Dysfunction and Death of Pancreatic Beta Cells in Type 2 Diabetes

  • Clara Ortega-Camarillo


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.


Beta-cell dysfunction Apoptosis Oxidative stress Mitochondria p53 Glucolipotoxicity 



Hydroxyl radical




Advanced glycation end products


Apoptosis-inducing factor


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


Endoplasmic reticulum stress


Enhancer of zeste homologue 2


Fas-associated death domain


Death receptor


Free fatty acids


Mitochondrial fission 1 protein


Forkhead box A1/2


Glyceraldehyde 3-phosphate


Downstream growth arrest and DNA damage-inducible protein


Glyceraldehyde 3-phosphate dehydrogenase


GATA-binding protein 4/6


Glucose transporter


Glucose-stimulated insulin secretion


Histone H3 tri methyl K27


Hepatocyte nuclear factor 1β


Islet amyloid polypeptide


Interferon gamma


Insulin-like growth factor 1


Interleukin 1 beta


Inducible nitric oxide synthases


Insulin gene


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


Nicotinamide adenine dinucleotide phosphate-oxidase


Neurogenic differentiation 1


Nuclear factor kappa B


Homeobox protein


NACHT, LRR, and PYD domains-containing protein 3


Nucleotide oligomerization domain (NOD)-like receptors


Nitric oxide


Nucleotide oligomerization domain


Transcription factor


Superoxide anion


O-linked β-N-acetylglucosamine


Opa1 mitochondrial dynamin like GTPase


P300/CBP-associated factor


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


Protein phosphatase-1


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


Serine C-palmitoyltransferase


Type 2 diabetes


Toll-like receptors


Tumor necrosis factor receptor type I


Tumor necrosis factor alpha


Thioredoxin-interacting protein


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.

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.


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.

Caspase (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases)

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.

Cytochrome c

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.

Dedifferentiation process

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.

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.


Proteins that participate in mitochondrial fusion.


Morphological changes in cell death caused by enzymatic degradation.


Generation of new cells.

Oxidative stress

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.

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.


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.

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 uncouple phosphorylation of ADP from electron transport.


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Suggested/Further Reading

  1. 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.Google Scholar
  2. Hasnain SZ, et al. Oxidative and endoplasmic reticulum stress in b-cell dysfunction in diabetes. J Mol Endocrinol. 2016;56:R33–54. 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.
  3. Kaufman B, et al. Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release. Mol Aspects Med. 2015;42:91–104. 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.
  4. Ortega-Camarillo C, et al. The role of p53 in pancreatic β-cell apoptosis. Immunoendocrinology. 2015;2:e1075.; © 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.
  5. 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. 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.
  6. Strycharz J, et al. Is p53 involved in tissue-specific insulin resistance formation? Oxid Med Cell Longev 2017; Article ID 9270549, 23 p. 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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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Clara Ortega-Camarillo
    • 1
  1. 1.Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro SocialMexico CityMexico

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