; 54(2):360-7. PMC: 3017313. DOI: 10.1007/s00125-010-1967-6. View

Hall E, Dayeh T, Kirkpatrick C, Wollheim C, Nitert M, Ling C . DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC Med Genet. 2013; 14:76. PMC: 3727960. DOI: 10.1186/1471-2350-14-76. View

Ou K, Yu M, Moss N, Wang Y, Wang A, Nguyen S . Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication. J Clin Invest. 2018; 129(1):209-214. PMC: 6307972. DOI: 10.1172/JCI99170. View

Teschendorff A, Marabita F, Lechner M, Bartlett T, Tegner J, Gomez-Cabrero D . A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2012; 29(2):189-96. PMC: 3546795. DOI: 10.1093/bioinformatics/bts680. View

Klug M, Rehli M . Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics. 2007; 1(3):127-30. DOI: 10.4161/epi.1.3.3327. View

10.

Houseman E, Accomando W, Koestler D, Christensen B, Marsit C, Nelson H . DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012; 13:86. PMC: 3532182. DOI: 10.1186/1471-2105-13-86. View

11.

Bouzakri K, Ribaux P, Tomas A, Parnaud G, Rickenbach K, Halban P . Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells. Diabetes. 2008; 57(5):1195-204. DOI: 10.2337/db07-1469. View

12.

Miguel-Escalada I, Bonas-Guarch S, Cebola I, Ponsa-Cobas J, Mendieta-Esteban J, Atla G . Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes. Nat Genet. 2019; 51(7):1137-1148. PMC: 6640048. DOI: 10.1038/s41588-019-0457-0. View

13.

Florath I, Butterbach K, Heiss J, Bewerunge-Hudler M, Zhang Y, Schottker B . Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults. Diabetologia. 2015; 59(1):130-138. DOI: 10.1007/s00125-015-3773-7. View

14.

Chen J, Behnam E, Huang J, Moffatt M, Schaid D, Liang L . Fast and robust adjustment of cell mixtures in epigenome-wide association studies with SmartSVA. BMC Genomics. 2017; 18(1):413. PMC: 5446715. DOI: 10.1186/s12864-017-3808-1. View

15.

Yan-Do R, MacDonald P . Impaired "Glycine"-mia in Type 2 Diabetes and Potential Mechanisms Contributing to Glucose Homeostasis. Endocrinology. 2017; 158(5):1064-1073. DOI: 10.1210/en.2017-00148. View

16.

Johnson W, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2006; 8(1):118-27. DOI: 10.1093/biostatistics/kxj037. View

17.

Song Z, Chen H, Fiket M, Alexander C, Chan D . OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007; 178(5):749-55. PMC: 2064540. DOI: 10.1083/jcb.200704110. View

18.

Hohmeier H, Mulder H, Chen G, Prentki M, Newgard C . Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes. 2000; 49(3):424-30. DOI: 10.2337/diabetes.49.3.424. View

19.

Fan X, Guo H, Dai B, He L, Zhou D, Lin H . The association between methylation patterns of DNAH17 and clinicopathological factors in hepatocellular carcinoma. Cancer Med. 2018; 8(1):337-350. PMC: 6346260. DOI: 10.1002/cam4.1930. View

20.

Sekhar R . GlyNAC (Glycine and -Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study. Antioxidants (Basel). 2022; 11(1). PMC: 8773349. DOI: 10.3390/antiox11010154. View