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Event: 1867

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Impaired, insulin secretion

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. The short name should be less than 80 characters in length. More help
Impaired, insulin secretion

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Cell term
pancreatic endocrine cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Organ term
pancreas

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

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
AChE inhibition leading to T2D KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
Vertebrates Vertebrates High NCBI
Invertebrates Invertebrates Moderate NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Male High
Female 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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Impaired insulin secretion refers to the inability to robustly secrete insulin in response to a nutrient or insulin secretagogue. In mammals, this can occur due to damage and/or dysfunction of the endocrine pancreas, specifically, β-cells (6). For example, streptozotocin-induced pancreatic β-cell death, used to model type 1 diabetes in rodents, results in the absence of nutrient-stimulated insulin secretion (7).

The mammalian endocrine pancreas is composed of clusters of cells known as islets of Langerhans that contain α-, β-, δ-, ε-, and pancreatic polypeptide-cells (11). Many non-mammal vertebrates have pancreatic islet equivalents and invertebrates cell clusters in other tissues that functionally act as equivalents (15). β-cells, which constitute the bulk of the mammalian islet, have intracellular granules (vesicles) that contain insulin. Insulin is translated from the insulin gene that encodes for preproinsulin. The immature preproinsulin undergoes cleavage and folding in the lumen of the endoplasmic reticulum to afford proinsulin that is stored in vesicles known as granules (18). Inside the granule, proinsulin is cleaved into mature insulin and C-peptide that go on to adopt a hexameric form in coordination with zinc ions (16).

In response to changes to blood nutrient levels, including glucose, lipids, and some amino acids, pancreatic β-cells secrete insulin into circulating blood by triggering exocytosis of insulin granules (6). Glucose, the primary insulin secretagogue, is absorbed via glucose transporters in β-cells, phosphorylated by glucokinase, and undergoes metabolism resulting in increased intracellular ATP (14). The increase in ATP:ADP results in closure of ATP-sensitive potassium channels leading to depolarization (2) and subsequent opening of voltage-gated calcium channels (20). The latter triggers the activation of exocytotic proteins syntaxin 1A (21), SNAP-26 (19), and synaptotagmin (19), that facilitate insulin granule exocytosis.

Insulin is an anabolic peptide hormone that works at target tissues, namely muscle and hepatic tissue, via the insulin receptor to have mitogenic and glycogenic effects, respectively (4). The insulin receptor is a tyrosine kinase that phosphorylates insulin responsive substrates (IRS). IRS proteins are kinases that phosphorylate enzymes including phosphatidylinositol 3-kase to mediate much of the downstream biochemical cascade associated with insulin signaling. 

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

There is no strict definition of hypoinsulinemia. For example, a serum measurement of <1.0 μU/mL has been reported as hypoinsulinemia (1). Adult human fasting serum insulin is typically in the range of 2 - 15 μIU/mL (13, 17).

Insulin can be sampled from blood, typically under fasting conditions, and measured in humans and research animals. More often, a dynamic measure of insulin secretion is more informative of pancreatic β-cell health with the most common being the glucose-stimulated insulin secretion test. Briefly, following the administration of a bolus of glucose, blood is collected in sequential intervals, typically 15-minutes, and insulin is measured.

In vivo: Insulin can be collected from blood plasma and measured via a commercially available enzyme-linked immunosorbent reaction (ELISA) kit. For example, blood is collected from the saphenous vein of mice via a capillary tube. Following centrifugation, plasma is collected and assayed via an ELISA as per manufacturer’s instructions. Briefly, the insulin protein binds to an antibody that is associated with a reporter enzyme. The concentration of insulin is estimated by calculating the activity of the reporter enzyme.

Ex Vivo/In vitro: Insulin can be collected from media and measured via a commercially available ELISA kit. For example, media from plates containing primary murine pancreatic islets exposed to a high concentration of glucose for 1 hour is collected and assayed via an ELISA as per manufacturer’s instructions.

Alternative measure: C-peptide, that is co-secreted with insulin, can also be collected and measured in vivo/vitro as outlined above (i.e., commercially available ELISA kit) as a surrogate measure of insulin secretion. This is a common method of assessing insulin secretion in humans and is often measured as part of a glucose tolerance test (12). Briefly, following the administration of a bolus of glucose, blood is collected in sequential intervals, typically every 30-minutes, and C-peptide is measured.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Taxonomy: Insulin-secreting cells are found in vertebrates including mammals, fish, amphibians, reptiles, and birds (10). Functional insulin equivalent-secreting cells are found in invertebrates including insects, worms, snails, and molluscs (5, 10). Models of type 1 diabetes featuring impaired insulin secretion have been utilized in invertebrates (for example, see 8).

