Suicide&nbsp;and attempted suicide by insulin: A systematic review

Majd A. Assad; Fatimah A. Alawami; Raihanah S. Al Khatem; Zahra Y. Al Daif; Zainb A. Alrumaih; Ritesh G. Menezes

doi:10.12688/f1000research.129331.1

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Systematic Review

Suicide and attempted suicide by insulin: A systematic review

[version 1; peer review: 1 approved with reservations]

Majd A. Assad¹, Fatimah A. Alawami ¹, Raihanah S. Al Khatem¹, Zahra Y. Al Daif¹, Zainb A. Alrumaih¹, Ritesh G. Menezes¹

Majd A. Assad¹, Fatimah A. Alawami ¹, [...] Raihanah S. Al Khatem¹, Zahra Y. Al Daif¹, Zainb A. Alrumaih¹, Ritesh G. Menezes¹

PUBLISHED 16 Jan 2023

Author details Author details

¹ College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 34212, Saudi Arabia

Majd A. Assad
Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation

Fatimah A. Alawami
Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation

Raihanah S. Al Khatem
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Zahra Y. Al Daif
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Zainb A. Alrumaih
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Ritesh G. Menezes
Roles: Conceptualization, Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Intentional insulin overdose either in people with diabetes or without can be used to attempt suicide. Massive insulin administration may result in coma and unexplained hypoglycemia. In this study, we aim at reviewing the demographic data of suicidal cases, the relation of psychiatric illness to dying by suicide and attempting suicide using insulin, route of insulin administration and outcome, post-mortem findings in suicide by insulin and collaborative evidence, initial presentation, blood glucose level and complications in attempting suicide cases.
Methods: PubMed, Web of Science, and Scopus databases were searched on October 4, 2021, using a comprehensive strategy review. The following search terms were applied: (Insulin) AND (toxicity OR overdose OR toxicology OR poisoning OR intoxication) AND (Suicide OR attempted suicide OR Self-harm OR Self harm). The search strategy was set based on PRISMA guideline; 11 papers were eligible for inclusion and additional 23 studies were added from the citation search. All English articles related to suicide and attempted suicide using insulin were included and no specific timeline or filter was used. Any non-English article and accidental or homicidal cases were excluded from the review.
Results: The analysis included 179 victims, aged between 13 to 76 years with male predominance and people with diabetes, especially T1DM, having higher prevalence, with subcutaneous injection being the most common route of administration. In addition, psychiatric illnesses and multiple suicide attempts were identified in many cases besides the use of insulin in a combination with other medications.
Conclusions: Dying by suicide using insulin is uncommon, however, as diabetes mellitus prevalence increases worldwide, it is expected that intentional insulin overdose will also increase. Furthermore, psychiatric illnesses and easy access to insulin are important factors that should be put into consideration.

Keywords

suicide, attempted suicide, insulin, overdose, self-poisoning

Corresponding author: Fatimah A. Alawami

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2023 Assad MA et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Assad MA, Alawami FA, Al Khatem RS et al. Suicide and attempted suicide by insulin: A systematic review [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:59 (https://doi.org/10.12688/f1000research.129331.1) First published: 16 Jan 2023, 12:59 (https://doi.org/10.12688/f1000research.129331.1) Latest published: 16 Jan 2023, 12:59 (https://doi.org/10.12688/f1000research.129331.1)

Introduction

Suicide is considered one of the increasing public health problems. According to the World Health Organization (WHO), more than 700,000 people die by suicide each year. Even more, it is considered the fourth leading cause of death among adolescents aged 15 to 19 years. In 2019, when suicidal cases were analyzed based on the socioeconomic status of different countries, 77% of the total reported suicide cases were among low and middle-income countries. Besides, ingestion of pesticides, hanging, and firearms were the most commonly reported methods.¹

The incidence of suicide is believed to be the highest among adolescents and increases more among those experiencing stressors of abuse, conflicts, and bullying. Moreover, even though women tend to have more suicidal attempts, the incidence of men dying by suicide is higher due to their tendency to choose more lethal methods and higher lethality acts, which explains why women are more likely to survive each attempt.²^,³ Regarding the methods of suicide, hanging is the most common method used among women, while firearms are most commonly used by men, with hanging being the most fatal method among both.²^,³ Concerning the profession, a higher risk of suicide is found to be among physicians, particularly those who are female.⁴

Insulin is a polypeptide hormone that is secreted by β cells of the pancreas and regulated by glucose level in the blood, some amino acids, autonomic mediators, and other hormones. Artificial insulin is an exogenous insulin given to all patients with T1DM, and some patients with T2DM. Insulin can be divided into rapid-acting (lispro, lispro-aabc, glulisine, aspart, and faster aspart), short-acting (regular insulin), intermediate-acting (neutral protamine hagedorn (NPH)), long-acting (glargine, detemir, and degludec), and premixed insulin.⁵^,⁶ Subcutaneous injection is the most commonly used route of administration of insulin, which can be delivered via various methods, including, vials, syringes, insulin pens, and insulin pumps.⁷ Since there is no safe medication, artificial insulin carries its side effects, and hypoglycemia is the most common one.⁶

Few cases of insulin overdose are reported every year, which can be accidental or intentional for the purpose of dying by suicide. Surprisingly, these reported cases include not only individuals with diabetes of both types but also those who do not have diabetes. People with massive insulin overdose might develop neurological complications, such as hypoglycemic coma, which can be reversible or result in death.⁸^,⁹

Although there are no clear studies stating that diabetes mellitus is a known risk factor for suicide, it is found that individuals with T1DM have 11 times higher risk of attempting suicide than people who do not have diabetes. Moreover, other studies conclude that suicidal ideation in people with diabetes mellitus was associated with these individuals not taking their medication.¹⁰

As insulin can be used as a method to attempt suicide, we aim in this paper to analyze research published on attempting or dying by suicide with insulin. The review focuses on six dimensions, which are the demographic data of suicidal cases, the relation of psychiatric illness to dying by and attempting suicide using insulin, route of insulin administration and outcome, post-mortem findings in suicide by insulin and collaborative evidence, initial presentation, blood glucose level and complications in attempting suicide cases.

