**6. Conclusions**

**4. Clinical toxicology of insulin poisoning**

114 Ultimate Guide to Insulin

and finally loss of consciousness, convulsions, and death.

unstable in postmortem blood [4].

**5. Insulin abuse**

An overdose of insulin is a potential life-threatening condition and requires urgent medical attention [40–46]. The clinical manifestations of hypoglycemia occur when the blood glucose level is less than 2.2–2.8 mmol/l (40–50 mg%). Symptomatology includes two groups of symptoms. The first one is caused by stimulation of the autonomic nervous system and includes profuse sweating, anxiety, tremor, and hunger. The second one is caused by progressive dysfunction of the central nervous system (CNS) due to neuroglycopenia and includes nausea, headache, dizziness, blurred vision, abnormal intellectual processes, behavioral disturbances,

The most optimal place of the treatment is clinical toxicology ward, but patients who are overdosed with insulin can be also treated in typical intensive care units or in less serious cases in general internal wards. To differentiate endogenous and exogenous insulin overdose, usually insulin/C-peptide [mol/mol] ratio is used, both in clinical and forensic settings [47]. Physiologically for every molecule of insulin formed, a corresponding molecule of C-peptide is formed. If the above-described ratio is >1, it indicates exogenous origin of insulin (as a result of accident, suicide, or homicide). However, it should be remembered that C-peptide is very

Treatment of hypoglycemia is initially based on the securing of basic vital functions (breathing and circulation). Subsequently, infusions of glucose solution adjusted to the current blood glucose levels are used. Depending on the clinical situation, other drugs are administered s.c. or i.v. (e.g., glucagon which is a glycogenolysis stimulator), as it was presented in above-cited clinical emergency case reports. In the past such specific methods of treatment and management have been reported as excision of insulin injection site or the use of artificial pancreas [48–50]. Assessment of patient prognosis relies on clinical findings. According to the results of prospective study of Mégarbane et al., the observed plasma insulin EC50 (the concentration which induces a response halfway between the baseline and maximum after a specified exposure time) is 46 mIU/l [51].

Tsujimoto et al. have described rare case of rapid onset reversible glycogen storage hepatomegaly caused by suicidal administration of a massive dose of long-acting insulin glargine and subsequent supplementation with large doses of glucose in a 41-year-old type-2 diabetic patient [52]. Supravital liver biopsy revealed hepatocytic glycogen deposition with edematous degeneration. PAS staining revealed many PAS-positive granules containing glycogen. The hepatic computed tomography (CT) attenuation was 83.7 Hounsfield units (HU), being markedly higher than the splenic attenuation (49.5 HU), which indicated pathology of the liver. Such situation (initially higher level of hepatocytic glycogen deposition) must be considered not only by clinicians but also by forensic histopathologist during examination of the insulin fatal poisoning victim's liver.

An interesting, still not fully explained phenomenon, connecting toxicology, diabetology, and psychiatry, is abuse of insulin as a psychoactive substance. Intentional abuse of insulin is quite rare, but not exceptional. Pudlo et al. described an insulin abuser—the 58-year-old patient who Despite the often quite clear circumstances of death and a well-established mechanism of action of insulin and its analogues, it is difficult to analytically confirm its excessive exogenous administration in postmortem biological material [8]. There are no uniform standards of conduct in this type of cases, both at the stage of the material sampling and laboratory analysis and in the interpretation of the obtained results.

If insulin overdose is suspected, it is necessary to take the different biological material during autopsy for further testing and to cautiously interpret its results [7]. It seems necessary to immediately develop a unified international standards/algorithm of conduct, similar to those used in clinical medicine, including the determination of insulin level and other parameters of carbohydrate metabolism in the postmortem biological material, taking into account all above-described possibilities and limitations of laboratory analysis [57–59].
