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Event: 1868

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

Hyperglycemia

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
Hyperglycemia

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

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
blood

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

Hyperglycemia is the inability to effectively lower blood glucose post-prandially and maintain glucose homeostasis. Hyperglycemia is a characteristic symptom of metabolic disorders including metabolic syndrome and type 2 diabetes (T2D) (11).

Blood glucose is primarily modulated by two pancreatic endocrine hormones, insulin and glucagon (13). The former is an anabolic peptide hormone secreted post-prandially by β-cells that lowers blood glucose by increasing glycogen storage in muscle and hepatic tissue. The latter is a catabolic peptide hormone secreted during fasting by α-cells that increases blood glucose by metabolizing stored glycogen.

The inability to maintain blood glucose homeostasis can occur due to damage to pancreatic β-cells and subsequent inability to secrete insulin in response to nutrients (11), and/or tolerance to the anabolic effects of insulin at target tissues known as insulin resistance (14).

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). ?

In humans, hyperglycemia is characterized as a random blood glucose of ≥ 200 mg/dL (11.1 mmol/L) (17).

In research animals, hyperglycemia is typically characterized as a significant difference in fasted blood glucose relative to a control group. To get a more dynamic understanding of blood glucose homeostasis, a glucose tolerance test can be performed. Briefly, following the administration of a bolus of glucose, blood glucose can be measured sequentially, typically in 15-minutes intervals for research animals (1) and 30-minutes in humans (6), for 120 minutes. Individual time points can be compared (i.e., 15-minutes post-glucose exposure) relative to controls as well as the overall area under the curve.

The most basic form of measuring blood glucose is applying a droplet of blood onto a glucometer. Most glucometers utilize the glucose oxidase method (10).

Glucose oxidase assay: The concentration of glucose in a sample, blood plasma or media, can be estimated using a commercially available glucose oxidase assay kit. Briefly, the sample is exposed to glucose oxidase that oxidizes glucose into gluconolactone and produces hydrogen peroxide as a by-product. The hydrogen peroxide reacts with a dye and the resulting colour change is measured using a colorimeter and used to estimate glucose concentration (16). A similar method utilizes a Beckman oxygen electrode to measure oxygen consumption to estimate glucose concentration (16).

Hexokinase assay: The concentration of glucose in a sample, blood plasma or media, can be estimated using a commercially available hexokinase assay kit. Briefly, the sample is exposed to hexokinase in the presence of adenosine triphosphate to produce glucose-6-phosphate (G6P) and adenosine diphosphate (3). The subsequent oxidation of G6P by G6P dehydrogenase to 6-phosphogluconate is coupled to the reduction of nicotinamide adenine dinucleotide (NAD+/NADH). The amount of reduction of NAD+ to NADH is used to estimate the concentration of glucose.

Ferricyanide oxidation assay: The concentration of glucose in a sample, blood plasma or media, can be estimated by oxidizing to gluconic acid with ferricyanide. Briefly, the sample is exposed to a ferricyanide salt and the amount of reduced ferricyanide can be determined by iodometric titration to estimate the concentration of glucose (5).

Glycated hemoglobin assay: The concentration of glycated hemoglobin in blood can be estimated using a variety of procedures that have been standardized (7).

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: Both vertebrates (15) and invertebrates (2, 12) use blood (or functional equivalents like hemolymph) that carry carbohydrates like glucose. Invertebrate models of hyperglycemia have been developed (for example, see 7, 8).

Life Stages: Glucose (or functional equivalents) is present in blood at all life stages and its concentration in serum can vary.

Sex Applicability: Both male and females have glucose in their blood (for example, see 4).

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.          Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP, Consortium NIHMMPC. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 3: 525–534, 2010. doi: 10.1242/dmm.006239.

2.          Caldari-Torres C, Banta-Long W, Bruss A, Choi E, Fiegel H, Jollis MS, Ly S, Viswanathan S. Hemolymph Glucose Levels as a Measure of Crayfish Stress: A Methodology Using a Human Glucometer. FASEB J 32: lb224–lb224, 2018. doi: https://doi.org/10.1096/fasebj.2018.32.1_supplement.lb224.