Methods

Databases and search string

Articles concerning suicide and attempted suicide by insulin were identified by searching Scopus (RRID:SCR_022559), PubMed (RRID:SCR_004846), and Web of Science (RRID:SCR_022706) databases. The search was done on October 4, 2021, and the following search terms were applied: (Insulin) AND (toxicity OR overdose OR toxicology OR poisoning OR intoxication) AND (suicide OR attempted suicide OR self-harm OR self harm). The search strategy was set based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline 2020.¹¹ The study was not registered in the International Prospective Register of Systematic Reviews (PROSPERO).

Inclusion and exclusion criteria

Inclusion criteria were set to include all English articles that focused on cases of suicide and suicide attempts using insulin with or without any other medication and no restrictions were used regarding the timeline and study design. Studies that reported homicides and cases of accidental (unintentional) overdoses using insulin and non-English articles were excluded from this review.

Selection process and data collection process

The search was done manually by two independent reviewers (MAA, FAA). In the preliminary search in PubMed, Web of Science, and Scopus, 216, 193, and 16 records were identified, respectively. Titles and abstracts of all records were evaluated for relevance. This was followed by a full-text assessment to ensure the eligibility of the records to be included in the review (Figure 1). Other reviewers (RSA, ZYA, ZAA, RGM) were consulted regarding any search issue, if present. Automation tools were not used in the selection process and data collection process.

Figure 1. A PRISMA flow chart for the literature search.

Results

The literature search identified a total of 425 records from PubMed (n = 216), Web of Science (n = 193), and Scopus (n = 16). After removing 196 duplicate records, an initial screening of 229 records was done and led to the exclusion of 187 articles. Further, a full-text review excluded 31 articles due to the following reasons: non-English articles (n = 29) (Derobert L et al.,¹² Domart A et al.,¹³ Lenhardt A,¹⁴ Richter R,¹⁵ Szabo Z et al.,¹⁶ Chlud K,¹⁷ Sachsse B,¹⁸ Bourgeois M et al.,¹⁹ Vincent V et al.,²⁰ Creutzfeldt W et al.,²¹ Euler-Rolle J et al.,²² Stofer A et al.,²³ Tourniaire J et al.,²⁴ Holldorf L et al.,²⁵ Marigo S et al.,²⁶ Bourgeois M,²⁷ Stefan J,²⁸ Zilker T et al.,²⁹ Schneider V et al.,³⁰ Hambrecht M et al.,³¹ Logemann E et al.,³² von Albert H et al.,³³ Szponar J et al.,³⁴ Wehner F et al.,³⁵ Nikolić S et al.,³⁶ Klimaszyk D et al.,³⁷ Uesugi K,³⁸ Chen L et al.,³⁹ Tong F et al.,⁴⁰ and articles that could not be retrieved (n = 2) (Lionte C et al.,⁴¹ Arbouche N et al.⁴²). From the primary search of the databases 11 records met the inclusion criteria. Also, an additional 23 records were identified by screening the references of the included studies from the primary search. Eventually, a total of 34 articles met the inclusion criteria and were considered in the present review.⁸^,⁹^,⁴³^–⁷³ A PRISMA flow chart for the literature search is shown in Figure 1.

The analyzed studies were published in a time period between 1934 and 2020. Most studies were case reports (n = 22), while few were case series (n = 3), retrospective cohort (n = 2), prospective study (n = 1), hospital based (n = 2), population based (n = 1), case-control (n = 1), case conference (n = 1) and cross-sectional (n = 1) studies. A summary of the important results is presented in Table 1.

Table 1. Demographic data, psychiatric illness, suicidal methods and outcomes.

