Iatrogenic Hypoglycemia Research Articles

Sustained Proinflammatory Effects of Hypoglycemia in People With Type 2 Diabetes and in People Without Diabetes.

Iatrogenic hypoglycemia activates the immune system and is associated with an increased risk for atherosclerotic disease. We determined acute and long-term effects of insulin-induced hypoglycemia on inflammatory markers in humans with or without type 2 diabetes. A total of 15 adults with type 2 diabetes and 16 matched control subjects (17 men and 14 women, age 59.6 ± 7.1 years, BMI 28.5 ± 4.3 kg/m2) underwent a hyperinsulinemic-euglycemic (5.31 ± 0.32 mmol/L) hypoglycemic (2.80 ± 0.12 mmol/L) glucose clamp. Blood was drawn during euglycemia and hypoglycemia and 1, 3, and 7 days later to determine circulating immune cell composition, function, and inflammatory proteins. In response to hypoglycemia, absolute numbers of circulating lymphocytes and monocytes significantly increased and remained elevated for 1 week. The proportion of CD16+ monocytes increased, and the proportion of CD14+ monocytes decreased, which was sustained for 1 week in people without diabetes. During hypoglycemia, ex vivo stimulated monocytes released more tumor necrosis factor-α and interleukin 1β, and less interleukin 10, particularly in people with diabetes. hs-CRP and 25 circulating inflammatory proteins increased, remaining significantly elevated 1 week after hypoglycemia. While levels at euglycemia differed, responses to hypoglycemia were broadly similar in people with or without type 2 diabetes. We conclude that hypoglycemia induces a proinflammatory response at the cellular and protein level that is sustained for 1 week in people with type 2 diabetes and control subjects.

Minimizing Hypoglycemia with Insulin Therapy

Iatrogenic hypoglycemia is the most feared and common complication of insulin therapy. Hypoglycemia can have serious consequences and can be potentially life-threatening. In addition to the neurological manifestations of severe hypoglycemia, hypoglycemia may be associated with cognitive dysfunction, cardiovascular events, arrhythmias, and increased mortality. Recurrent episodes of hypoglycemia may lead to hypoglycemia unawareness, which increases the risk of severe hypoglycemia. Therefore, prevention of hypoglycemia remains a priority in persons with diabetes on insulin therapy. The “THINK” strategy provides a comprehensive approach for diabetes care providers to minimize the risk of hypoglycemia related to insulin therapy by mitigating factors that increase the risk. This requires setting reasonable glycemic Targets keeping in mind a person's risk of hypoglycemia; choosing the right Tools such as insulin formulation and regimen with lower risk and adequate glucose monitoring; judicious Titration of insulin doses; use of modern Technology such as continuous glucose monitoring, continuous subcutaneous insulin infusion, and sensor augmented pumps in patients at high risk; maintaining Harmony between insulin dose, diet, physical activity, and changes in lifestyle; Individualization of diabetes therapy; ensuring there are No errors in insulin administration; and empowering patients with Knowledge about hypoglycemia. The THINK strategy offers a handy tool for tailoring insulin therapy to minimize hypoglycemia risk.

371-P: Predicting Real-World Nonsevere Hypoglycemia in Americans with Diabetes (iNPHORM)

Iatrogenic non-severe hypoglycemia (NSH) is a common and known precursor of severe hypoglycemia. Still, virtually no valid risk estimators exist to predict daytime and nocturnal NSH (NSDH, NSNH) in the general US population with diabetes. To redress this gap, we analyzed primary, self-reported data from the 1-year, prospective iNPHORM study. Adults (18-90 years old) with insulin- and/or secretagogue-treated type 1 or 2 diabetes (T1D, T2D) were recruited from a US-wide probability-based internet panel. Twelve monthly emailed questionnaires assessed NSH risk. Prognostic models were built for recurrent 30-day NSDH and NSNH using negative binomial and machine learning penalized regression with lasso. Missing data were multiply imputed with chained equations. N=986 were analyzed (T1D: 17%; age: 51 [SD: 14.3] years; male: 49.6%; T1D/T2D duration: 12 [IQR: 14] years; retention rate: 86.2%) . Among T2D respondents, 38% were on insulin alone, 38% secretagogues alone, and 24% insulin plus secretagogues. Follow-up incidence proportions and 30-day rates of NSDH and NSNH were 79.6% (95% CI: 77.0-82.0%) and 1.70 (95% CI: 1.59-1.82) , and 53.7% (95% CI: 50.5-56.7%) and 0.69 (95% CI: 0.64-0.75) , respectively. Risks of 30-day NSDH and NSNH increased with insulin+secretagogue therapy; A1C≤7%; insulin pump, continuous glucose monitoring, beta blockers, and antibiotics use; decreased number of medications; T1D and diabetes education; increased past severe hypoglycemia requiring healthcare; chronic kidney disease; depression; food insecurity; lack of insurance; younger age; female sex; and White race; risks decreased with A1C≥7.1%, cognitive impairment, hypoglycemia unawareness, and insurance. As well, higher income predicted NSNH risk. The optimism adjusted c-statistics for NSDH and NSNH risks were 0.78 and 0.77, respectively. As the first US study to prospectively estimate real-world NSDH and NSNH risk, iNPHORM provides important insight into individual-level event detection and prevention. Disclosure A.Ratzki-leewing: Consultant; Eli Lilly and Company, Other Relationship; Sanofi. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. J.E.Black: None. G.Zou: None. S.Webster-bogaert: None. B.L.Ryan: None. Funding Sanofi Global

