Aop: 393


A descriptive title which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Acetylcholine esterase inhibition leading to type 2 diabetes

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
AChE inhibition leading to T2D

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help


List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Geronimo Matteo (1) (2)

1: Department of Biology, University of Ottawa 2: Environmental Health Science and Research Bureau, Health Canada

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Arthur Author   (email point of contact)


List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Arthur Author


The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on January 10, 2022 06:14
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Acetylcholinesterase (AchE) Inhibition April 29, 2020 17:21
Impaired, insulin secretion June 24, 2021 14:46
Type 2 diabetes June 24, 2021 15:28
Hyperglycemia June 24, 2021 15:05
AchE Inhibition leads to Impaired, insulin secretion June 15, 2021 14:00
AchE Inhibition leads to Hyperglycemia June 25, 2021 08:21
Impaired, insulin secretion leads to Hyperglycemia June 15, 2021 14:00
Hyperglycemia leads to T2D June 21, 2021 11:37


In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Epidemiological evidence suggests that exposure to organophosphate pesticides (OPPs), known acetylcholine esterase (AChE) inhibitors, is associated with hyperglycemia and type 2 diabetes (T2D). This is supported by in vitro/ex vivo and in vivo data that highlights OPP exposure causing impaired insulin secretion and hyperglycemia, respectively. A potential pathway that links AChE inhibition to T2D is proposed.

Inhibition of AChE is associated with suppressed insulin secretion in the β-cells of the islets of Langerhans of the endocrine pancreas in response to changes to blood nutrient levels. Given the role of insulin as an anabolic peptide, impaired insulin secretion results in the inability to maintain blood glucose homeostasis leading to hyperglycemia. Chronic hyperglycemia is characteristic of metabolic disorders and if left untreated, can develop into T2D. T2D is a disorder that negatively impacts quality of life and causes significant damage to every organ system in the body.

The weight of evidence for AChE leading to impaired insulin secretion is moderate as there is some biological plausibility and significant in vitro/ex vivo and in vivo experimental data. The weight of evidence of impaired insulin secretion leading to hyperglycemia and the latter leading to T2D is high as the biological plausibility is well elucidated and the data is homogenous for these event relationships.

This AOP has implications for regulators as rates of T2D are increasing throughout the developed and developing world causing significant burden on financial and health care systems.

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 12 Acetylcholinesterase (AchE) Inhibition AchE Inhibition
3 KE 1867 Impaired, insulin secretion Impaired, insulin secretion
4 KE 1868 Hyperglycemia Hyperglycemia
5 AO 1873 Type 2 diabetes T2D

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help
Title Adjacency Evidence Quantitative Understanding
AchE Inhibition leads to Hyperglycemia non-adjacent Moderate Low

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help


The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
3 to < 6 years Moderate
6 to < 11 years Moderate
11 to < 16 years Moderate
16 to < 21 years Moderate
Adult High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. 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

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Male High
Female High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Taxonomy: The domain limiting KE is the AO (T2D). While diabetic-like pathology exists in mammals and invertebrate models of metabolic dysfunction have been developed, T2D is clinically defined as a human disease.

Life Stages: While T2D is traditionally defined as an adult-onset disease (1), children as young as 4 years old have been diagnosed in Canada (14) and rates of child T2D have been increasing globally (17).

Sex: While T2D is more common in men, it also occurs in women (18).

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

There is high weight of evidence that impaired insulin secretion is essential for hyperglycemia and T2D. The weight of evidence is high as the biological plausibility is established and the quantitative understanding is understood. Chemicals that decrease function or destroy pancreatic β-cells impair nutrient-stimulated insulin secretion and cause in hyperglycemia in mammalian models. Importantly, restoration of β-cell function and/or population restores nutrient-stimulated insulin secretion and causes blood glucose to approach normoglycemia.

For example, streptozotocin-mediated destruction of pancreatic β-cells is a firmly established method for studying impaired insulin secretion, hyperglycemia, and diabetic-pathology in animal models (6). Select reports detailing partial or complete reversal of impaired nutrient-stimulated insulin secretion and subsequent normoglycemia following streptozotocin-mediated destruction of β-cells are highlighted.

  • Exposure to flavonoids isolated from Oreocnide integrifolia in mice (sex not specified) leaves dose-dependently restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (2).
  • Exposure to pancreatic endoplasmic reticulum kinase in male mice partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (7).
  • Exposure to dipeptidyl peptidase-4 inhibitors in male mice restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (9, 16). This effect was dose-dependent in one study (9).
  • Exposure to the flavonoid naringenin in male mice partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (11).
  • Co-exposure to exenatide (a glucagon-like peptide-1 receptor agonist) and leptin in male mice restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (13).
  • Exposure to OGT2115 (a heparanase inhibitor) in male mice partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (15).
  • Exposure to Catharanthus roseus leaf powder in male rats partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to controls (12).
  • Adenovirus-mediated exposure to the transcription factor neurogenin 3 in mice (sex not specified) partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia in rats relative to controls (20).
  • Calorie restriction in male rats partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to rats fed ad libitum (21).
  • Genetic knock-down of soluble epoxide hydroxylase in male mice partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to wildtype animals (8).
  • Genetic knock-down of small heterodimer partner in male mice partially restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to wildtype mice (10).

