Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.

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Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes

Diabetologia ◽

10.1007/s00125-016-4188-9 ◽

2016 ◽

Vol 60 (4) ◽

pp. 668-678 ◽

Cited By ~ 38

Author(s):

Ting Yuan ◽

Sahar Rafizadeh ◽

Kanaka Durga Devi Gorrepati ◽

Blaz Lupse ◽

Jose Oberholzer ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Islets ◽

Reciprocal Regulation

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Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

Scientific Reports ◽

10.1038/s41598-018-20340-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 6

Author(s):

Sophie Bauer ◽

Charlotte Wennberg Huldt ◽

Kajsa P. Kanebratt ◽

Isabell Durieux ◽

Daniela Gunne ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pancreatic Islets ◽

Ex Vivo ◽

Functional Coupling ◽

Human Pancreatic Islets ◽

Diabetes Model

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Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets

Environmental Epigenetics ◽

10.1093/eep/dvz015 ◽

2019 ◽

Vol 5 (3) ◽

Cited By ~ 3

Author(s):

Ge Li ◽

Tihomira D Petkova ◽

Eleonora Laritsky ◽

Noah Kessler ◽

Maria S Baker ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Pancreatic Islets ◽

Cell Function ◽

Control Male ◽

Small Litter ◽

Endoplasmic Reticulum Calcium ◽

Expression Of Genes ◽

Β Cell Function

Abstract Pancreatic islets of type 2 diabetes patients have altered DNA methylation, contributing to islet dysfunction and the onset of type 2 diabetes. The cause of these epigenetic alterations is largely unknown. We set out to test whether (i) islet DNA methylation would change with aging and (ii) early postnatal overnutrition would persistently alter DNA methylation. We performed genome-scale DNA methylation profiling in islets from postnatally over-nourished (suckled in a small litter) and control male mice at both postnatal day 21 and postnatal day 180. DNA methylation differences were validated using quantitative bisulfite pyrosequencing, and associations with expression were assessed by RT-PCR. We discovered that genomic regions that are hypermethylated in exocrine relative to endocrine pancreas tend to gain methylation in islets during aging (R2 = 0.33, P < 0.0001). These methylation differences were inversely correlated with mRNA expression of genes relevant to β cell function [including Rab3b (Ras-related protein Rab-3B), Cacnb3 (voltage-dependent L-type calcium channel subunit 3), Atp2a3 (sarcoplasmic/endoplasmic reticulum calcium ATPase 3) and Ins2 (insulin 2)]. Relative to control, small litter islets showed DNA methylation differences directly after weaning and in adulthood, but few of these were present at both ages. Surprisingly, we found substantial overlap of methylated loci caused by aging and small litter feeding, suggesting that the age-associated gain of DNA methylation happened much earlier in small litter islets than control islets. Our results provide the novel insights that aging-associated DNA methylation increases reflect an epigenetic drift toward the exocrine pancreas epigenome, and that early postnatal overnutrition may accelerate this process.

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