Regulation of insulin secretion in diabetes: Molecular mechanism and applications

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, 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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