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Regulation of insulin secretion in diabetes: Molecular mechanism and applications

Wu, Rui LU (2024) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Diabetes is a highly ageing-related disease manifesting with a deteriorated capacity of insulin secretion and uncontrolled blood glucose-raising, hyperglycemia. In this thesis, we aim to explore the underlying roles of CaV channels and aging-associated genetic changes in the development of Type 2 diabetes (T2D).
In pancreatic β-cells, the active of voltage-gated calcium (CaV) channels play an essential role in the glucose-stimulated insulin secretion (GSIS). The CaV channel is a heteromeric complex consisting of four subunits: α1, β, γ, and α2δ. Based on the structure of α1, CaV channels are categorized into L-, P/Q-, N-, R-, and T-types. Previous studies have shown that calcium influx is primarily dependent on L-type CaV channels,... (More)
Diabetes is a highly ageing-related disease manifesting with a deteriorated capacity of insulin secretion and uncontrolled blood glucose-raising, hyperglycemia. In this thesis, we aim to explore the underlying roles of CaV channels and aging-associated genetic changes in the development of Type 2 diabetes (T2D).
In pancreatic β-cells, the active of voltage-gated calcium (CaV) channels play an essential role in the glucose-stimulated insulin secretion (GSIS). The CaV channel is a heteromeric complex consisting of four subunits: α1, β, γ, and α2δ. Based on the structure of α1, CaV channels are categorized into L-, P/Q-, N-, R-, and T-types. Previous studies have shown that calcium influx is primarily dependent on L-type CaV channels, while the function of T-type calcium is unclear. In this study, we confirm that T-type CaV3.2 contributes to calcium influx by initiating membrane depolarization and activating L-type CaV. Additionally, we demonstrate that the subunit CaVγ4 participates in the regulation of GSIS via L-type CaV channels Cav1.2 and CaV1.3. Moreover, this regulation relies on insulin gene expression through the activation of CaMKII and MafA.
Aging is a recognized risk factor for T2D development, and the decline in pancreatic β-cell function is linked to genetic changes during aging. In this study, we develop a pancreatic β-cell model through prolonged culturing of INS-1 832/13 cells. By analyzing changes in gene expression following the long-term culturing period, we identify three aging-associated differentially expressed genes (DEGs) involved in insulin secretion or insulin production.
Recent studies have shown that a magnetic field can improve hyperglycemia in diabetic mice by enhancing insulin sensitivity, but the effect of a magnetic field on insulin secretion is unclear. In this study, we prove that a dynamic magnetic field upregulates insulin gene expression in low-content insulin-secreting INS-1 832/13 cells. This enhancement is combined with the activation of Pdx-1, the transcription factor that regulates insulin gene expression.
In summary, we investigate the mechanisms regulating insulin production and secretion through Cav channels and DEGs. Additionally, we present evidence supporting the potential of magnetic treatment in restoring β-cell function, suggesting a novel avenue for further exploration in the field of diabetes research.
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author
supervisor
opponent
  • Associate Professor Perego, Carla, Università degli Studi di Milano
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Insulin production/secretion, CaV channels, DEGs, aging, magnetic field
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2024:35
pages
70 pages
publisher
Lund University, Faculty of Medicine
defense location
Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
defense date
2024-03-15 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-528-2
language
English
LU publication?
yes
id
c37e22b2-432d-4377-b11f-bdcc479f2b54
date added to LUP
2024-02-23 15:52:52
date last changed
2024-02-27 08:10:44
@phdthesis{c37e22b2-432d-4377-b11f-bdcc479f2b54,
  abstract     = {{Diabetes is a highly ageing-related disease manifesting with a deteriorated capacity of insulin secretion and uncontrolled blood glucose-raising, hyperglycemia. In this thesis, we aim to explore the underlying roles of CaV channels and aging-associated genetic changes in the development of Type 2 diabetes (T2D).<br/>In pancreatic β-cells, the active of voltage-gated calcium (CaV) channels play an essential role in the glucose-stimulated insulin secretion (GSIS). The CaV channel is a heteromeric complex consisting of four subunits: α1, β, γ, and α2δ. Based on the structure of α1, CaV channels are categorized into L-, P/Q-, N-, R-, and T-types. Previous studies have shown that calcium influx is primarily dependent on L-type CaV channels, while the function of T-type calcium is unclear. In this study, we confirm that T-type CaV3.2 contributes to calcium influx by initiating membrane depolarization and activating L-type CaV. Additionally, we demonstrate that the subunit CaVγ4 participates in the regulation of GSIS via L-type CaV channels Cav1.2 and CaV1.3. Moreover, this regulation relies on insulin gene expression through the activation of CaMKII and MafA.<br/>Aging is a recognized risk factor for T2D development, and the decline in pancreatic β-cell function is linked to genetic changes during aging. In this study, we develop a pancreatic β-cell model through prolonged culturing of INS-1 832/13 cells. By analyzing changes in gene expression following the long-term culturing period, we identify three aging-associated differentially expressed genes (DEGs) involved in insulin secretion or insulin production.<br/>Recent studies have shown that a magnetic field can improve hyperglycemia in diabetic mice by enhancing insulin sensitivity, but the effect of a magnetic field on insulin secretion is unclear. In this study, we prove that a dynamic magnetic field upregulates insulin gene expression in low-content insulin-secreting INS-1 832/13 cells. This enhancement is combined with the activation of Pdx-1, the transcription factor that regulates insulin gene expression.<br/>In summary, we investigate the mechanisms regulating insulin production and secretion through Cav channels and DEGs. Additionally, we present evidence supporting the potential of magnetic treatment in restoring β-cell function, suggesting a novel avenue for further exploration in the field of diabetes research.<br/>}},
  author       = {{Wu, Rui}},
  isbn         = {{978-91-8021-528-2}},
  issn         = {{1652-8220}},
  keywords     = {{Insulin production/secretion; CaV channels; DEGs; aging; magnetic field}},
  language     = {{eng}},
  number       = {{2024:35}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Regulation of insulin secretion in diabetes: Molecular mechanism and applications}},
  year         = {{2024}},
}