3.          Dickson LM, Buchmann EJ, Janse Van Rensburg C, Norris SA. The impact of differences in plasma glucose between glucose oxidase and hexokinase methods on estimated gestational diabetes mellitus prevalence. Sci Rep 9: 7238, 2019. doi: 10.1038/s41598-019-43665-x.

4.          Faerch K, Borch-Johnsen K, Vaag A, Jørgensen T, Witte DR. Sex differences in glucose levels: a consequence of physiology or methodological  convenience? The Inter99 study. Diabetologia 53: 858–865, 2010. doi: 10.1007/s00125-010-1673-4.

5.          Hulme AC, Narain R. The ferricyanide method for the determination of reducing sugars: A modification of the Hagedorn-Jensen-Hanes technique. Biochem J 25: 1051–1061, 1931. doi: 10.1042/bj0251051.

6.          Jagannathan R, Neves JS, Dorcely B, Chung ST, Tamura K, Rhee M, Bergman M. The Oral Glucose Tolerance Test: 100 Years Later. Diabetes Metab Syndr Obes 13: 3787–3805, 2020. doi: 10.2147/DMSO.S246062.

7.          Little RR. Glycated Hemoglobin Standardization  – National Glycohemoglobin Standardization Program (NGSP) Perspective. 41: 1191–1198, 2003. doi: doi:10.1515/CCLM.2003.183.

8.          Matsumoto Y, Sumiya E, Sugita T, Sekimizu K. An invertebrate hyperglycemic model for the identification of anti-diabetic drugs. PLoS One 6: e18292–e18292, 2011. doi: 10.1371/journal.pone.0018292.

9.          Musselman LP, Fink JL, Baranski TJ. Similar effects of high-fructose and high-glucose feeding in a Drosophila model of obesity and diabetes [Online]. PLoS One 14: e0217096, 2019. https://doi.org/10.1371/journal.pone.0217096.

10.        Norouzi P, Faridbod F, Larijani B, Ganjali MR. Glucose biosensor based on MWCNTs-gold nanoparticles in a nafion film on the glassy carbon electrode using flow injection FFT continuous cyclic voltammetry. Int J Electrochem Sci 5: 1213–1224, 2010.

11.        Porte Jr. D. Mechanisms for Hyperglycemia in the Metabolic Syndrome: The Key Role of β-Cell Dysfunction. Ann N Y Acad Sci 892: 73–83, 1999. doi: https://doi.org/10.1111/j.1749-6632.1999.tb07786.x.

12.        Principe SC, Augusto A, Costa TM. Point-of-care testing for measuring haemolymph glucose in invertebrates is not a valid method. Conserv Physiol 7: coz079–coz079, 2019. doi: 10.1093/conphys/coz079.

13.        Röder P V, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 48: e219–e219, 2016. doi: 10.1038/emm.2016.6.

14.        Tomas E, LIn Y-S, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. Hyperglycemia and Insulin Resistance: Possible Mechanisms. Ann N Y Acad Sci 967: 43–51, 2002. doi: https://doi.org/10.1111/j.1749-6632.2002.tb04262.x.

15.        Umminger BL. Relation of whole blood sugar concentrations in vertebrates to standard metabolic rate. Comp Biochem Physiol Part A Physiol 56: 457–460, 1977. doi: https://doi.org/10.1016/0300-9629(77)90267-5.

16.        Yuen VG, McNeill JH. Comparison of the glucose oxidase method for glucose determination by manual assay and automated analyzer. J Pharmacol Toxicol Methods 44: 543–546, 2000. doi: https://doi.org/10.1016/S1056-8719(01)00117-4.

17.        Diagnosis and classification of diabetes mellitus. Diabetes Care 33, 2010. doi: 10.2337/dc10-S062.