Insulin Overdose Research Articles

Critical Low Catastrophe: A Case Report of Treatment-Refractory Hypoglycemia following Overdose of Long-Acting Insulin

Overdose of long-acting insulin can cause unpredictable hypoglycemia for prolonged periods of time. The initial treatment of hypoglycemia includes oral carbohydrate intake as able and/or parenteral dextrose infusion. Refractory hypoglycemia following these interventions presents a clinical challenge in the absence of clear guidelines for management. Octreotide has sometimes been used, but its use is generally limited to sulfonylurea overdose. In this case report, we present a case of refractory hypoglycemia following an overdose of 900 units of long-acting insulin glargine that failed to respond to usual modes of therapy mentioned above. Stress-dose corticosteroids were then initiated, followed by subsequent improvement in IV dextrose and glucagon requirements and blood glucose levels. Hence, corticosteroids may serve as an adjunctive therapy in managing hypoglycemia and can be considered earlier in the course of treatment in patients with refractory hypoglycemia to prevent volume overload, especially when large volumes of dextrose infusions are required.

53. PRACTICE MAKES PERFECT: USING REPETITIVE, SMALL-CHANGE SIMULATION FOR EMERGENT PEDIATRIC SCENARIOS

Background Simulation is a cornerstone of residency training across disciplines. Studies show repeated exposure to the same case scenario may improve medical decision making, but little is known about how this affects the learning experience. Methods All pediatric residents participate in simulation exercises both in situ and at our state-of-the-art simulation center. Each scenario includes a nurse and parent who are simulated actors, as well as a child mannequin. Residents at all phases of training work in groups of 3-4. Two categories of simulation scenarios were created. The first reviewed management of status epilepticus - one patient with known epilepsy and the second a hypoglycemic child with an insulin overdose. The second category was management of tachycardia - one patient with sepsis and the second with supraventricular tachycardia. The patient's age, weight, overall appearance, and vital signs were identical in each category. Subtle differences in history and physical exam were present, which residents had to elucidate without prompting. Each group performed two different cases with the same chief complaint. Groups were assessed using the Simulation Team Assessment Tool (STAT), a validated tool published in Resuscitation. Results Seven groups of residents participated from July to December 2019 for 14 total cases. The average STAT score for resident teams participating in the first tachycardia case was 13.75/16 (0.86), while the average in the second scenario was 18/18 (1.00). The average STAT score for teams participating in the first seizure case was 12.3/16 (0.77), while the average in the second case was 15.66/18 (0.87). Average resident satisfaction scores were equal across first and second scenarios at 4.85/5. Conclusions Repetitive simulation using subtle differences in history and physical exam allows for an opportunity to practice important life-saving skills for pediatric residents, while also allowing for some variation and avoidance of repetition bias. This format can easily be modified and applied towards other emergent pediatric situations based on learner needs.

89-LB: The Effect of GIP on Plasma Glucose in a Setting of Prandial Insulin Overdose and Physical Activity after Meal Intake in Patients with Type 1 Diabetes

Gluco-regulatory effects of the insulinotropic and glucagonotropic gut hormone glucose-dependent insulinotropic polypeptide (GIP) in type 1 diabetes (T1D) are unclear. We evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of prandial insulin over-dose and physical activity after meal ingestion. In a randomized, placebo-controlled, double-blinded, crossover study, 12 men with T1D (age [mean±SD]: 26±6.6 years; BMI: 23±2.3 kg/m2; HbA1c: 6.5±2.7% (48.4±6.3 mmol/mol); diabetes duration: 11.3±5.5 years; plasma C-peptide <200 pmol/L) underwent three separate study days involving a liquid mixed meal test with 125% of regular prandial insulin dose, 30 minutes of intermediate bicycling (60 minutes after mixed-meal), and 270 minute infusions of GIP, the GIP receptor antagonist GIP(3-30)NH2 and placebo, respectively. The GIP infusion attenuated postprandial plasma glucose excursions (Cmax-Cmin) by [mean±SEM] 1.5±0.5 mmol/L and 0.92±0.56 mmol/L compared to GIP(3-30)NH2 and placebo, respectively (P=0.03). Infused glucose needed to avoid plasma glucose <2.5 mmol/L was similar on all 3 study days (P=0.13). In conclusion, GIP infusion seems to attenuate postprandial plasma glucose excursions without significantly increasing the need of glucose to avoid hypoglycemia in patients with T1D. Disclosure B. Hoe: None. S.M. Nguyen Heimbürger: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.B. Lynggaard: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S. Engberg: None. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

Adaptive Impulsive Offset-Free MPC to Handle Parameter Variations for Type 1 Diabetes Treatment

Physiological variations in people with type 1 diabetes constantly change the insulin requirements of patients which, if not compensated, can lead to insulin overdose or insulin insufficiency causi...

