Abstract
β-cells represent the functional unit of pancreatic islets, and they are responsible for glucose homeostasis regulation. β-cells possess the ability to modify insulin secretion according to the organism-specific needs. Thus, during physiological changes such as pregnancy or obesity, glycemia is increased concomitantly with the ability of β-cells to secrete insulin. However, when demand for insulin chronically increases, a steady stimulation of β-cells eventually may lead to death. In spite of the conducted efforts in order to elucidate the glucotoxicity mechanisms acting on β-cells, they remain largely unknown. Hyperglycemia promotes several metabolic alterations such as glucolipotoxicity, mitochondrial alterations, oxidative stress, endoplasmic reticulum stress, amyloid polypeptide accumulation, and proinflammatory cytokine accumulation. The latter are commonly engaged during apoptosis triggering in β-cells. In recent years, p53 has been also proposed as a major trigger of apoptosis in β-cells during hyperglycemia conditions. Because insulin-producing cells are cultured using high glucose levels, the presence of p53 in mitochondria induces apoptosis. The insight on the mechanisms triggering cell death in pancreatic β-cells will support the proposal of alternatives for prevention and/or cell protection also contributing to the treatment of diabetic patients.
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Abbreviations
- AGE:
-
Advanced glycation end products
- AIF:
-
Apoptosis inducing factor
- Apaf-1:
-
Apoptotic protease-activating factor 1
- ATF6:
-
Activating transcription factor 6
- ATM:
-
ATM serine/threonine kinase protein
- Bak:
-
Bcl-2 homologous antagonist killer
- Bax:
-
Bcl-2-associated X protein
- Bcl-2:
-
B-cell lymphoma 2
- Bcl-xl:
-
B-cell lymphoma-extra large
- BH (1–4):
-
Bcl-2 homology domains
- Bok:
-
Bcl-2 related ovarian killer
- Caspasa:
-
Cysteine-aspartic proteases, cysteine aspartases
- CHOP:
-
C/EBP homologous protein
- ChREBP:
-
Carbohydrate response element-binding protein
- Drp1:
-
Dynamin-related protein 1
- ΔΨm:
-
Mitochondrial membrane potential
- eif2α:
-
Eukaryotic translation initiation factor 2α
- ER:
-
Reticulum stress
- ERE:
-
Endoplasmic reticulum stress
- EZH2:
-
Enhancer of Zeste Homologue 2
- FADD:
-
FAS-associating death domain-containing protein
- Fas:
-
Death receptor
- FFA:
-
Free fatty acids
- Fis1:
-
Mitochondrial fission 1 protein
- FOX A1/2:
-
Forkhead box
- G3P:
-
Glyceraldehyde 3-phosphate
- GADD34:
-
Downstream growth arrest and DNA damage-inducible protein
- GAPDH:
-
Glyceraldehyde-3-phosphate dehydrogenase
- GATA4/6:
-
GATA-binding protein
- GLUT:
-
Glucose transporter
- GSIS:
-
Glucose-stimulated insulin secretion
- H3K27me3:
-
Histone H3 trimethyl K27
- HNF1β:
-
Hepatocyte nuclear factor
- IAPP:
-
Islet amyloid polypeptide
- IFNγ:
-
Interferon gamma
- IGF1:
-
Insulin-like growth factor 1
- IL-1β:
-
Interleukin 1 beta
- iNOS:
-
Nitric oxide synthases inducible
- Ins :
-
Insulin gene
- INS1:
-
Insulin secreting beta-cell-derived line
- IRE1α:
-
Inositol-requiring enzyme
- IRS-2:
-
Insulin receptor substrate
- Isl:
-
Islet
- MafA:
-
Musculo aponeurotic fibrosarcoma protein A
- Mdm2:
-
Murine double minute 2
- Mff:
-
Mitochondrial fission factor
- Mfn:
-
Mitofusin
- Mouse db/db:
-
Model of obesity, diabetes, and dyslipidemia with a mutation in leptin receptor
- mTOR:
-
Mammalian target of rapamycin
- NAD+:
-
Nicotinamide adenine dinucleotide
- NADH:
-
Nicotinamide adenine dinucleotide reduced
- NADPH oxi:
-
Nicotinamide adenine dinucleotide phosphate-oxidase
- NeuroD1:
-
Neurogenic differentiation 1
- NF-κB:
-
Nuclear factor kappa B
- Nkx:
-
Homeobox protein
- NLRP3:
-
NACHT, LRR, and PYD domain-containing protein 3
- NLRs:
-
Nucleotide oligomerization domain (NOD)-like receptors
- NO:
-
Nitric oxide
- NOD :
-
Nucleotide oligomerization domain
- Notch:
-
Transcription factor
- •OH:
-
Hydroxyl radical
- 8-OHdG:
-
8-hydroxy-2′-deoxyguanosine
- O−2:
-
Superoxide anion
- O-GlcNAc:
-
O-linked β-N-acetylglucosamine
- Opa1:
-
Protein of mitocondrial internal membrane
- P/CAF:
-
P300/CBP-associated factor
- p16:
-
Cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1
- p21:
-
Cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1
- p27:
-
Cyclin-dependent kinase inhibitor 1B
- p300/CBP:
-
E1A binding protein p300/CREB-binding protein
- p38 MAPK:
-
P38 mitogen-activated protein kinases
- p53:
-
Tumor protein p53
- PARP:
-
Poly ADP ribose polymerase
- Pax4:
-
Transcription factors paired box gene 4
- Pdx1:
-
Pancreatic and duodenal homeobox 1
- PERK:
-
Protein kinase-like ER kinase
- PI3k:
-
Phosphatidylinositol-3-kinases
- PKC:
-
Protein kinase C
- PP-1:
-
Protein phosphatase 1
- Ptf1α:
-
Pancreas transcription factor 1α
- RAMP1:
-
Receptor activity-modifying protein 1
- Rfx 6:
-
Regulatory factor x
- RING-finger:
-
Really interesting new gene
- RINm5F:
-
Rat insulinoma cells
- ROS:
-
Reactive oxygen species
- Sox9 SRY:
-
Sex-determining region Y-box 9
- SPT:
-
Serine C-palmitoyltransferase
- T2D:
-
Type 2 diabetes
- TLRs:
-
Toll-like receptors
- TNFRI:
-
Tumor necrosis factor receptor type I
- TNFα:
-
Tumor necrosis factor alpha
- TXNIP:
-
Thioredoxin-interacting protein
- UCP2:
-
Uncoupling protein 2
- UDP-GlcNAc:
-
Uridine diphosphate N-acetylglucosamine
- UPR:
-
Unfolded protein response
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Further Reading
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–25. The author presents a unified mechanism that links overproduction of superoxide by the mitochondrial electron-transport chain to high glucose-mediated damage and diabetes complications. This paper provides the basis for understanding of the origin of ROS and oxidative stress in diabetes.
Grieco E, Brusco N, Licata G, Fignani D, Formichi C, Nigi L, Sebastiani G, Dotta F. Landscape of microRNAs in cell: between phenotype maintenance and protection. Int J Mol Sci. 2021;22:803–21. https://doi.org/10.3390/ijms22020803. This review is about the most important miRNAs regulating the maintenance and the robustness of β cell identity.
Hasnain SZ, et al. Oxidative and endoplasmic reticulum stress in b-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54. https://doi.org/10.1530/JME-15-0232. Here, the importance of deleterious effects of oxidative stress and endoplasmic reticulum stress-induced unfolded protein response is evaluated on β-cell insulin synthesis and secretion as well as on inflammatory signaling and apoptosis. Additionally, the authors describe recent findings on how inflammatory cytokines contribute to β-cell dysfunction and protect interleukin 22.
Hayden MR. An immediate and long-term complication of COVID-19 may be type 2 diabetes mellitus: the central role of β-cell dysfunction, apoptosis and exploration of possible mechanisms. Cell. 2020;9:2475–98. https://doi.org/10.3390/cells9112475. The author review COVID-19 participation on development of type 2 diabetes.
Hudish LI, Reusch JE, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Investig. 2019;129:4001–8. https://doi.org/10.1172/JCI129188. These authors focus on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS.
Kaufman B, et al. Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release. Mol Aspects Med. 2015;42:91–104. https://doi.org/10.1016/j.mam.2015.01.004. Pancreatic β-cell function and insulin release is mitochondria dependent. In this work, the authors review mitochondrial metabolism and control of mitochondrial mass as they relate to pancreatic β-cell function.
Ortega-Camarillo C, et al. The role of p53 in pancreatic β-cell apoptosis. Immunoendocrinology. 2015;2:e1075. https://doi.org/10.14800/ie.1075. © 2015. This paper examines p53 mobilization to a mitochondrion and its phosphorylation, as well as the activation of the intrinsic route of β-cell apoptosis by hyperglycemia. They also describe how hyperglycemia affects the p53 degradation pathways.
Sharma RB, Alonso LC. Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well? Curr Diab Rep. 2014;14(6):492. https://doi.org/10.1007/s11892-014-0492-2. This paper reviews free fatty acids’ (FFAs) positive and negative effects on beta cell survival and insulin secretion. It also examines strong new findings that lipids may also impair compensatory beta cell proliferation.
