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Stimulus-Secretion Coupling in Beta-Cells: From Basic to Bedside

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Calcium Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1131))

Abstract

Insulin secretion in humans is usually induced by mixed meals, which upon ingestion, increase the plasma concentration of glucose, fatty acids, amino acids, and incretins like glucagon-like peptide 1. Beta-cells can stay in the off-mode, ready-mode or on-mode; the mode-switching being determined by the open state probability of the ATP-sensitive potassium channels, and the activity of enzymes like glucokinase, and glutamate dehydrogenase. Mitochondrial metabolism is critical for insulin secretion. A sound understanding of the intermediary metabolism, electrophysiology, and cell signaling is essential for comprehension of the entire spectrum of the stimulus-secretion coupling. Depolarization brought about by inhibition of the ATP sensitive potassium channel, together with the inward depolarizing currents through the transient receptor potential (TRP) channels, leads to electrical activities, opening of the voltage-gated calcium channels, and exocytosis of insulin. Calcium- and cAMP-signaling elicited by depolarization, and activation of G-protein-coupled receptors, including the free fatty acid receptors, are intricately connected in the form of networks at different levels. Activation of the glucagon-like peptide 1 receptor augments insulin secretion by amplifying calcium signals by calcium induced calcium release (CICR). In the treatment of type 2 diabetes, use of the sulfonylureas that act on the ATP sensitive potassium channel, damages the beta cells, which eventually fail; these drugs do not improve the cardiovascular outcomes. In contrast, drugs acting through the glucagon-like peptide-1 receptor protect the beta-cells, and improve cardiovascular outcomes. The use of the glucagon-like peptide 1 receptor agonists is increasing and that of sulfonylurea is decreasing. A better understanding of the stimulus-secretion coupling may lead to the discovery of other molecular targets for development of drugs for the prevention and treatment of type 2 diabetes.

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Abbreviations

[Ca2+]c :

Cytoplasmic free Ca2+ concentration

EPAC:

Exchange protein directly activated by cAMP

KATP :

ATP-sensitive potassium channel

NBD:

Nucleotide binding domain

PKA:

Protein kinase A

SCHAD:

short chain 3-hydroxyacyl-CoA dehydrogenase

SUR1:

Sulfonylurea receptor 1

VGCC:

Voltage-gated Ca2+ channel

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Acknowledgements

Financial support was obtained from the Karolinska Institutet and the Uppsala County Council.

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  1. Department of Clinical Science and Education, Södersjukhuset, Research Center, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

  2. Department of Emergency Care and Internal Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden

    Md. Shahidul Islam

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Correspondence to Md. Shahidul Islam .

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  1. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

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Islam, M.S. (2020). Stimulus-Secretion Coupling in Beta-Cells: From Basic to Bedside. In: Islam, M. (eds) Calcium Signaling. Advances in Experimental Medicine and Biology, vol 1131. Springer, Cham. https://doi.org/10.1007/978-3-030-12457-1_37

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