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Event: 2037

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Pancreatic beta cell dysfunction

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Beta cell dysfunction
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
insulin secreting cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
endocrine pancreas

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
insulin secretion Beta cell decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
AhR activation leads to increased diabetes risk KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Beta cells are insulin-producing cells in the endocrine pancreas or “islets”. After a meal, beta cells respond to the increase in blood sugar by secreting insulin to stimulate glucose uptake in peripheral tissues. Without sufficient insulin, blood sugar levels remain elevated (Kahn et al., 2021; Walker et al., 2021). Beta cell dysfunction typically manifests as decreased insulin secretion in response to glucose (Cersosimo et al., 2014; Eizirik et al., 2020). Chronic hyperglycemia, one of the hallmarks of diabetes, partly results from the inability of beta cells to produce and secrete enough insulin (Cersosimo et al., 2014; Eizirik et al., 2020). Chronic inflammation, obesity, insulin resistance, and diets high in saturated fat contribute to beta cell dysfunction (Kahn et al., 2021; Kalwat et al., 2021).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Proinsulin-to-insulin ratio. Plasma proinsulin-to-insulin ratio is used to assess beta cell function in human populations. This ratio can provide insights in intracellular insulin processing, and thus is a marker of insulin function (Cersosimo et al., 2014). However, fasting proinsulin-to-insulin ratios do not always correlate with other measures of beta cell function and may have limited applications in assessing beta cell function in non-diabetic individuals (Cersosimo et al., 2014; Egan et al., 2021). Proinsulin and insulin levels can be measured using protein ELISAs (Kim et al., 2000).

Proinsulin-to-c-peptide ratio. When proinsulin is cleaved, insulin and c-peptide are produced in equal amounts, but c-peptide is degraded more slowly in the body than insulin (Karas et al., 2021; Leighton et al., 2017). C-peptide levels are typically measured using radioimmunoassays (Egan et al., 2021; Kim et al., 2000).

Homoeostasis model assessment (HOMA). HOMA is based on population-level human data and is calculated under fasted conditions. HOMA models are used to estimate beta cell dysfunction (HOMA-B), insulin resistance (HOMA-IR), and insulin sensitivity (HOMA-S) (Cersosimo et al., 2014).

Glucose-stimulated insulin secretion (GSIS). GSIS is a common assay used to assess beta cell function in humans and rodent models. In vivo, GSIS is measured by collecting plasma samples during a glucose tolerance test. Meanwhile, ex vivo GSIS involves directly exposing isolated “islets” (endocrine pancreas) to different glucose conditions (e.g., high/low glucose concentrations). Insulin ELISAs are used to measure insulin content in plasma (in vivo GSIS) or in supernatant (ex vivo GSIS) (al Rijjal & Wheeler, 2022).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Pancreatic beta cell dysfunction is one of the main drivers of diabetes, a condition that affects individuals across all life stages (International Diabetes Association, 2021). Beta cell dysfunction and diabetes have been observed in many species, including humans, rodents, cats, dogs, and some wild animals (e.g., non-human primates, birds) (Niaz et al., 2018).  However, diabetes is mainly studied in human and rodent models (Niaz et al., 2018; Walker et al., 2021). It is also important to note that there are sex-based differences in beta cell physiology and response to stressors (Gannon et al., 2018).

References

List of the literature that was cited for this KE description. More help

al Rijjal, D., & Wheeler, M. B. (2022). A protocol for studying glucose homeostasis and islet function in mice. STAR Protocols, 3(1). https://doi.org/10.1016/J.XPRO.2022.101171

Cersosimo, E., Solis-Herrera, C., Trautmann, M. E., Malloy, J., & Triplitt, C. L. (2014). Assessment of pancreatic β-Cell function: Review of methods and clinical applications. Current Diabetes Reviews, 10(1), 2. https://doi.org/10.2174/1573399810666140214093600

Egan, A. M., Laurenti, M. C., Hurtado Andrade, M. D., Dalla Man, C., Cobelli, C., Bailey, K. R., & Vella, A. (2021). Limitations of the fasting proinsulin to insulin ratio as a measure of β-cell health in people with and without impaired glucose tolerance. European Journal of Clinical Investigation, 51(6). https://doi.org/10.1111/eci.13469

Eizirik, D. L., Pasquali, L., & Cnop, M. (2020). Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nature Reviews Endocrinology, 16, 349–362. https://doi.org/10.1038/s41574-020-0355-7

Gannon, M., Kulkarni, R. N., Tse, H. M., & Mauvais-Jarvis, F. (2018). Sex differences underlying pancreatic islet biology and its dysfunction. Molecular Metabolism, 15, 82. https://doi.org/10.1016/J.MOLMET.2018.05.017

International Diabetes Association. (2021). IDF Diabetes Atlas, 10th edition. www.diabetesatlas.org

Kahn, S. E., Chen, Y.-C., Esser, N., Taylor, A. J., van Raalte, D. H., Zraika, S., & Verchere, C. B. (2021). The β cell in diabetes: Integrating biomarkers with functional measures. Endocrine Reviews, 42(5), 528–583. https://doi.org/10.1210/endrev/bnab021

Kalwat, M. A., Scheuner, D., Rodrigues-Dos-Santos, K., Eizirik, D. L., & Cobb, M. H. (2021). The pancreatic ß-cell response to secretory demands and adaption to stress. Endocrinology, 162(11), 1–22. https://doi.org/10.1210/endocr/bqab173

Karas, J. A., Wade, J. D., & Hossain, M. A. (2021). The chemical synthesis of insulin: An enduring challenge. In Chemical Reviews (Vol. 121, Issue 8, pp. 4531–4560). American Chemical Society. https://doi.org/10.1021/acs.chemrev.0c01251

Kim, N. H., Kim, D. L., Choi, K. M., Baik, S. H., & Choi, D. S. (2000). Serum insulin, proinsulin and proinsulin/insulin ratio in Type 2 diabetic patients: As an index of β-cell function or insulin resistance. The Korean Journal of Internal Medicine, 15(3), 195. https://doi.org/10.3904/KJIM.2000.15.3.195

Leighton, E., Sainsbury, C. A., & Jones, G. C. (2017). A practical review of c-peptide testing in diabetes. Diabetes Therapy, 8(3), 475. https://doi.org/10.1007/S13300-017-0265-4

Niaz, K., Maqbool, F., Khan, F., Hassan, F. I., Momtaz, S., & Abdollahi, M. (2018). Comparative occurrence of diabetes in canine, feline, and few wild animals and their association with pancreatic diseases and ketoacidosis with therapeutic approach. Veterinary World, 11(4), 410. https://doi.org/10.14202/VETWORLD.2018.410-422

Walker, J. T., Saunders, D. C., Brissova, M., & Powers, A. C. (2021). The human islet: Mini-organ with mega-impact. Endocrine Reviews, 42(5), 605–657. https://doi.org/10.1210/endrev/bnab010