Life Stages: Insulin secretion is observed neonatally (3) and continues throughout life.

Sex Applicability: Insulin secretion occurs in both males and females (8). 

Evidence for Perturbation by Stressor

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

1.          Anno T, Kaneto H, Shigemoto R, Kawasaki F, Kawai Y, Urata N, Kawamoto H, Kaku K, Okimoto N. Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports. Endocrinol diabetes Metab case reports 2018: 17–155, 2018. doi: 10.1530/EDM-17-0155.

2.          Ashcroft FM, Harrison DE, Ashcroft SJH. Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells. Nature 312: 446–448, 1984. doi: 10.1038/312446a0.

3.          Aynsley-Green A, Hawdon JM, Deshpande S, Platt MW, Lindley K, Lucas A. Neonatal insulin secretion: implications for the programming of metabolic  homeostasis. Acta Paediatr Jpn  Overseas Ed 39 Suppl 1: S21-5, 1997.

4.          Coops K, White M. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 [Online]. Diabetologia 55: 2565–2582, 2012. https://pubmed.ncbi.nlm.nih.gov/22869320/.

5.          Falkmer S. Insulin production in vertebrates and invertebrates. Gen Comp Endocrinol 3: 184–191, 1972. doi: https://doi.org/10.1016/0016-6480(72)90147-5.

6.          Fu Z, R. Gilbert E, Liu D. Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Curr Diabetes Rev 9: 25–53, 2012. doi: 10.2174/15733998130104.

7.          Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc 1: 1–21, 2021. doi: 10.1002/cpz1.78.

8.          Gannon M, Kulkarni RN, Tse HM, Mauvais-Jarvis F. Sex differences underlying pancreatic islet biology and its dysfunction. Mol Metab 15: 82–91, 2018. doi: 10.1016/j.molmet.2018.05.017.

9.          Graham P, Pick L. Drosophila as a Model for Diabetes and Diseases of Insulin Resistance. Curr Top Dev Biol 121: 397–419, 2017. doi: 10.1016/bs.ctdb.2016.07.011.

10.        Heller SR. The Comparative Anatomy of Islets. Uppsala, Sweden: Springer, 2010.

11.        In’t Veld P, Marichal M. Microscopic Anatomy of the Human Islet of Langerhans. In: The Islets of Langerhans. Uppsala, Sweden: Springer, 2010.

12.        Leighton E, Sainsbury CA, Jones GC. A Practical Review of C-Peptide Testing in Diabetes. Diabetes Ther 8: 475–487, 2017. doi: 10.1007/s13300-017-0265-4.

13.        Li S, Huang S, Mo Z-N, Gao Y, Yang X-B, Chen X-J, Zhao J-M, Qin X. Generating a reference interval for fasting serum insulin in healthy nondiabetic  adult Chinese men. Singapore Med J 53: 821–825, 2012.

14.        Meglasson M, Matschinsky F. Pancreatic Islet Glucose Metabolism and Regulation of Insulin Secretion. Diabetes Metab Res Rev 2: 163–214, 1986.

15.        Slack JM. Developmental biology of the pancreas. Development 121: 1569–1580, 1995. doi: 10.1242/dev.121.6.1569.

16.        Smith GD, Pangborn WA, Blessing RH. The structure of T6 human insulin at 1.0 A resolution. Acta Crystallogr D Biol Crystallogr 59: 474–482, 2003. doi: 10.1107/s0907444902023685.

17.        Tohidi M, Ghasemi A, Hadaegh F, Derakhshan A, Chary A, Azizi F. Age- and sex-specific reference values for fasting serum insulin levels and insulin  resistance/sensitivity indices in healthy Iranian adults: Tehran Lipid and Glucose Study. Clin Biochem 47: 432–438, 2014. doi: 10.1016/j.clinbiochem.2014.02.007.

18.        Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol 217: 2273–2289, 2018. doi: 10.1083/jcb.201802095.

19.        Wiser O, Trus M, Hernández A, Renström E, Barg S, Rorsman P, Atlas D. The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci U S A 96: 248–253, 1999. doi: 10.1073/pnas.96.1.248.

20.        Yang SN, Berggren PO. The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology. Endocr Rev 27: 621–676, 2006. doi: 10.1210/er.2005-0888.

21.          Yang SN, Larsson O, Bränström R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Köhler M, Meister B, Berggren PO. Syntaxin 1 interacts with the LD subtype of voltage-gated Ca2+ channels in pancreatic β cells. Proc Natl Acad Sci U S A 96: 10164–10169, 1999. doi: 10.1073/pnas.96.18.10164.