Strycharz J, et al. Is p53 involved in tissue-specific insulin resistance formation? Oxid Med Cell Longev. 2017;2017:9270549, 23p. https://doi.org/10.1155/2017/9270549. The protein p53 is connected with metabolic defects underlying cellular aging, obesity, inflammation and β-cells apoptosis. Additionally, the authors discuss p53 regulation of multiple biochemical processes such as glycolysis, oxidative phosphorylation, lipolysis, lipogenesis, 𝛽-oxidation, gluconeogenesis, and glycogen synthesis.
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Glossary
- Adipokines
-
Cytokines (cell signaling proteins) secreted by adipose tissue.
- Amylin
-
A 37-amino acid peptide hormone, discovered in 1987, which is co-located and co-secreted with insulin by the pancreatic beta-cells in response to nutrient stimuli.
- Antioxidant
-
Molecule that inhibits the oxidation of other molecules.
- Apoptosis (a-po-toe-sis)
-
Was first used by Kerr, Wyllie, and Currie in 1972 to describe a morphologically distinct form of cell death and energy-dependent biochemical mechanisms.
- Apoptosome
-
Molecular complex of two major components—the adapter protein apoptotic protease activating factor 1 (Apaf1) and the pro caspase-9. These are assembled during apoptosis upon Apaf1 interaction with cytochrome c. Apoptosome assembly triggers effector caspase activation.
- Cardiolipin
-
Phospholipid important of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition.
- Caspase (cysteine-aspartic proteases, cysteine aspartases, or cysteine-dependent aspartate-directed proteases)
-
Family of protease enzymes playing essential roles in apoptosis and inflammation.
- Ceramides
-
Family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid.
- Cytochrome c
-
Heme protein serving as electron carrier in respiration. Cytochrome c is also an intermediate of apoptosis.
- Cytokines
-
Cell signaling small proteins. Involved in autocrine signalling, paracrine signalling, and endocrine signalling as immunomodulating agents
- Dedifferentiation process
-
Processes by which cell that were specialized for a specific function lose their specialization.
- Fission
-
Division of mitochondria into new mitochondria.
- Flavoprotein
-
Proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN).
- Fusion
-
Process mediated by several large GTPases whose combined effects lead to the dynamic mitochondrial networks seen in many cell types.
- Glucolipotoxicity
-
Combined, deleterious effects of elevated glucose, and fatty acid levels on pancreatic beta-cell function and survival.
- Hyperlipidemia
-
Elevation of fats or lipids in the blood.
- Hyperplasia
-
Enlargement of an organ or tissue caused by an increase in the cell proliferation rate.
- Inflammasome
-
A multiprotein cytoplasmic complex which activates one or more caspases, leading to the processing and secretion of pro-inflammatory cytokines—e.g., IL-1 beta, IL-18, and IL-33. Assembly of inflammasomes depends on the NOD-like receptor family members, such as the NALP proteins kinase: enzyme-catalyzing phosphorylation of an acceptor molecule by ATP.
- Misfolded proteins
-
Are proteins structurally abnormal, and thereby disrupt the function of cells, tissues, and organs. Proteins that fail to fold into their normal configuration; in this misfolded state, the proteins can become noxious in some way and can lose their normal function.
- Mitofusins
-
Proteins that participate in mitochondrial fusion.
- Necrosis
-
Morphological changes in cell death caused by enzymatic degradation.
- Neogenesis
-
Generation of new cells.
- Oxidative stress
-
Pathological changes in living organisms in response to excessive levels of intracellular free radicals.
- Proenzyme
-
Precursor of an enzyme, requiring some change (hydrolysis of an inhibiting fragment that masks an active grou**) to render it active form.
- Proteasome
-
An intracellular complex enzymatic that degrades misfolded or damaged proteins (proteolysis), after damaged proteins are tagged by ubiquitin.
- Resistance to insulin
-
Pathological condition in which cells fail to respond normally to the hormone insulin.
- RING finger domain
-
Really interesting new gene-finger is a proteins domain that plays a key role in the ubiquitination process.
- Stem cells
-
Undifferentiated biological cells that can differentiate into specialized cells and can divide.
- Sumoylation
-
Small ubiquitin-like modifier (or SUMO) proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. Post-translational modification involved in various cellular processes.
- Triacylglycerol
-
Ester of glycerol with three molecules of fatty acid.
- Ubiquitin
-
Small (8.5 kDa) regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms and regulated proteolysis.
- Ubiquitin ligase
-
Protein that recruits, recognizes a protein substrate, and catalyzes the transfer of ubiquitin from the E2 enzyme to the protein substrate.
- Uncoupling proteins
-
Proteins that uncouples phosphorylation of ADP from electron transport.
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Camarillo, C.O. (2023). Dysfunction and Death of Pancreatic Beta-Cells in Type 2 Diabetes. In: Rodriguez-Saldana, J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-031-25519-9_13
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