Using a genetic model of diabetes (db/db male mice), vindoline (an alkaloid found in Catharanthus roseus) exposure restored nutrient-stimulated insulin secretion and decreased hyperglycemia relative to untreated animals (19).   

In humans living with insulin-dependent diabetes (type 1 diabetes or late-stage T2D) pancreatic islet transplantation to hepatic tissue is increasingly successful at restoring nutrient-stimulated insulin secretion, ameliorating hyperglycemia, and partially reversing the diabetic pathology (2, 4, 5).

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

Overall, the collective biological plausibility for this AOP is low to moderate and empirical evidence is moderate. The biological plausibility KE1 to KE2 and KE2 to AO is strongly established and there is substantial empirical evidence (mainly incidence concordance) to support these relationships.

This AOP is limited by the low biological plausibility and moderate empirical evidence (mainly incidence concordance) to support MIE to KE1. The majority of studies reviewed and those in literature utilize OPPs as AChE inhibitors. However, these chemicals may activate alternative pathways to impair insulin secretion and cause hyperglycemia as AChE knock-out mice are normoglycemic. Future experiments where AChE loss of function is reversed (via genetic and/or pharmacological intervention) are encouraged to better establish biological plausibility. Therefore, future iterations of this AOP may change as more evidence is acquired/reviewed to elucidate the relationship between AChE inhibition and impaired insulin secretion.

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help


Summary of Bio. Plausibility Evidence

WOE call

MIE to KE1

AChE inhibition leads to impaired insulin secretion

The mechanism by which AChE inhibition results in diminished insulin secretion is not fully understood. However, increased cholinergic signaling is associated with potentiated insulin secretion. Given that AChE increases cholinergic signaling, these data are contradictory and require further research. 


KE1 to KE2

Impaired insulin secretion leads to hyperglycemia

Dysfunction and/or damage to β-cells, the primary insulin secreting cells, impairs the ability to adequately respond to changes to blood nutrients levels and secrete insulin accordingly. In turn, this reduces the ability to anabolize nutrients like glucose leading to excess glucose in the blood.


KE2 to AO

Hyperglycemia leads to T2D

The inability to maintain glucose homeostasis resulting in excessive blood glucose is a defining symptom of T2D. Hyperglycemia furthers diabetic etiology by damaging all organ systems.  



Summary of Empirical Evidence

WOE call

MIE to KE1

AChE inhibition leads to impaired insulin secretion

There are several in vitro/ex vivo experimental studies that highlight the inhibitory effect of AChE inhibitors on nutrient-stimulated insulin secretion. Further, there are some in vivo experimental studies that associate AChE inhibitor exposure with hypoinsulinemia.


KE1 to KE2

Impaired insulin secretion leads to hyperglycemia

There is substantial in vitro/ex vivo and in vivo evidence as well as human data that support that impaired nutrient-stimulated insulin secretion results in the inability to maintain blood glucose homeostasis leading to hyperglycemia.


KE2 to AO

Hyperglycemia leads to T2D

There is substantial human and in vivo experimental evidence to support that hyperglycemia is a characteristic symptom of and leads to T2D. 



Summary of Quantitative Understanding

WOE call

MIE to KE1

AChE inhibition leads to impaired insulin secretion

The quantitative relationship between AChE inhibition and impaired insulin is not well understood. Most studies use OPP exposure as a surrogate for AChE inhibition and do not measure AChE activity. Further, insulin secretion differs between stimuli, species, and experimental conditions. These factors make understanding the degree of change necessary in AChE activity to affect insulin secretion difficult to elucidate.  


KE1 to KE2

Impaired insulin secretion leads to hyperglycemia

The quantitative relationship between insulin secretion and blood glucose is well understood. In most studies reviewed, decreases in blood insulin are associated with a dose-dependent increase in hyperglycemia.


KE2 to AO

Hyperglycemia leads to T2D

The quantitative relationship between blood glucose and T2D is well established. Blood glucose concentrations beyond established thresholds is considered hyperglycemia and part of the diagnostic criterion of T2D. 


Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help


List the bibliographic references to original papers, books or other documents used to support the AOP. More help

1.          ADA (American Diabetes Association). American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 33 Suppl 1: S62–S69, 2010. doi: 10.2337/dc10-S062.