Advances in Neuropathologic Research of Hypoglycemic Brain Damage Caused by Insulin Overdose.

The number of death from insulin overdose, including accidental poisoning, suicide and homicide, is increasing these years. The forensic diagnosis of death from insulin overdose is a tough task. Glucose is the main energy source of the brain. Therefore, hypoglycemic brain damage is considered to be the main reason of death from insulin overdose. Recently, research of hypoglycemic brain damage caused by insulin overdose is gradually being paid attention in the field of forensic medicine. This paper summarizes the neuropathologic changes, pathophysiologic process and potential neural molecular markers of hypoglycemic brain damage caused by insulin overdose in terms of forensic neuropathology, providing reference for the research and practice in forensic medicine related fields.

Regarding a successful treatment with artificial pancreas for a patient who attempted suicide using a high‐dose insulin s.c. injection

Dear Editor, We read with great interest an article published in Acute Medicine and Surgery by Toshihiro Sakurai et al. entitled “Successful treatment with artificial pancreas for a patient who attempted suicide using a high-dose insulin s.c. injection”.1 This article states that artificial pancreas (AP) systems can control blood glucose (BG) concentrations without a risk of hypoglycemia. We would like to share our understanding of the differences between APs intended for hospitalized patients and wearable APs intended for diabetes outpatients. To aid our discussion, we would consider a case published by Shah et al. in which a wearable AP, the MiniMed 670G (Medtronic Diabetes, Northridge, CA, USA) failed to prevent a suicide caused by an intentional insulin overdose. This wearable, insulin-only AP system not only failed to prevent the patient’s suicide from multiple large insulin boluses, but it actively contributed to the suicide. This is because the system continued administering prescheduled basal insulin even after the patient had become extremely hypoglycemic.2 It is important to distinguish between hospital APs for inpatients and wearable APs for outpatients. A hospital AP, like the STG-55 used by Sakurai et al., can deliver glucose i.v. Another AP intended for hospital use is being developed by Admetsys. This system, like the STG-55, is intended to deliver both insulin and glucose i.v.3 Almost every marketed wearable AP system delivers only insulin to lower elevated BG concentrations and nothing to raise the BG concentration in the event of hypoglycemia. These systems respond to hypoglycemia by halting insulin delivery, but they do not administer any agent to actively raise the BG concentration. An investigational wearable AP for outpatients containing two hormones from Beta Bionics (Boston, MA, USA), currently in development, could deliver glucagon s.c. to raise the BG concentration in the case of hypoglycemia.4 However, this agent would still be less effective than i.v. glucose, which is available with a hospital AP. Sakurai et al.’s patient benefitted from a hospital AP because they could receive glucose i.v., which is the best method for raising BG levels after an intentional insulin overdose. In the case reported by Sakurai et al., we believe a wearable AP would not have saved the patient. Recently a glucagon-only closed-loop system was proposed by Mulla et al.5 to treat hypoglycemia in hospitals. This system might seem promising for treating a hypoglycemic patient like the case reported by Sakurai et al. However, this system has drawbacks. These include: (i) this system cannot lower elevated BG concentrations, so it is not a true AP, (ii) this system is experimental and not cleared. In conclusion, we recommend that if a hypoglycemic patient appears to have taken an intentional insulin overdose, then the patient should be immediately brought to a hospital where i.v. glucose is available either through a hospital AP system or through standard treatments and monitoring. A patient using a wearable AP system should not depend on this device to correct their hypoglycemia from an insulin overdose. Approval of the research protocol: N/A. Informed consent: N/A. Registry and registration no. of the study: N/A. Animal studies: N/A. Conflict of interest: David C. Klonoff is a consultant for Dexcom, Eoflow, Fractyl, Lifecare, Novo, Roche Diagnostics, and Thirdwayv. The other authors have no conflict of interest. We acknowledge Annamarie Sucher-Jones for her expert editorial assistance.