Reference	Country	Year	Study design (no. of cases)	Age (year)	Sex	Diabetes status	Psychiatric and behavioral illnesses	Method used	Route	Dose of insulin (Unit)	Outcomes (suicide or attempted suicide)
Beardwood.⁴³	USA^a	1934	Case report (1)	50	Female	Diagnosed with diabetes	Depression	Insulin	NM^b	400	Attempted suicide
Vogl et al.⁴⁴	USA^a	1949	Case report (1)	63	Male	Diagnosed with diabetes	Depression, 1 previous suicide attempt with insulin	Protamine zinc insulin	SC^c	2000	Attempted suicide
Blotner.⁴⁵	USA^a	1954	Case report (1)	46	Male	Did not have diabetes	No	Insulin Morphine Dilaudid	NM^b	200	Attempted suicide
Hänsch et al.⁴⁶	Belgium	1977	Case report (1)	27	Male	T1DM^d	Depression	Insulin	Injection	1200	Suicide
Martin et al.⁴⁷	Australia	1977	Case series (4)	1. 20 2. 47 3. 22 4. 53	1. Female 2. Female 3. Male 4. Female	T1DM^d (4)	Depression (4)	1. Insulin (ultralente) 2. Insulin (NPH) and Diazepam 3. Insulin (NPH), Alcohol and Barbiturate 4. Insulin (semilente) and Nitrazepam	Injection	3000 240 1600 80	Attempted suicide
Campbell et al.⁴⁸	UK^e	1982	Case report (1)	21	Male	T1DM^d	Substance use (Alcohol)	Insulin (soluble) Protamine zinc insulin	SC^c	200 200	Attempt suicide
Levine et al.⁴⁹	UK^e	1982	Case report (1)	26	Male	T1DM^d	Substance use (Alcohol)	Insulin Actrapid insulin and Leo Retard	SC^c	800 1600	Attempt suicide
Gin et al.⁵⁰	France	1983	Case report (1)	70	Female	T1DM^d	NM^b	Insulin	SC^c	400	Attempt suicide
Jefferys et al.⁵¹	UK^e	1983	Prospective (18)	NM^b	NM^b	Diagnosed with diabetes (7) Did not have diabetes (4) NM^b (7)	NM^b	Insulin (ultratard) (2) Insulin (monotard) (1) Insulin (zinc suspension lente) (1) Insulin (isophane) (3) Insulin (protamine zinc) (1) Insulin (semilente) (1) Insulin (actrapid) (1) Insulin (8)	NM^b	NM^b	Suicide (6) Attempt suicide (12)
Critchley et al.⁵²	Scotland	1984	Hospital-based study (20)	16-43 (15) NM (5)	Male (8) Female (7) NM (5)	Did not have diabetes (3) Relative of person with diabetes (2) Nurse (1) T1DM^c (12)	NM^b	Insulin - Insulin alone (12) - Mixtures of Insulins (8)	NM^b	100-6000	Attempt suicide (18), Suicide (2)
Kaminer et al.⁵³	USA^a	1988	Case series (2)	1. 13 2. 16	Female (2)	T1DM^d	1. Dysthymic disorder and parent-child problem- substance use disorder 2. Major depression and borderline personality disorder	1. Insulin (regular) 2. Insulin (regular)	SC^c	1. 150 2. 600	Attempt suicide
Cooper.⁵⁴	UK^e	1991	Case report (1)	56	Male	Did not have diabetes	Major depression occurring in mixed personality disorder with prominent borderline and narcissistic features	Insulin	Injection	NM^b	Attempt suicide
Patel.⁵⁵	UK^e	1992	Case report (1)	Late twenties	Female	Did not have diabetes	Depression and personality disorder	Insulin Temazepam	NM^b	NM^b	Suicide
Roberge et al.⁵⁶	USA^a	1992	Case conference (1)	33	Male	T1DM^d	Depression	Insulin (regular + NPH)	Injection	NM^b	Attempt suicide
Fasching et al.⁵⁷	Austria	1994	Case report (1)	35	Male	T1DM^d	Manic-depressive disorder	Insulin (regular + NPH) Flunitrazepam	SC^c	750 750	Attempt suicide
Kernbach-Wightona et al.⁵⁸	Germany	1998	Retrospective cohort study (12)	21-61	Male (8) Female (4)	Did not have diabetes (2) Relative of a person with diabetes (2) T1DM^d (6) T2DM^f (3) NM^b (1)	Depression/previous suicide attempt (8) Drug dependence (1) Substance use (Alcohol) (4)	Insulin	NM^b	1220 (mean)	Suicide
Winston.⁵⁹	USA^a	2000	Case series (4)	1. 48 2. 36 3. 24 4. 44	1. Male 2. Female 3. Male 4. Male	Did not have diabetes	1. NM^b 2. NM^b 3. Depression 4. Depression and substance use (Alcohol)	1. Insulin (NPH) 2. Insulin 3. Insulin 4. Insulin (Novolin) and Diphenhydramine	Injection	1. 100 2. NM^b 3. NM^b 4. 100	Suicide
Junge et al.⁶⁰	Germany	2000	Case report (1)	68	Male	Did not have diabetes	Depression	Insulins Beta blocker (Metoprolol)	Injection	NM^b	Suicide
Jolliet P et al.⁶¹	Switzerland	2001	Case report (1)	48	Female	Did not have diabetes	No	Insulin Short acting Long acting Clomipramine Diazepam Oxazepam Flurazepam Acetylsalicylate	SC^c	1000 1000	Attempt suicide
Tofade et al.⁶²	USA^a	2004	Case report (1)	33	Female	Did not have diabetes, relative of a person with diabetes	Obsessive-compulsive disorder Depression	Insulin Glargine Aspart	SC^c	300 200	Attempt suicide
Boileau et al.⁶³	France	2006	Hospital-based study (7)	Adolescents	Females and males (*)	T1DM^d	NM^b	Insulin	Injection	1000 – 4000	Attempt suicide
Wong et al.⁶⁴	South China	2006	Case report (1)	32	Female	Did not have diabetes	Depression	Insulin (Protaphane)	Injection	210	Attempt suicide
Mégarbane et al.⁶⁵	France	2007	Retrospective Study (25)	26-67	Male (11) Female (14)	Diabetic (13)	Psychiatric history (20)	Insulin Rapid-acting (14) Intermediate- or slow-acting (13) Both (2) Benzodiazepines (17)	Injection	135-988	Suicide (2) Attempt suicide (23)
Fuller et al.⁶⁶	USA^a	2009	Case report (1)	37	Male	T1DM^d	Depression Substance use (Alcohol) Previous suicide attempt by insulin	Insulin Glargine	SC^c	150	Attempt suicide
Russell et al.¹⁰	USA^a	2009	Case report (1)	18	Female	T1DM^d	Reported panic attacks and social anxiety Substance use (clonazepam and cannabis daily) Two previous suicide attempts with insulin	Insulin	NM^b	NM^b	Attempt suicide
Lu et al.⁶⁷	USA^a	2011	Case report (1)	51	Female	T1DM^d	Schizoaffective disorder Borderline personality disorder Polysubstance use (alcohol, tobacco, and cocaine) Multiple previous suicide attempts (clonazepam, ziprasidone, trazodone)	Insulin Glargine	SC^c	2700	Attempt suicide
Schober et al.⁶⁸	Austria	2011	Cross sectional (55)	14-15	Male Female (*)	T1DM^d	The wish of uncontrolled binge eating, self-destructive behaviors in stress situations including suicidal ideation and attention seeking behavior to the parents or caregivers, in addition to the feeling of being high in hypoglycemia.	Insulin (55) Insulin overdose only (13) Insulin overdose and omission (42)	SC^c	NM^b	Attempt suicide
Gundgurthi et al.⁸	India	2012	Case report (1)	27	Female	Did not have diabetes, insulin was taken from hospital	Depression	Insulin	NM^b	NM^b	Attempt suicide
Löfman et al.⁶⁹	Finland	2012	Population based study (8)	27-56	Female (1) Male (7)	T1DM^d (6); T2DM^f (2)	Depression and substance use	Insulin Antidepressants Anxiolytics CVS drugs	NM^b	NM^b	Suicide
Doğan et al.⁷⁰	Turkey	2012	Case report (1)	76	Male	T2DM^f	Panic disorder Dementia	Insulin Glargine	SC^c	500	Attempt suicide
Svingos et al.⁹	USA^a	2013	Case report (1)	51	Male	Did not have diabetes, relative of a person with diabetes	Depression Two previous suicide attempts (one with chlordiazepoxide) Polysubstance use (primarily alcohol)	Insulin Aspart Lispro Insulin Aspart Lispro Glargine	Oral	3000	Attempt suicide
Palmiere et al.⁷¹	Switzerland	2015	Case control (1)	68	Female	Did not have diabetes	NM^b	Insulin (Insuman Rapid)	Injection	40	Suicide
Essafi et al.⁷²	Tunisia	2017	Case report (1)	49	Male	Did not have diabetes, relative of a person with diabetes	Behavioral disorder	Insulin Glargine	SC^c	500	Attempt suicide
Stein et al.⁷³	Israel	2020	Case report (1)	17	Female	T1DM^c	Anorexia nervosa (Purging type) Social anxiety disorder Depression Obsessive compulsive disorder	Insulin	NM^b	NM^b	Attempt suicide

