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Mechanisms controlling pancreatic islet cell function in insulin secretion

Nature Reviews Molecular Cell Biology volume 22, pages 142–158 (2021)Cite this article

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Abstract

Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic β-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory mechanisms and is essential for the control of blood levels of glucose. The deregulation of these mechanisms leads to various pathologies, most notably type 2 diabetes, which is driven by the combined lesions of impaired insulin action and a loss of the normal insulin secretion response to glucose. Glucose stimulates insulin secretion from β-cells in a bi-modal fashion, and new insights about the underlying mechanisms, particularly relating to the second or amplifying phase of this secretory response, have been recently gained. Other recent work highlights the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of the β-cell glucose response. These advances provide a new perspective for the understanding of the β-cell failure that triggers type 2 diabetes.

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Fig. 1: Islet cell architecture and fundamental signalling pathways of GSIS.
Fig. 2: Pyruvate cycling pathways implicated in the regulation of GSIS.
Fig. 3: Pentose monophosphate shunt, phosphoenolpyruvate cycle and their nucleotide metabolites in GSIS.
Fig. 4: Glycerolipid/FFA cycle for the amplification of GSIS.
Fig. 5: Other hormones in control of insulin secretion.

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Acknowledgements

Work cited in this review from the authors’ laboratories was supported by NIH grants DK046492-25 (to C.B.N.) and RO1 DK123075 (to J.E.C.), a career development award 1-18-JDF-017 from the American Diabetes Association (to J.E.C.), and a Borden Scholar award (to J.E.C.). The authors are grateful for the contributions of collaborators and members of their labs to the cited work, including Drs. Mette Jensen, Guofang Zhang, Megan Capozzi and Kimberly El.

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Authors and Affiliations

  1. Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA

    Jonathan E. Campbell & Christopher B. Newgard

  2. Department of Medicine, Endocrinology and Metabolism Division, Duke University Medical Center, Durham, NC, USA

    Jonathan E. Campbell & Christopher B. Newgard

  3. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    Jonathan E. Campbell & Christopher B. Newgard

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  1. Jonathan E. Campbell
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Correspondence to Christopher B. Newgard.

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C.B.N. is a member of the Eli Lilly Global Diabetes Advisory Board. J.E.C. has a sponsored research agreement with Eli Lilly that has supported a portion of his work referenced in this article.

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Glossary

Insulin resistance

Referring to a condition in which the effect of insulin to promote the uptake and storage of glucose and other metabolic fuels is blunted; a major contributing metabolic lesion in type 2 diabetes.

Secretagogues

Referring to metabolites and hormones that stimulate hormone secretion. Mainly used in this article as a general term for agents that stimulate insulin secretion from β-cells.

Stimulatory glucose

Referring to glucose levels above those typically found in fasting mammals (∼4 mM); insulin secretion increases in a linear fashion as glucose levels increase above those found in the fasted state.

Euglycaemic values

Referring to the tight control of glucose levels achieved in humans without diabetes or without insulin resistance, ranging from 3.9 mM in the fasted state to 5.5 mM in the fed state.

Km

Also known as the Michaelis constant, it is the concentration of a substrate (glucose in the case of glucokinase) that permits an enzyme to achieve half of its maximal activity (Vmax).

Anaplerotic enzyme

From the Greek meaning ‘to fill up’, referring to an enzyme that contributes substrate to the tricarboxylic acid (TCA) cycle that is used for a non-oxidative purpose, for example, the exit of TCA cycle intermediates from the mitochondria to participate in cytosolic metabolism.

Reducing equivalent shuttle

Referring to a series of reactions by which cytosolic NADH is converted to mitochondrial NADH and FADH, involving the metabolism of organic acids in the cytosol to their reduced forms, followed by transport into the mitochondria for re-oxidation by FAD-linked or NAD-linked enzymes. Examples are the malate–aspartate shuttle and the glycerol phosphate shuttle.

Stable isotope flux methods

Use of stable isotope-labelled substrates (for example, 13C-glucose or 13C-glutamine) to discern their metabolic fates by analysing the labelling of their metabolic by-products by mass spectrometry or NMR.

Reductive (counter-clockwise) TCA cycle flux

Referring to the metabolism of substrates (for example, glutamine) in the TCA cycle in a ‘counter-clockwise’ fashion, requiring their reductive rather than oxidative metabolism.

Pentose monophosphate shunt pathway

One of the major pathways of glucose-6-phosphate in mammalian cells; it produces ribose-5-phosphate for nucleotide synthesis and is a source of NADPH via its first two enzymatic steps, catalysed by glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase.

Glutathione

(GSH). A tripeptide (composed of cysteine, glycine and glutamate) with a major role in the regulation of the cellular redox state via its intra-conversion between its oxidized and reduced forms.

Proglucagon-derived peptides

Referring to peptides produced by the processing of the proglucagon precursor, including glucagon, GLP1, GLP2, oxyntomodulin, glicentin, major proglucagon fragment and glicentin-related pancreatic peptide.

mTOR

Standing for ‘mammalian target of rapamycin’; a protein kinase that serves important signalling roles for the regulation of protein synthesis, insulin action and intermediary metabolism.

Pancreatic ductal cells

These cells form the epithelial lining of structures that deliver pancreatic enzymes to the duodenum. In response to specific challenges in rodents, these cells can differentiate to form new insulin-producing β-cells (‘neogenesis’).

Streptozotocin

A glucosamine-nitrosourea compound that is particularly toxic to β-cells and is used as an agent for creating experimental type 1 diabetes in animal models.

ER stress

Occurs when the capacity of the endoplasmic reticulum (ER) to fold proteins becomes saturated.

Unfolded protein response

A group of signal transduction pathways that are activated by ER stress.

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Campbell, J.E., Newgard, C.B. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat Rev Mol Cell Biol 22, 142–158 (2021). https://doi.org/10.1038/s41580-020-00317-7

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