Insulin aspart abuse and overdose

Insulin aspart abuse and overdose

Case report of seven hypothermia deaths – The importance of biochemical assays to identify the cause of a death

To investigate the use of biochemical markers in combination for the postmortem diagnosis of hypothermia. To estimate physiological values for lactate in postmortem samples by an internal study. Case #1: a 31-year-old female was found dead and naked. She had been undergoing treatment for thyroid disease. Case #2: a 55-year-old female was found dead in the wild. She had been undergoing psychiatric treatment for depression. Case #3: a 35-year-old male was found naked in a river. Alcoholic. Case #4: a 60-year-old female was found on her back in a field after an accident on the public highway. She had multiple sclerosis. Case #5: a 21-year-old male was found dead next to the highway in a sleeping bag. Case #6: a 77-year-old male was found dead hang on a mouldboard plough five days after his disappearance. Case #7: a 49-year-old female was found dead in the bush after hospitalization for depression. Analysis of the biochemical markers (glucose, lactate, HbA1c and TSH) was conducted on vitreous humor, peripheral blood by electrochemiluminescence Roche Cobas ® 6000. All values were < 0.1 mmol/L for glucose. Other values are presented in Table 1 . An internal study was performed on 160 postmortem samples from different contexts of death (homicide, suicide, injuries) to propose physiological values for lactate in vitreous humor, which are unknown. Contrary to the other parameters whose physiological values were < 0.1 mmol/L for glucose (vitreous humor), from 0.27 to 4.20 mUI/L for TSH (peripheral blood), and < 5.6% for HbA1c (peripheral blood). The median physiological value for lactate was 26 mmol/L. The determined physiological values for lactates were between 17 and 35 mmol/L. To identify the cause of death, different parameters must be considered. The combination of results for biochemical markers and other molecules such as acetone and isopropanol are the proof of ketoacidosis [1] . In addition, the effect of high levels of bromazepam was discussed in case #1. Furthermore, the differences between cases of diabetic ketoacidosis by hyperglycemia or insulin overdose were reported [2] . The negative lactate values in these cases were one of the most important factors in identifying the cause of death. In fact, the collapse of lactate values in vitreous humor might be a pathognomonic sign of hypothermia and could establish a postmortem diagnosis.

Plasma-insulin-cognizant adaptive model predictive control for artificial pancreas systems

An adaptive model predictive control (MPC) algorithm with dynamic adjustments of constraints and objective function weights based on estimates of the plasma insulin concentration (PIC) is proposed for artificial pancreas (AP) systems. A personalized compartment model that translates the infused insulin into estimates of PIC is integrated with a recursive subspace-based system identification to characterize the transient dynamics of glycemic measurements. The system identification approach is able to identify stable, reliable linear time-varying models from closed-loop data. An MPC algorithm using the adaptive models is designed to compute the optimal exogenous insulin delivery for AP systems without requiring any manually-entered meal information. A dynamic safety constraint derived from the estimation of PIC is incorporated in the adaptive MPC to improve the efficacy of the AP and prevent insulin overdosing. Simulation case studies demonstrate the performance of the proposed adaptive MPC algorithm.

Mechanics of controlled release of insulin entrapped in polyacrylic acid gels via variable electrical stimuli

Controlled release insulin delivery systems possess multiple advantages over conventional ones, including maintaining desired blood glucose levels for prolonged periods and minimizing complications due to insulin overdose. Compared to other controlled-release mechanisms, electro-responsive polymers present the advantages of high controllability and ability to be coupled with microelectronics. This paper reports the possibility of using electro-responsive polyacrylic acid (PAA) and polymethacrylic acid (PMA) hydrogels for controlled delivery of insulin using intermittent electrical signals via matrix deformation. PAA hydrogels showed very good electrical responsivity under both constant and step current inputs, releasing up to 80% of protein at 10V stimulus, compared to 20% release in the absence of stimulus. Analysis of spatial variation under electrical stimuli suggested that release of protein is a combined effect of deformation of the hydrogel and electrophoresis of protein molecules. Binding interaction analysis revealed that insulin entrapment is largely due to hydrogen bonding between the polymer matrix and insulin, and flooding the matrix with electrical charge likely disrupts the attractive forces that kept protein in place helping the release of the proteins. Understanding the molecular interactions affecting insulin retention and release mechanisms of PAA hydrogels is useful for developing and optimizing hydrogel-based controlled drug release systems.