a United States of America.

b Not mentioned.

c Subcutaneous.

d Type 1 Diabetes Mellitus.

e United Kingdom.

f Type 2 Diabetes Mellitus.

* The exact number of men and women. However, the article stated that the female percentage was significantly higher among those individuals.

** Among the 20 cases, only 15 individuals were with known age and sex, in the remaining five patients age and sex were not mentioned.

Demographic data of suicidal cases

The analysis included 179 people (Table 1). The age of these individuals ranged from 13 to 76 years. A total of 51 of them were men and 43 were women, while the rest were unknown (n = 85). Regarding work status, only 21 of the people mentioned their occupations, 16 of them were healthcare providers (physicians, nurses, anesthetists, pharmacists, and paramedics). Other occupations included students (n = 2), teacher (n = 1), and unemployed (n = 3).

The cases that were included in the various articles were reported from multiple countries, including: Austria (n = 56), France (n = 33), United Kingdom (n = 25), Germany (n =13), United States (n = 11), Switzerland (n = 2), Belgium (n = 1), South China (n = 1), Finland (n = 8), India (n = 1), Israel (n = 1), Scotland (n = 1), Australia (n = 1), Turkey (n = 1), and the only Arabic country was Tunisia (n = 1).

Concerning the diabetes mellitus status, the majority of the people had been diagnosed with diabetes (n = 130). Moreover, 35 did not have diabetes, seven were relatives of an individual with diabetes and for seven their diabetic status was not mentioned. In regard to type of diabetes mellitus, T1DM (n = 102) showed greater prevalence than T2DM (n = 21).

Relation of psychiatric illness to dying by and attempting suicide using insulin

In regard to psychiatric status, 67 of the individuals had a mental illness and 58 showed behavioral disturbances (Table 1). The highest prevalence of mental illnesses included depressive disorders (n = 29), followed by alcohol use disorder (n = 11), and other substance use (n = 5), including clonazepam and cannabis (n = 1), tobacco and cocaine (n = 1), while the rest of the substances were not mentioned. Other psychiatric illnesses included anxiety and panic disorders (n = 3), obsessive compulsive disorder (n = 2), borderline personality disorder (n = 3), manic-depressive disorder (n = 1), dysthymic disorder (n = 1), eating disorder (n = 1), and dementia (n = 1). Previous suicidal attempts were also reported among individuals who had a psychiatric illness (n = 12).

Route of insulin administration and outcome

Different routes of insulin administration were reported (Table 1), with the majority of cases (n = 68) using the subcutaneous route. Notably, oral administration of insulin was reported in one case in which an individual had a suicide attempt via ingesting a large amount of insulin vials. In 46 cases the route of administration was an injection and it was not mentioned in 64 of the cases.

Insulin injections in combination with other medications were reported in 28 of the cases. The most common medication reported was benzodiazepines (n = 23). Other medications were antidepressants (n = 3), anxiolytics (n = 2), morphine (n = 1), dihydromorphinone (n = 1), non-steroidal anti-inflammatory drugs (NSAIDs) (n = 1), antihistamine (n = 1), beta blockers (n = 1), barbiturate (n = 1), and cardiovascular system drugs (n = 1).

Out of all individuals who were included in the study (n = 179) the majority (n = 141) attempted suicide, while only a few (n = 38) were suicide cases.

Post-mortem findings in suicide by insulin and collaborative evidence

History and circumstances, including the scene of the act and suicidal notes, were mentioned in 22 out of 38 cases. In 14/22, needles and empty insulin vials were found at the scene. In one case, missing drugs from the individual’s cabinet were found, including a vial of Novolin 70/30, a syringe, and 12 capsules of 25 mg diphenhydramine. In addition, there were four individuals who left a suicide note at the scene, three out of them were written notes, and there was one case where verbal suicidal intent was mentioned.