2.          Anazawa T, Okajima H, Masui T, Uemoto S. Current state and future evolution of pancreatic islet transplantation. Ann Gastroenterol Surg 3: 34–42, 2018. doi: 10.1002/ags3.12214.

3.          Ansarullah, Bharucha B, Dwivedi M, Laddha NC, Begum R, Hardikar AA, Ramachandran A V. Antioxidant rich flavonoids from Oreocnide integrifolia enhance glucose uptake and insulin secretion and protects pancreatic β-cells from streptozotocin insult. BMC Complement Altern Med 11: 126, 2011. doi: 10.1186/1472-6882-11-126.

4.          Bertuzzi F, De Carlis L, Marazzi M, Rampoldi AG, Bonomo M, Antonioli B, Tosca MC, Galuzzi M, Lauterio A, Fava D, Dorighet P, De Gasperi A, Colussi G. Long-term Effect of Islet Transplantation on Glycemic Variability. Cell Transplant 27: 840–846, 2018. doi: 10.1177/0963689718763751.

5.          Bruni A, Gala-Lopez B, Pepper AR, Abualhassan NS, Shapiro AJ. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab Syndr Obes 7: 211–223, 2014. doi: 10.2147/DMSO.S50789.

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

7.          Kim MJ, Kim MN, Min SH, Ham DS, Kim JW, Yoon KH, Park KS, Jung HS. Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes. Metabolism 97: 87–91, 2019. doi: 10.1016/j.metabol.2018.12.007.

8.          Luo P, Chang HH, Zhou Y, Zhang S, Hwang SH, Morisseau C, Wang CY, Inscho EW, Hammock BD, Wang MH. Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis. J Pharmacol Exp Ther 334: 430–438, 2010. doi: 10.1124/jpet.110.167544.

9.          Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, Feng Y, Zhu L, Li C, Howard AD, Moller DE, Thornberry NA, Zhang BB. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic β-cell mass and function in a rodent model of type 2 diabetes. Diabetes 55: 1695–1704, 2006. doi: 10.2337/db05-1602.

10.        Noh JR, Hwang JH, Kim YH, Kim KS, Gang GT, Kim SW, Kim DK, Shong M, Lee IK, Choi HS, Lee CH. The orphan nuclear receptor small heterodimer partner negativelyregulates pancreatic beta cell survival and hyperglycemia in multiplelow-dose streptozotocin-induced type 1 diabetic mice. Int J Biochem Cell Biol 45: 1538–1545, 2013. doi: 10.1016/j.biocel.2013.05.004.

11.        Rajappa R, Sireesh D, Salai MB, Ramkumar KM, Sarvajayakesavulu S, Madhunapantula SR V. Treatment with naringenin elevates the activity of transcription factor Nrf2 to protect pancreatic β-cells from streptozotocin-induced diabetes in vitro and in vivo. Front Pharmacol 9: 1–20, 2019. doi: 10.3389/fphar.2018.01562.

12.        Rasineni K, Bellamkonda R, Singareddy SR, Desireddy S. Antihyperglycemic activity of Catharanthus roseus leaf powder in  streptozotocin-induced diabetic rats. Pharmacognosy Res 2: 195–201, 2010. doi: 10.4103/0974-8490.65523.

13.        Sakai T, Kusakabe T, Ebihara K, Aotani D, Yamamoto-Kataoka S, Zhao M, Gumbilai VMJ, Ebihara C, Aizawa-Abe M, Yamamoto Y, Noguchi M, Fujikura J, Hosoda K, Inagaki N, Nakao K. Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet. Am J Physiol - Endocrinol Metab 307: E712–E719, 2014. doi: 10.1152/ajpendo.00272.2014.

14.        Sawatsky L, Halipchuk J, Wicklow B. Type 2 diabetes in a four-year-old child. CMAJ 189: E888–E890, 2017. doi: 10.1503/cmaj.170259.

15.        Song WY, Jiang XH, Ding Y, Wang Y, Zhou MX, Xia Y, Zhang CY, Yin CC, Qiu C, Li K, Sun P, Han X. Inhibition of heparanase protects against pancreatic beta cell death in streptozotocin-induced diabetic mice via reducing intra-islet inflammatory cell infiltration. Br J Pharmacol 177: 4433–4447, 2020. doi: 10.1111/bph.15183.

16.        Takeda Y, Fujita Y, Honjo J, Yanagimachi T, Sakagami H, Takiyama Y, Makino Y, Abiko A, Kieffer TJ, Haneda M. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia 55: 404–412, 2012. doi: 10.1007/s00125-011-2365-4.

17.        Temneanu OR, Trandafir LM, Purcarea MR. Type 2 diabetes mellitus in children and adolescents: a relatively new clinical problem within pediatric practice [Online]. J Med Life 9: 235–239, 2016.

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