Dysfunction and Death of Pancreatic Beta Cells in Type 2 Diabetes
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 cytokines accumulation. The latter is 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 induce 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 treatment of diabetic patients.
KeywordsBeta-cell dysfunction Apoptosis Oxidative stress Mitochondria p53 Glucolipotoxicity
Advanced glycation end products
Apoptotic protease-activating factor 1
Activating transcription factor 6
ATM serine/threonine kinase protein
Bcl-2 homologous antagonist killer
Bcl-2-associated X protein
B-cell lymphoma 2
B-cell lymphoma-extra large
- BH (1–4)
Bcl-2 homology 1–4 domains
Bcl-2 related ovarian killer
Cysteine-aspartic proteases, cysteine aspartases
C/EBP homologous protein
Carbohydrate response element binding protein
Dynamin-related protein 1
Eukaryotic translation initiation factor 2α
Endoplasmic reticulum stress
Enhancer of zeste homologue 2
Fas-associated death domain
Free fatty acids
Mitochondrial fission 1 protein
Forkhead box A1/2
Downstream growth arrest and DNA damage-inducible protein
Glyceraldehyde 3-phosphate dehydrogenase
GATA-binding protein 4/6
Glucose-stimulated insulin secretion
Histone H3 tri methyl K27
Hepatocyte nuclear factor 1β
Islet amyloid polypeptide
Insulin-like growth factor 1
Interleukin 1 beta
Inducible nitric oxide synthases
Insulin-secreting beta cell-derived line
Inositol-requiring enzyme 1α
Insulin receptor substrate-2
Musculoaponeurotic fibrosarcoma protein A
Murine double minute 2
Mitochondrial fission factor
- Mouse db/db
Model of obesity, diabetes, and dyslipidemia with a mutation in leptin receptor
Mammalian target of rapamycin
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide reduced
- NADPH oxi
Nicotinamide adenine dinucleotide phosphate-oxidase
Neurogenic differentiation 1
Nuclear factor kappa B
NACHT, LRR, and PYD domains-containing protein 3
Nucleotide oligomerization domain (NOD)-like receptors
Nucleotide oligomerization domain
Opa1 mitochondrial dynamin like GTPase
Cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1
Cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1
Cyclin-dependent kinase inhibitor 1B
E1A binding protein p300/CREB-binding protein
- p38 MAPK
P38 mitogen-activated protein kinases
Tumor protein p53
Poly (ADP-ribose) polymerase
Transcription factors paired box gene 4
Pancreatic and duodenal homeobox 1
Protein kinase-like ER kinase
Protein kinase C
Pancreas transcription factor 1α
Receptor activity-modifying protein 1
- Rfx 6
Regulatory factor x 6
- RING finger
Really Interesting New Gene
Rat insulinoma cells
Reactive oxygen species
- Sox9 SRY
Sex-determining region Y-box 9
Type 2 diabetes
Tumor necrosis factor receptor type I
Tumor necrosis factor alpha
Uncoupling protein 2
Uridine diphosphate N-acetylglucosamine
Unfolded protein response
Mitochondrial membrane potential
Cytokines (cell signaling proteins) secreted by adipose tissue.
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.
Molecule that inhibits the oxidation of other molecules.
Was first used by Kerr, Wyllie, and Currie in 1972 to describe a morphologically distinct form of cell death and energy-dependent biochemical mechanisms.
Molecular complex of two major components – the adapter protein apoptotic protease-activating factor 1 (Apaf1) and the procaspase-9. These are assembled during apoptosis upon Apaf1 interaction with cytochrome c. Apoptosome assembly triggers effector caspase activation.
Phospholipid important of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition.
Family of protease enzymes playing essential roles in apoptosis and inflammation.
Family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid.
Heme protein serving as electron carrier in respiration. Cytochrome c is also an intermediate of apoptosis.
Cell signaling small proteins. Involved in autocrine signaling, paracrine signaling, and endocrine signaling as immunomodulating agents.
Processes by which cell that were specialized for a specific function lose their specialization.
Division of mitochondria into new mitochondria.
Proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN).
Process mediated by several large GTPases whose combined effects lead to the dynamic mitochondrial networks seen in many cell types.
Combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival.
Elevation of fats or lipids in the blood.
Enlargement of an organ or tissue caused by an increase in the cell proliferation rate.
A multiprotein cytoplasmic complex which activates one or more caspases, leading to the processing and secretion of proinflammatory 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 protein kinase: enzyme catalyzing phosphorylation of an acceptor molecule by ATP.
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.
Proteins that participate in mitochondrial fusion.
Morphological changes in cell death caused by enzymatic degradation.
Generation of new cells.
Pathological changes in living organisms in response to excessive levels of intracellular free radicals.
Precursor of an enzyme, requiring some change (hydrolysis of an inhibiting fragment that masks an active grouping) to render it active form.
An intracellular complex enzymatic that degrades misfolded or damaged proteins (proteolysis), after damaged proteins are tagged by ubiquitin.
Pathological condition in which cells fail to respond normally to the hormone insulin.
Really Interesting New Gene finger is a proteins domain that plays a key role in the ubiquitination process.
Undifferentiated biological cells that can differentiate into specialized cells and can divide.
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. Posttranslational modification involved in various cellular processes.
Ester of glycerol with three molecules of fatty acid.
Small (8.5 kDa) regulatory protein that has been found in almost all tissues (ubiquitously) of eukaryotic organisms and regulated proteolysis.
Protein that recruits, recognizes a protein substrate, and catalyzes the transfer of ubiquitin from the E2 enzyme to the protein substrate.
Proteins that uncouple phosphorylation of ADP from electron transport.
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