The external examination of 19 of the cases showed evidence of injection sites in multiple sites of the body including gluteal region, antecubital fossa, umbilicus, and thighs. Some of these injections were new, and some were old ones. In one case, external examination showed evidence of vomitus at the corner of the mouth, fingernail cyanosis and petechiae.

Furthermore, autopsy was performed in 38 cases, gross findings of the pancreas, lung, brain and heart were reported. Pancreas findings included fibrosis and autolysis. Brain findings included hypoglycemic brain damage with cortical laminar necrosis, cerebral and mid-brain infarcts, and cerebral edema. Lung findings included an evidence of aspiration of gastric contents that was extending into intra-pulmonary compartment with acute congestion of the lung, whereas heart findings included the presence of epicardial petechiae. The rest of microscopic autopsy findings and toxicological analysis of the provided cases are summarized in Table 2.

Table 2. Investigations and autopsy findings pertinent to insulin toxicity.

Authors	History and circumstances	External examination	Autopsy findings		Toxicological analysis
Authors	History and circumstances	External examination	Gross	Microscopic	Toxicological analysis
Hänsch et al.⁴⁶	Scene Three empty insulin vials and empty ampules of distilled water, injection-needles and a little syringe Note Prescription-form with the following text: "I apologize for the troubles I have caused you. I have always meant well, but things always go wrong". Signed and dated	Injection sites Back of the left and the left gluteal zone	Pancreas Autolyzed	No suspicious traumatic lesions	Insulin: negative
Critchley et al.⁵²			Brain Hypoglycemic brain damage with cortical laminar necrosis. Cerebral and mid-brain infarcts (1 case)
Patel.⁵⁵	Scene Unused hypodermic needle and some nursing literature on AIDS was found in her room. A single Temazepam tablet was found in her bag with no suicidal note. No suspicious circumstances	Injection site Careful examination fails to reveal any injection needle mark. Others Evidence of vomitus at the corner of the mouth, fingernail cyanosis and petechial.	Lung aspiration of gastric contents extending into intra-pulmonary compartment with acute congestion of the lung. Heart epicardial petechial. Brain Slightly edematous	Lung Fine pleural petechial hemorrhage and acute inflammatory reaction to the aspirated material in the distal bronchioles.	Blood Insulin: 1,257 μunits/ml
Kernbach-Wighton et al.⁵⁸	Scene Injection needles and hypodermic syringes, empty or partly filled insulin vials found (11 cases)	Injection sites Recent ones (11 cases) Old ones (7 cases)	Brain Cerebral edema Pancreas Fibrosis (3 cases)		Blood (12 cases) HbA1c mean: 9.7% Insulin mean: 49 mU/ml Ethanol mean: 0.71 g% Urine Glucose mean: 1549 mg/dl (6 cases) Ethanol mean: 0.98 g CSF^a (12 cases) Glucose mean: 10 mg/dl Lactate mean: 191 mg/dl Insulin mean: 63 mU/ml Vitreous body (12 cases) Glucose mean: 39 mg/dl Lactate mean: 92 mg/dl
Winston.⁵⁹	Case 1 Note - Known to carry a suicide note in his pocket Remain in vegetated state for eight years, then died from pneumonia as a complication of insulin overdose Case 2 Scene - Insulin bottled and a syringe found Note - Verbal note several weeks earlier, "If I ever kill myself, it will be with insulin." Two days after admission, life support was withdrawn due to brain death Case 3 Witnessed injecting himself with insulin several hours before he was found unresponsive. Case 4 Scene - Missing drugs from her cabinet included: a vial of Novolin 70/30, a syringe, and 12 capsules of 25 mg diphenhydramine	Injection Site Case 1 Probable injection site in the left antecubital fossa Case 3 Two recent injection site in the left arm Case 4 No visible injection sites	Case 1 An autopsy was not performed Case 2 An autopsy was not performed		Case 1 Not done Case 2 Not done Case 3 Blood - Alcohol: 0.121% - Metabolites of marijuana Vitreous humor - Insulin: 31 μU/ml - Glucose: 26 mg/dl. Case 4: Femoral blood - Insulin: 840 μU/ml - C peptide: 0.5 ng/ml - Diphenhydramine, alcohol: not detected
Winston.⁵⁹			Case 3 Pancreas - Normal Case 4 Pancreas - Fibrosis	No microscopic evidence of pancreatic cancer
Junge et al.⁶⁰	Scene - Three empty disposable syringes and an empty ampoule of insulin Note - He left a suicide note	Injection site Three recent subcutaneous injection sites at a distance of 6 cm to the right and left of the naves		Injection site Bleeding in the needle channel and interstitial edema	Blood Alcohol: 122 mg/dl C-peptide: below 0.5 mU/ml (the measurement threshold) Insulin: 1848.8 mU/ml B-blocker Metoprolol: 0.4 mg/ml Urine Alcohol: 1.97 mg/dl Liquor Insulin: 6.9 mU/ml Aqueous humor Alcohol: 1.66 mg/dl Insulin: 0.4 mU/ml
Palmiere et al.⁷¹	Witnessed	Injection sites In the right thigh		Injection sites Bleeding in the needle channel and interstitial edema Liver Glycogen depletion in Periodic Acid-Schiff (PAS) staining Thigh tissue: Positive insulin staining via anti-insulin antibodies Immunohistochemistry	Femoral blood Glycated hemoglobin: 5.2% (33 mmol/mL) (normal) β-hydroxybutyrate: 144 mmol/L (normal) Blood Insulin: 582.50 mU/L (high) C-peptide: 0.10 μg/L (low) Glucagon: 55 pg/mL (low) Anti-insulin antibodies: 7.5% (normal) Vitreous humor Insulin: 11.50 mU/L (normal) C-peptide: 0.30 μg/L (low) Glucose: 0.10 mmol/L Bile Insulin: 19.80 mU/L (high) C-peptide: 0.40 μg/L (low) Pericardial fluid Insulin: 67.80 mU/L C-peptide: 0.50 μg/L (low) CSF^a Insulin: 17.30 mU/L (normal) C-peptide: 0.10 μg/L (low) Glucose: 0.10 mmol/L

a Cerebrospinal fluid.