Delayed hypoglycemic effect of insulin overdose in a diabetic child: a case report

Background: Insulin overdose can result in fatal hypoglycemia. We report on a diabetic child who received an unintentional insulin overdose. Case Presentation: A 13-year-old girl with type 1 diabetes, who was on insulin pump therapy, developed high blood glucose (BG) level due to pump malfunction. She gave herself 7 ml (700 units) instead of seven units by an error. She presented to hospital 2 hours later when this was recognized. The initial BG in the emergency room was 13.9 mmol/l. A dextrose infusion was started 6 hours after the insulin injections when her BG dropped significantly before it reached a lowest level of 3.3 mmol/l, 9 hours after the event. It was only possible to discontinue this infusion 15 hours after insulin injections when BG was stable. Conclusion: Hypoglycemia could be delayed in insulin overdose in diabetic children. This may necessitate prolonged monitoring beyond the usual half-life of insulin.

Association of insulin-manipulation and psychiatric disorders: A systematic epidemiological evaluation of adolescents with type 1 diabetes in Austria.

Background/ObjectiveThe aim of this study was to systematically assess the association of insulin‐manipulation (intentional under‐ and/or overdosing of insulin), psychiatric comorbidity and diabetes complications.MethodsTwo diagnostic interviews (Diabetes‐Self‐Management‐Patient‐Interview and Children's‐Diagnostic‐Interview for Psychiatric Disorders) were conducted with 241 patients (age 10‐22) with type 1 diabetes (T1D) from 21 randomly selected Austrian diabetes care centers. Medical data was derived from medical records.ResultsPsychiatric comorbidity was found in nearly half of the patients with insulin‐manipulation (46.3%) compared to a rate of 17.5% in patients, adherent to the prescribed insulin therapy. Depression (18.3% vs 4.9%), specific phobia (21.1% vs 2.9%), social phobia (7.0% vs 0%), and eating disorders (12.7% vs 1.9%) were elevated in patients with insulin‐manipulation. Females (37.7%) were more often diagnosed (P = 0.001) with psychiatric disorders than males (18.4%). In females, the percentage of psychiatric comorbidity significantly increased with the level of non‐adherence to insulin therapy. Insulin‐manipulation had an effect of +0.89% in HbA1c (P = <0.001) compared to patients adherent to insulin therapy, while there was no association of psychiatric comorbidity with metabolic control (HbA1c 8.16% vs 8.12% [65.68 vs 65.25 mmol/mol]). Ketoacidosis, severe hypoglycemia, and frequency of outpatient visits in a diabetes center were highest in patients with insulin‐manipulation.ConclusionsThis is the first study using a systematic approach to assess the prevalence of psychiatric disorders in patients who do or do not manipulate insulin in terms of intentional under‐ and/or overdosing.Internalizing psychiatric disorders were associated with insulin‐manipulation, especially in female patients and insulin‐manipulation was associated with deteriorated metabolic control and diabetes complications.

Insulin degludec overdose in an adolescent with type 1 diabetes: proactive management including monitoring using the Freestyle Libre flash glucose monitoring system.

SummaryAn adolescent with type 1 diabetes and a history of self-harm, which included intentional overdoses and insulin omission, presented with an insulin degludec overdose. She had been commenced on the ultra-long-acting insulin, degludec, with the aim of reducing ketoacidosis episodes in response to intermittent refusal to take insulin. Insulin degludec was administered under supervision as an outpatient. Because it was anticipated that she would attempt a degludec overdose at some stage, the attending clinicians implemented a proactive management plan for this (and related) scenarios. This included long-term monitoring of interstitial glucose using the Abbott Freestyle Libre flash glucose monitor. The patient took a witnessed overdose of 242 units of degludec (usual daily dose, 32 units). She was hospitalised an hour later. Inpatient treatment was guided primarily by interstitial glucose results, with capillary and venous glucose tests used as secondary measures to assess the accuracy of interstitial glucose values. Four days of inpatient treatment was required. The patient was managed with high glycaemic loads of food and also intermittent intravenous dextrose. No hypoglycaemia was documented during the admission. In summary, while a degludec overdose may require several days of inpatient management, in situations where proactive management is an option and the dose administered is relatively modest, it may be possible to avoid significant hypoglycaemia. In addition, this case demonstrates that inpatient interstitial glucose monitoring may have a role in managing insulin overdose, especially in situations where the effect of the insulin overdose on glucose levels is likely to be prolonged.Learning points:Degludec overdoses have a prolonged effect on blood glucose levels, but if the clinical situation allows for early detection and management, treatment may prove easier than that which is typically needed following overdoses of a similar dose of shorter acting insulins.Inpatient real-time interstitial monitoring helped guide management, which in this context included the prescription of high dietary carbohydrate intake (patient led) and intravenous 10% dextrose (nurse led).Use of inpatient interstitial glucose monitoring to guide therapy might be considered ‘off label’ use, thus, both staff and also patients should be aware of the limitations, as well as the benefits, of interstitial monitoring systems.The Libre flash glucose monitor provided nurses with low cost, easy-to-use interstitial glucose results, but it is nevertheless advisable to check these results against conventional glucose tests, for example, capillary ‘finger-stick’ or venous glucose tests.

