PMID- 35090905
OWN - NLM
STAT- MEDLINE
DCOM- 20220301
LR  - 20220301
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 294
DP  - 2022 Apr 1
TI  - Divergent effects of HIV reverse transcriptase inhibitors on pancreatic beta-cell 
      function and survival: Potential role of oxidative stress and mitochondrial 
      dysfunction.
PG  - 120329
LID - S0024-3205(22)00029-7 [pii]
LID - 10.1016/j.lfs.2022.120329 [doi]
AB  - Antiretroviral therapy (ART), a life-saving treatment strategy in HIV/AIDS, has 
      been implicated in increasing the risk of type 2 diabetes mellitus (T2DM). Direct 
      damaging effects on beta-cell function and survival by either non-nucleoside 
      reverse transcriptase inhibitors (NNRTIs) or nucleoside/tide reverse 
      transcriptase inhibitors (NRTIs) may predispose individuals to developing T2DM or 
      if already type 2 diabetic, to insulin dependency. The aim of this study was to 
      investigate the effects of the NNRTIs efavirenz, rilpivirine and doravirine, and 
      the NRTIs tenofovir disoproxil fumarate and emtricitabine, on beta-cell function 
      and survival while suggesting potential cellular and molecular mechanism(s). Our 
      results show contrasting effects within the NNRTI class as doravirine did not 
      cause damaging effects in the rat insulinoma INS-1E cells while efavirenz and 
      rilpivirine reduced insulin release and cell viability, and induced apoptosis in 
      INS-1E cells. Additionally, efavirenz and rilpivirine increased ROS generation, 
      disrupted Deltapsim and upregulated the mRNA and protein expression of CHOP and GRP78, 
      key markers of endoplasmic reticulum stress. In silico docking studies predict a 
      possible inhibition of the mitochondrial ATP synthase by rilpivirine. On the 
      contrary, both the NRTIs tenofovir disoproxil fumarate and emtricitabine did not 
      affect GSIS, cell viability and apoptosis/necrosis levels in INS-1E cells. The 
      deleterious effects observed in beta-cells exposed to efavirenz or rilpivirine 
      may be, at least partially, mediated by oxidative stress and mitochondrial 
      toxicity. These findings provide potential mechanism(s) by which efavirenz and 
      rilpivirine may contribute to the pathogenesis of T2DM and the progression of 
      T2DM to insulin dependency in HIV-infected type 2 diabetics.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Maandi, Soulef Chahinez
AU  - Maandi SC
AD  - Centre for Stress and Age-Related Disease, School of Applied Sciences, University 
      of Brighton, Brighton, UK. Electronic address: S.Maandi2@uni.brighton.ac.uk.
FAU - Maandi, Meriem Tinhinane
AU  - Maandi MT
AD  - Centre for Stress and Age-Related Disease, School of Applied Sciences, University 
      of Brighton, Brighton, UK.
FAU - Patel, Anneka
AU  - Patel A
AD  - Brighton and Sussex Medical School, Brighton, UK.
FAU - Manville, Rian W
AU  - Manville RW
AD  - Centre for Stress and Age-Related Disease, School of Applied Sciences, University 
      of Brighton, Brighton, UK.
FAU - Mabley, Jon Gunnarsson
AU  - Mabley JG
AD  - Centre for Stress and Age-Related Disease, School of Applied Sciences, University 
      of Brighton, Brighton, UK.
LA  - eng
PT  - Journal Article
DEP - 20220126
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Alkynes)
RN  - 0 (Benzoxazines)
RN  - 0 (Cyclopropanes)
RN  - 0 (Insulin)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Reverse Transcriptase Inhibitors)
RN  - FI96A8X663 (Rilpivirine)
RN  - JE6H2O27P8 (efavirenz)
SB  - IM
MH  - Alkynes/pharmacology
MH  - Animals
MH  - Benzoxazines/pharmacology
MH  - Cyclopropanes/pharmacology
MH  - *Endoplasmic Reticulum Stress
MH  - Insulin/metabolism
MH  - Insulin-Secreting Cells/drug effects/*pathology
MH  - Insulinoma/metabolism/*pathology
MH  - Mitochondria/drug effects/*pathology
MH  - *Oxidative Stress
MH  - Pancreatic Neoplasms/metabolism/pathology
MH  - Rats
MH  - Reactive Oxygen Species/metabolism
MH  - Reverse Transcriptase Inhibitors/*pharmacology
MH  - Rilpivirine/pharmacology
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Diabetes
OT  - HIV
OT  - Mitochondrial function
OT  - Oxidative stress
OT  - Pancreatic beta-cell
EDAT- 2022/01/30 06:00
MHDA- 2022/03/03 06:00
CRDT- 2022/01/29 05:35
PHST- 2021/10/01 00:00 [received]
PHST- 2022/01/04 00:00 [revised]
PHST- 2022/01/10 00:00 [accepted]
PHST- 2022/01/30 06:00 [pubmed]
PHST- 2022/03/03 06:00 [medline]
PHST- 2022/01/29 05:35 [entrez]
AID - S0024-3205(22)00029-7 [pii]
AID - 10.1016/j.lfs.2022.120329 [doi]
PST - ppublish
SO  - Life Sci. 2022 Apr 1;294:120329. doi: 10.1016/j.lfs.2022.120329. Epub 2022 Jan 
      26.