Initial presentation, blood glucose level and complications in cases of attempted suicide

In 141 cases of attempted suicide, the clinical findings, initial glucose level, and complications are summarized in Table 3. The initial presentation in those who attempted suicide by insulin varies from asymptomatic to loss of consciousness and coma. Furthermore, in all individuals, where the initial blood glucose level was measured, the blood glucose levels were ranging from 2 to 234 mg/dl. Finally, complications were only found in nine cases in the form of significant neurological sequelae related to insulin intoxication, such as cognitive damage and recurrent hypoglycemic coma.

Table 3. Clinical presentation and complications in individuals attempting suicide.

Author	Blood glucose level (mg/dl) (*)	Presentation	Complications
Beardwood⁴³	64	Found lying on the ground in pain and complaining of feeling sick. Findings • Slightly unconscious and weak • Flushed face, dilated neck vein and forceful carotid pulse • Slight tachycardia, cold body bathed in perspiration • Fine in all extremities	No complications
Vogl et al.⁴⁴	No blood sugar level measured upon admission	Presented to the hospital asymptomatic (**)	Multiple hypoglycemic attacks including three Coma attacks in the first six days. No complication.
Blotner⁴⁵	42	Unconscious and could not be aroused Findings • Moist, perspired skin • Deviation of the eye with pin-point pupil • Flaccid arms and legs	No complications
Martin et al.⁴⁷	2-99	Case 1 Semiconscious Case 2 Conscious Case 3 Deeply unconscious and responding to painful stimuli only Case 4 Semi-comatose	Case 1 No complications Case 2 No complications Case 3 Residual brain damage Case 4 No complications
Campbell et al. ⁴⁸	25.2	Conscious and, sweating	No complications
Levine et al.⁴⁹	180-234	NM^a	No complications
Gin et al.⁵⁰	18	Coma and hyperreflexia	No complications
Jefferys et al.⁵¹	NM^a	NM^a	No complications (7) Severe brain damage (5)
Critchley et al.⁵²	9-97 (mean 29)	Coma occurred in six individuals	No complications
Kaminer et al.⁵³	NM^a	Case 1 NM^a Case 2 Loss of consciousness	No complications
Cooper.⁵⁴	7.21	Comatose	Permeant cognitive damage, especially in respect to language and short term memory, in addition to, verbal and locomotor ataxia.
Roberge et al.⁵⁶	30	Palpitation and light-headedness	No complications
Fasching et al.⁵⁷	< 39.6	Unconscious Findings Responsive with slow reactivity Palpable injection sites of subcutaneous insulin in the abdominal fat and right hip	No complications
Jolliet et al.⁶¹	Undetectable	Found comatose at home Four points on Glasgow coma scale	No complications
Tofade et al.⁶²	122	Diaphoretic and tremulous	No complications
Boileau et al.⁶³	NM^a	NM^a	Recurrent hypoglycemic coma
Wong et al.⁶⁴	NM^a	Dizziness and cold sweating	No complications
Mégarbane et al.⁶⁵	NM^a	NM^a	Significant neurological sequelae (two cases)
Fuller et al.⁶⁶	170	Tremulous, diaphoretic, and mildly tachycardic	No complications
Russell et al.¹⁰	25	Generalized tonic-clonic seizure (witnessed)	No complications
Lu et al.⁶⁷	29	Lightheadedness and nausea	No complications
Schober et al.⁶⁸	NM^a	NM^a	NM^a
Gundgurthi et al.⁸	35	Drowsy Diaphoresis Bradycardia Hypotension	Coma with complete recovery without any other neurological-related complications
Löfman et al.⁶⁹	NM^a	NM^a	NM^a
Doğan et al.⁷⁰	30	Diaphoresis	No complications
Svingos et al.⁹	48	Mild weakness	No complications
Essafi et al.⁷²	90	Asymptomatic^**	No complications
Stein et al.⁷³	NM^a	NM^a	NM^a

a Not mentioned.

* At initial presentation.

** Hypoglycemic symptoms presented and were managed at home.

Discussion

Diabetes and psychiatric illnesses can co-exist and have a significant impact on people’s lives. Studies showed that there is a significant association between diabetes and alcohol use disorder, substance use, mood disorders, anxiety disorders, and psychotic disorders, which puts them at an increased risk of suicide.⁷⁴^,⁷⁵ This goes in harmony with this systematic review where 67 out of 179 (37.43%) reported cases were diagnosed with mental illnesses. Furthermore, insulin overdose, alongside its congeners, is not an uncommon method of suicide attempts among individuals with diabetes.⁷⁶ However, publications regarding the incidence of insulin suicide are scarce.¹⁰ In the current existing data, those with T1DM showed higher incidence of insulin suicide (n = 102) than in T2DM (n = 21), which represents 63.35% and 13.04%, respectively. This could be explained by two possible reasons. First, T1DM is managed mainly by insulin, which makes it readily accessible to them.⁷⁶ Second, generally, the incidence of dying by suicide is considered to be higher among newly diagnosed youth with T1DM. The suicidal ideation and attempts are believed to be related to symptomology and initial psychiatric status shortly after being diagnosed.⁷⁷

Although multiple professions are prone to die by suicide, the medical field is considered a high-risk profession. Multiple studies reported a higher incidence of anxiety and depression among physicians. It may be attributed to the stressful work environment and the emotional burden when facing illness, breaking bad news, and death.⁴^,⁷⁸^,⁷⁹ Up to this point, self-poisoning is the most common method of suicide among healthcare providers.⁸⁰ In addition to that, the thorough medical knowledge of the rapid lethal insulin-induced hypoglycemia can make the available insulin in hospitals a feasible weapon for suicide.⁸¹ This systematic review showed that 9.93% (n = 16) of victims were healthcare providers and, as anticipated, most of them were suffering from mental illnesses.