Capabilities of Next-Generation Patch Pump: Improved Precision, Instant Occlusion Detection, and Dual-Hormone Therapy.

Insulin pumps allow patients to attain better blood glucose control with more lifestyle flexibility. Their size and cost, however, limit their usefulness. Current CSII pumps are bulky, intrusive, and expensive. SFC Fluidics is addressing these problems by developing a new type of wearable patch pump based on the patented electro-chemiosmotic (ECO) microfluidic pumping technology. This nonmechanical pumping technology allows accurate and precise delivery of very small amounts of insulin and/or other drugs, including concentrated insulin. The pump engine is small and can be made inexpensively from injection molded parts, allowing its use in a disposable or semidisposable pod format. In addition, a single ECO pump engine can be used to deliver two drugs through independent pathways. Other features of SFC Fluidics' pod include latching safety valves that prevent accidental overdosing of insulin due to pressure changes and an instantaneous occlusion sensor that can immediately detect delivery failure at the first missed dose. These features allow for the development of a series of patch pumps that will offer users the benefit of CSII therapy in a more discreet and reliable patch pump form.

Non-Fatal Amlodipine and Insulin Overdose in an Elderly Person

Background:Amlodipine belongs to the dihydropyridine class of calcium channel blockers (CCB). We present a patient who concomitantly overdosed on amlodipine and subcutaneous insulin. Case Presentation:An elderly man presented within 2 hours to the Emergency department after ingesting 140mg of amlodipine and self-injected 2 cartridges of NovoMix 30/70(600 units) in a suicidal attempt. He developed mild hypotension and had multiple episodes of hypoglycemia but was otherwise asymptomatic. He was managed with activated charcoal, low dose noradrenaline and multiple doses of dextrose for his hypoglycaemia. He was discharged well after 3 days. Discussion:The clinical manifestations of dihydropyridine toxicity are hypotension, hyperglycaemia and metabolic acidosis. Our patient was elderly with multiple medical problems but he was alert and haemodynamically stable on presentation. Activated charcoal is the recommended form of decontamination when the patient presents early. He also developed initial hyperglycemia, which correlates with the degree of the calcium channel blocker overdose. The early coadministration of insulin would correct the patient’s hyperglycemia, acidosis, myocardial function and even provide inotropic support. It may be possible that the subcutaneous route of administering high dose insulin has similar effects as those of intravenous HIET. Our patient’s hypoglycaemia occurred about 12 hours of the overdose, which is expected after an insulin overdose. He required many boluses of dextrose infusions before his blood sugar level stabilised. Conclusion:It is postulated that self-administration of insulin and early decontamination could have resulted in patient’s good outcome despite having ingested a potentially fatal dose of amlodipine.

A Systematic Review on Insulin Overdose Cases: Clinical Course, Complications and Treatment Options.

