PMID- 36264270
OWN - NLM
STAT- MEDLINE
DCOM- 20221128
LR  - 20230117
IS  - 1464-5491 (Electronic)
IS  - 0742-3071 (Print)
IS  - 0742-3071 (Linking)
VI  - 39
IP  - 12
DP  - 2022 Dec
TI  - Loss of tetraspanin-7 expression reduces pancreatic beta-cell exocytosis Ca(2+) 
      sensitivity but has limited effect on systemic metabolism.
PG  - e14984
LID - 10.1111/dme.14984 [doi]
LID - e14984
AB  - BACKGROUND: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune 
      type 1 diabetes and known to regulate beta-cell L-type Ca(2+) channel activity. 
      However, the role of Tspan7 in pancreatic beta-cell function is not yet fully 
      understood. METHODS: Histological analyses were conducted using immunostaining. 
      Whole-body metabolism was tested using glucose tolerance test. Islet hormone 
      secretion was quantified using static batch incubation or dynamic perifusion. 
      beta-cell transmembrane currents, electrical activity and exocytosis were measured 
      using whole-cell patch-clamping and capacitance measurements. Gene expression was 
      studied using mRNA-sequencing and quantitative PCR. RESULTS: Tspan7 is expressed 
      in insulin-containing granules of pancreatic beta-cells and glucagon-producing 
      alpha-cells. Tspan7 knockout mice (Tspan7(y/-) mouse) exhibit reduced body weight and 
      ad libitum plasma glucose but normal glucose tolerance. Tspan7(y/-) islets have 
      normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. 
      Depolarisation-triggered Ca(2+) current was enhanced in Tspan7(y/-) beta-cells, but 
      beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged 
      suggesting that exocytosis was less sensitive to Ca(2+) . TSPAN7 knockdown (KD) 
      in human pseudo-islets led to a significant reduction in insulin secretion 
      stimulated by 20 mM K(+) . Transcriptomic analyses show that TSPAN7 KD in human 
      pseudo-islets correlated with changes in genes involved in hormone secretion, 
      apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca(2+) 
      sensitivity was reduced in a human beta-cell line (EndoC-betaH1) following Tspan7 KD. 
      CONCLUSION: Tspan7 is involved in the regulation of Ca(2+) -dependent exocytosis 
      in beta-cells. Its function is more significant in human beta-cells than their rodent 
      counterparts.
CI  - (c) 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on 
      behalf of Diabetes UK.
FAU - McLaughlin, Kerry
AU  - McLaughlin K
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Acreman, Samuel
AU  - Acreman S
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
AD  - Institute of Neuroscience and Physiology, Department of Physiology, Metabolic 
      Research Unit, University of Goteborg, Goteborg, Sweden.
FAU - Nawaz, Sameena
AU  - Nawaz S
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Cutteridge, Joseph
AU  - Cutteridge J
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Clark, Anne
AU  - Clark A
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Knudsen, Jakob G
AU  - Knudsen JG
AD  - Section for Cell Biology and Physiology, Department of Biology, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Denwood, Geoffrey
AU  - Denwood G
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Spigelman, Aliya F
AU  - Spigelman AF
AD  - Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, 
      Edmonton, Alberta, Canada.
FAU - Manning Fox, Jocelyn E
AU  - Manning Fox JE
AD  - Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, 
      Edmonton, Alberta, Canada.
FAU - Singh, Sumeet Pal
AU  - Singh SP
AD  - IRIBHM, Universite Libre de Bruxelles (ULB), Brussels, Belgium.
FAU - MacDonald, Patrick E
AU  - MacDonald PE
AD  - Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, 
      Edmonton, Alberta, Canada.
FAU - Hastoy, Benoit
AU  - Hastoy B
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
FAU - Zhang, Quan
AU  - Zhang Q
AUID- ORCID: 0000-0002-3626-4855
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, 
      Churchill Hospital, Oxford, UK.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221031
PL  - England
TA  - Diabet Med
JT  - Diabetic medicine : a journal of the British Diabetic Association
JID - 8500858
RN  - IY9XDZ35W2 (Glucose)
RN  - 0 (Insulin)
RN  - 0 (Tetraspanins)
RN  - 0 (TSPAN7 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Exocytosis/physiology
MH  - Glucose/metabolism
MH  - Insulin/metabolism
MH  - *Insulin-Secreting Cells/metabolism
MH  - *Islets of Langerhans/metabolism
MH  - Tetraspanins/genetics/metabolism
PMC - PMC9828109
OTO - NOTNLM
OT  - exocytosis
OT  - insulin
OT  - synaptotagmin
OT  - tetraspanin-7
OT  - beta-cell
COIS- The authors do not have any relevant conflict of interest to disclose.
EDAT- 2022/10/21 06:00
MHDA- 2022/11/19 06:00
PMCR- 2023/01/09
CRDT- 2022/10/20 10:43
PHST- 2022/10/08 00:00 [revised]
PHST- 2022/09/12 00:00 [received]
PHST- 2022/10/18 00:00 [accepted]
PHST- 2022/10/21 06:00 [pubmed]
PHST- 2022/11/19 06:00 [medline]
PHST- 2022/10/20 10:43 [entrez]
PHST- 2023/01/09 00:00 [pmc-release]
AID - DME14984 [pii]
AID - 10.1111/dme.14984 [doi]
PST - ppublish
SO  - Diabet Med. 2022 Dec;39(12):e14984. doi: 10.1111/dme.14984. Epub 2022 Oct 31.