In reality, many individuals who are chronically ill, including those with diabetes, attempt suicide using a combination of different prescribed medications.⁸² A very recent study found that a benzodiazepine overdose can be linked to hypoglycemia.⁸³ Surprisingly, we found that the most common medication used in combination with insulin is a benzodiazepine, which can be explained by the fact that a lower threshold of insulin will be needed to result in death. In addition to benzodiazepines, the consumption of alcohol was also associated with an increased risk of hypoglycemia the day after the intake. This is most likely due to the inhibitory properties of alcohol to hepatic gluconeogenesis.⁸⁴^,⁸⁵ This systematic review reported eight attempted suicides by individuals with diabetes who were also suffering from alcohol use disorder. This suggests a higher risk for those individuals to develop life-threatening hypoglycemic episodes, even though alcohol was not consumed on the same day of the event.

Despite the fact that hypoglycemia symptoms are usually typical, almost all of them are nonspecific. For this, the only evidence to know that the individual is suffering from hypoglycemia is to measure blood glucose level. Studies have shown that the threshold of developing hypoglycemia symptoms is when plasma glucose level falls below 80 mg/dL, while cognitive dysfunction mainly develops at 45 mg/dL. Moreover, the most commonly reported symptoms were mild, which include a combination of diplopia, diaphoresis, palpitations, and blurred vision. Furthermore, more severe symptoms were also reported in 65% of the cases, which are unconsciousness or amnesia, and generalized convulsions.⁸⁶ In this systematic review, most of the findings of the reported cases are consistent with the previous studies, excluding a single case who had a glucose level of 25.2 mg/dL without any symptoms except for diaphoresis. For this, it is believed that signs and symptoms of hypoglycemia can vary greatly among people despite the blood glucose level readings.

The absence of autopsy and histology findings makes the diagnosis of hypoglycemia very challenging.⁸⁷ Although biochemistry analysis is the only current way to estimate hypoglycemia, post-mortem blood glucose levels have no diagnostic value in determining hypoglycemia. After death, the persisting cells still have the ability to metabolize blood glucose, which results in a rapid variable decrease in blood glucose levels, making the diagnosis of insulin-induced hypoglycemia difficult.⁸⁸ Thus, in order to estimate ante-mortem glucose levels, according to Traube’s formula, a measurement of post-mortem glucose and lactate in both cerebrospinal fluid (CSF) and vitreous humor, and also hemoglobin A1c should be obtained. All these measurements are combined in a score, where a score of less than 50 is almost diagnostic of hypoglycemia.⁵⁸ However, some studies suggested that the combined measurements of glucose and lactate in vitreous humor and CSF have no value in estimating blood glucose concentration before death.⁸⁸ Yet, this cannot be evaluated by this systematic review since no data was reported in this regard. We found that the mean glucose levels in vitreous humor is 22.37, while 5.9 in CSF. These findings were limited to the few studies that had performed the biochemistry analysis in vitreous humor and CSF. Even though post-mortem analysis of insulin is challenging, fortunately, a new promising validated quantitative method has been introduced. It quantifies human insulin and its various analogues in samples obtained from post-mortem blood and tissues (kidney, liver, and skeletal muscles) with an accuracy reaching 70% up to 130%, using liquid chromatography-mass spectrometry with high-resolution mass spectrometry (LC-MS/HRMS) analysis. This method provides quantitative measures of both therapeutic and toxic levels of insulin. It was tested on several forensic cases, and it identified the insulin prescribed to the victims even though many types of insulin were undetermined before death. However, this assay has five steps for sample preparation (tissue sample size reduction, homogenization, extraction, concentration, and immunopurification), which is a very time-consuming process.⁸⁹^,⁹⁰ Moreover, insulin is considered a large molecular weight substance, which makes it challenging to reach certainty of post-mortem insulin toxicity. For this, routine determination of insulin in post-mortem specimens is not offered frequently.⁹¹ This can explain the variation among the cases included in this systematic review where the results of insulin levels were ranging from negative to 1,848.8 mU/ml.

Our review was subject to several limitations. First, evaluation of the accuracy of post-mortem glucose measurements could not be done since the included articles were mainly focusing on the characteristics of victims, interventions, and complications rather than detection of insulin overdose. Second, as post-mortem insulin analysis is a new method, data in case reports were limited in this regard. Thus, it is recommended that further research and assessment of the accuracy and feasibility of postmortem insulin analysis as it is a new promising method to detect insulin in suicide cases.

Implications

Our findings regarding the demographic characteristics of suicides by insulin and attempted suicides advocate physicians to do routine psychological assessments among high-risk people, including individuals with diabetes, relatives of those with diabetes and healthcare providers. This will help in improving the preventative measures of suicide and decrease the burden of suicidality in the community. Furthermore, to diagnose patients who died by insulin suicide, post-mortem insulin analysis should be considered.