A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications besides hypoglycaemia following large insulin overdoses is not readily apparent from the literature. A systematic search, compilation and review of case reports on insulin overdoses, published 1986-2017, was performed in PubMed, EMBASE, Cochrane and PROSPERO databases. Of 1523 published articles, 45 cases of insulin overdoses were included with a total median insulin dose of 900 international units (IU) (range 26-4800 IU). Hospitalization occurred in 44 cases with a median hospitalization duration of 94 hr (range 12-721 hr), and one-third (n = 15) admitted to the intensive care unit. First-line treatment was IV glucose treatment in 95% of cases. Treatment options besides IV glucose that were reported beneficial included glucagon IV or intramuscular (IM), octreotide IV or IM, surgical excision, hydrocortisone IV and oral intake of complex carbohydrates. Prevalent complications were intermittent cerebral impairment (73%), hypokalaemia (49%), other electrolyte disturbances (42%), and hepatic disturbances (7%) and cardiac toxicity (e.g. cardiac arrhythmia) (9%). Long-term consequences were one case of lasting hypoglycaemic encephalopathy and one death. In conclusion, following large insulin overdoses, in-hospital admission and treatment with IV glucose may be needed for up to a week. Monitoring of electrolytes and hepatic and cardiac functions seems important. Several experimental treatment options may be considered in addition to glucose administration. With appropriate pre- and in-hospital treatment, cases with severe hypoglycaemia and neurologic complications may have a favourable outcome.

Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports.

SummaryHypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non-diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores.Learning points:It is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia.Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in everyday clinical practice.Herein, we reported similar 2 cases of hypoinsulinemic hypoglycemia without diabetes presumably triggered by severe liver injury.In both cases, hypoglycemia was improved by glucose infusion, although their liver injury was not improved.We should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly subjects with low body weight.

Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity

In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.

Evaluation of the usefulness of the immunoradiometric method for post-mortem measurement of insulin concentration in the intraocular fluid: preliminary results.

In medicolegal practice, rare cases associated with suicidal, criminal or accidental overdose of insulin are both analytically and forensically challenging. The determination of insulin in post-mortem blood has limited diagnostic value, mainly on account of post-mortem chemical degradation processes (particularly hemolysis), and hence is not useful in medicolegal practice. The aims of the study were: 1) to assess the usefulness of the immunoradiometric method, used in clinical practice, for post-mortem measurement of insulin concentration in the intraocular fluid, 2) to preliminarily evaluate the usefulness of the obtained results for toxicological and medicolegal assessment, and 3) to verify on the basis of our own material the validity of the cited literature data on the effect of hemolysis on the result of insulin level determination in post-mortem blood. The study material consisted of 93 samples of intraocular fluid collected during consecutive medicolegal autopsies performed in the Department of Forensic Medicine and Forensic Toxicology, Medical University of Silesia in Katowice. In addition, 10 samples of peripheral blood taken from living people (5 women and 5 men) for clinical and diagnostic purposes were analyzed. Insulin(e) IRMA KIT from IMMUNOTECH was used for the analyses. In 86 (92.5%) samples, the insulin concentration was below the analytical sensitivity of the method (less than 0.5 μIU/ml), while in 7 cases it was in the range of 1.42-24.42 μIU/ml. Determination of the insulin level in the intraocular fluid by the immunoradiometric method provides an opportunity for objective verification of poisoning, however this claim requires further research.

Pharmacokinetics of insulin disappearance after massive overdosing

Long-term glucose supplementation is required to prevent hypoglycemia after massive insulin overdosing. We fitted the blood insulin concentration-time profile to the model: I = A·exp(-a·t) + B·exp(-b·t), where I (μU/mL) is the serum/plasma insulin concentration, A (μU/mL) and B (μU/mL) are the peak insulin concentrations of each component, a (time-1) and b (time-1) are the time constants of each component, and t (h) is the time elapsed from the peak of blood insulin level. Additional components were considered as needed. Patient 1 had auto-injected 600 U NovoRapid® 30Mix, and Patient 2 had auto-injected 300 U Novolet®R (regular) and 1,800 U NovoLet®N (NPH). We used the disappearance of therapeutic doses of the respective insulin in healthy individuals as controls, and we obtained parameters by Excel solver. In Patient 1, the parameter values were A = 1490.04 and a = 0.15 for insulin aspart and B = 60.66 and b = 0.04 for protaminated aspart. In Patient 2, the values were A = 784.45 and a = 0.38 for regular insulin and B = 395.84 and b = 0.03 for NPH. Compared with controls, the half-lives (t1/2) for insulin aspart and protaminated aspart were 4 and 2 times longer, respectively, in Patient 1. In Patient 2, the t1/2 for regular and NPH insulin were 2 and 7 times longer than those in the controls, respectively. In conclusion, the t1/2 for insulin was elongated 2 to 7 times after massive overdosing, explaining why glucose supplementation is needed for long periods in these cases.