Conclusions

Insulin overdose as a method of dying by suicide is not uncommon among those with diabetes, however, it can lead to unfavorable neurological sequelae and death. As the prevalence of diabetes mellitus is increasing worldwide and insulin is one of the medications used in the management, it is expected that self-poisoning with insulin will be also increased in both individuals with diabetes and those without diabetes. It is crucial that physicians suspect insulin self-poisoning as one of the differential diagnoses when an individual, with diabetes or without, presents with a coma or unexplained hypoglycemia especially if it is prolonged or recurrent. Evaluation and early management of psychiatric illnesses especially among those with diabetes, mainly depression, are some of the important measures that may prevent suicidality. In addition, easy access to insulin in those without diabetes in the case of individuals with relatives or friends who have diabetes, or among healthcare providers should be considered. Since post-mortem evaluation of insulin toxicity victims is challenging, attention needs to be given to developing a more accurate approach to establish and confirm the diagnosis of insulin poisoning. At the end, managing an individual who presents with intentional insulin poisoning should include a multidisciplinary team and be treated as a whole, from all aspects rather than managing only the individual’s presentation.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA checklist for ‘Suicide by insulin: a systematic review’. https://doi.org/10.6084/m9.figshare.21762530.⁹²

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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¹ College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 34212, Saudi Arabia

Majd A. Assad
Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation

Fatimah A. Alawami
Roles: Conceptualization, Methodology, Resources, Writing – Original Draft Preparation

Raihanah S. Al Khatem
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Zahra Y. Al Daif
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Zainb A. Alrumaih
Roles: Conceptualization, Methodology, Writing – Original Draft Preparation

Ritesh G. Menezes
Roles: Conceptualization, Supervision, Writing – Review & Editing

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No competing interests were disclosed.

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The author(s) declared that no grants were involved in supporting this work.

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Assad MA, Alawami FA, Al Khatem RS et al. Suicide and attempted suicide by insulin: A systematic review [version 1; peer review: 1 approved with reservations]. F1000Research 2023, 12:59 (https://doi.org/10.12688/f1000research.129331.1)

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Fabio Del Duca, Sapienza University of Rome, Rome, Italy

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https://doi.org/10.5256/f1000research.142011.r240289

This article deal with the insulin overdose as a cause of suicide. Insulin overdose is a relatively common method of suicide, particularly among individuals with diabetes. This is concerning due to the associated neurological complications and risk of death. Authors ... Continue reading

This article deal with the insulin overdose as a cause of suicide. Insulin overdose is a relatively common method of suicide, particularly among individuals with diabetes. This is concerning due to the associated neurological complications and risk of death. Authors support that physicians should consider insulin self-poisoning as a potential cause when faced with a coma or unexplained hypoglycemia, especially if recurrent. Preventative measures must be added, including addressing psychiatric conditions, particularly depression, early on, and controlling access to insulin, especially in those without diabetes who may have connections to individuals with the condition. Due to the challenges in post-mortem evaluation, efforts should be directed towards developing more accurate diagnostic approaches for insulin poisoning. Managing intentional insulin poisoning requires a comprehensive, multidisciplinary approach, considering all aspects rather than focusing solely on the individual's immediate presentation.

The article is well written for this journal. I advice you to add this paper: [ Ref 1 ]
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Are the rationale for, and objectives of, the Systematic Review clearly stated?

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Are sufficient details of the methods and analysis provided to allow replication by others?

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Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

References

1. Manetti AC, Visi G, Spina F, De Matteis A, et al.: Insulin and Oral Hypoglycemic Drug Overdose in Post-Mortem Investigations: A Literature Review.Biomedicines. 2022; 10 (11). PubMed Abstract | Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: forensic medicine

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Fabio Del Duca, Sapienza University of Rome, Rome, Italy

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13 May 2024 | for Version 1

Fabio Del Duca, Sapienza University of Rome, Rome, Italy

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Approved With Reservations

This article deal with the insulin overdose as a cause of suicide. Insulin overdose is a relatively common method of suicide, particularly among individuals with diabetes. This is concerning due to the associated neurological complications and risk of death. Authors support that physicians should consider insulin self-poisoning as a potential cause when faced with a coma or unexplained hypoglycemia, especially if recurrent. Preventative measures must be added, including addressing psychiatric conditions, particularly depression, early on, and controlling access to insulin, especially in those without diabetes who may have connections to individuals with the condition. Due to the challenges in post-mortem evaluation, efforts should be directed towards developing more accurate diagnostic approaches for insulin poisoning. Managing intentional insulin poisoning requires a comprehensive, multidisciplinary approach, considering all aspects rather than focusing solely on the individual's immediate presentation.

The article is well written for this journal. I advice you to add this paper: [ Ref 1 ]
In fact this paper seems to fit into your study, please add.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes
Are sufficient details of the methods and analysis provided to allow replication by others?

Yes
Is the statistical analysis and its interpretation appropriate?

Yes
Are the conclusions drawn adequately supported by the results presented in the review?

Yes

References

1. Manetti AC, Visi G, Spina F, De Matteis A, et al.: Insulin and Oral Hypoglycemic Drug Overdose in Post-Mortem Investigations: A Literature Review.Biomedicines. 2022; 10 (11). PubMed Abstract | Publisher Full Text

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

forensic medicine

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

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Suicide and attempted suicide by insulin: A systematic review

Abstract

Keywords

Introduction

Methods

Databases and search string

Inclusion and exclusion criteria

Selection process and data collection process

Figure 1. A PRISMA flow chart for the literature search.

Results

Table 1. Demographic data, psychiatric illness, suicidal methods and outcomes.

Demographic data of suicidal cases

Relation of psychiatric illness to dying by and attempting suicide using insulin

Route of insulin administration and outcome

Post-mortem findings in suicide by insulin and collaborative evidence

Table 2. Investigations and autopsy findings pertinent to insulin toxicity.

Initial presentation, blood glucose level and complications in cases of attempted suicide

Table 3. Clinical presentation and complications in individuals attempting suicide.

Discussion

Implications

Conclusions

Data availability

Underlying data

Reporting guidelines

References

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