372-P: Predicting Real-World Severe Hypoglycemia in Americans with Diabetes (iNPHORM)

Most prediction models for diabetes-related iatrogenic severe hypoglycemia (SH) have derived from trial/administrative records subject to poor generalizability, ascertainment bias, and incomplete data capture. Redressing this gap, iNPHORM leveraged the clinical and methodological advantages of prospective self-report to develop and internally validate a 1-year SH prediction model for use in real-world clinical contexts. Adults (18-90 years old) with insulin- and/or secretagogue-treated type 1 or 2 diabetes (T1D, T2D) were recruited from a US-wide probability-based internet panel and followed for one year. Monthly emailed questionnaires assessed SH incidence and related factors. To model recurrent 1-year SH (daytime + nocturnal) , Andersen-Gill Cox proportional hazards regression was performed on participants completing ≥1 follow-up. Missing data were multiply imputed with chained equations. Machine learning penalized regression with lasso was used to select clinically plausible predictors. A total of 986 (T1D: 17%) participants were analyzed (retention rate: 86.2%) . The mean age was 51 (SD: 14.3) years, 49.6% were male, and the median duration of T1D/T2D was 12 (IQR: 14) years. Among T2D participants, 38% were on insulin (without secretagogues) , 38% on secretagogues (without insulin) , and 24% on insulin plus secretagogues. Across follow-up, 35.1% (95% CI: 32.2-38.1%) reported ≥1 SH, and the annual rate was 4.97 (95% CI: 4.13-5.99) . Combination insulin-secretagogue therapy; use of an insulin pump and continuous glucose monitoring; decreased age; increased previous SH requiring healthcare utilization; chronic kidney disease; and food insecurity predicted 1-year SH risk. The optimism adjusted c-statistic was 0.75. iNPHORM is the first long-term, prospective study on SH prediction in the general US population with T1D and T2D. Our 7-variable model can be used to identify patients at high-risk of SH, leading to more valid, cost-effective prevention strategies in the real world. Disclosure A.Ratzki-leewing: Consultant; Eli Lilly and Company, Other Relationship; Sanofi. S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. J.E.Black: None. G.Zou: None. S.Webster-bogaert: None. B.L.Ryan: None. Funding Sanofi Global

Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response.

There is evidence that fibroblast growth factor (FGF) levels may be implicated in hypoglycaemia, with FGF19 being a potential contributor to insulin-independent pathways driving postprandial hypoglycaemia following bariatric surgery and basic FGF (FGF2) being elevated following mild hypoglycaemia occurring after the glucose tolerance test. However, their response following severe iatrogenic hypoglycaemia is unknown and therefore this pilot exploratory study was undertaken. A case-control study of aged-matched type 2 diabetes (T2D; n=23) and control (n=23) subjects who underwent a hyperinsulinaemic clamp, initially to euglycaemia in T2D (5 mmol/L; 90 mg/dl), and then to hypoglycaemia (<2 mmol/L; <36 mg/dl) with subsequent follow-up time course to 24 h. FGF and FGF receptor proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. At baseline, FGF12 (p= .006) was higher and FGF20 (p= .004) was lower in T2D versus controls. At hypoglycaemia, FGF7 was lower in T2D. Post-hypoglycaemic levels of FGF18, FGF19, FGF20 and FGF23 were lower while FGF12 and FGF16 were higher in T2D versus control at different time points. No differences between T2D and controls were seen for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF10, FGF21 or any of the FGF receptors. At 24 h post-hypoglycaemia, FGF20 (p= .01) differed between controls and T2D, while the levels for the other proteins measured returned to baseline. None of the FGF proteins altered from baseline to euglycaemia when clamped in T2D subjects. FGF23 negatively correlated with fasting blood glucose, but no FGFs correlated with body mass index in T2D. Severe transient hypoglycaemia modulated FGF7, 16, 19, 20 and 23 (known to be associated with diabetes), together with FGF18 and 12, not previously reported to be associated with diabetes but that may be important in the pathophysiology of hypoglycaemia; FGF20 remained low at 24 h. Taken together, these data suggest that recurrent hypoglycaemia may contribute to the development of complications through changes in FGF proteins.

IDF21-0095 Continuous glucose monitoring calibrated with point of care devices or glucometers for self monitoring of blood glucose

Background: Iatrogenic hypoglycemia is an important complication for patients with diabetes. To detect a risk of hypoglycemia accurately during hospitalization, increasing accuracy of continuous glucose monitor (CGM) is necessary. Aim: We examined differences in calibration accuracy between point of care devices and “glucometers that were compliant with ISO15197:2013” (ISO compliant glucometers) when using personal CGM during hospitalization. Method: This was a prospective study where personal-CGM (GUARDIAN CONNECT) was worn for 6 days (CGM attachment: day 1) and blood glucose levels used to calibrate were obtained using point of care devices (StatStrip Xpress Glucose/Ketone) or ISO compliant glucometers (ACCU-CHEK Guide) using a randomized crossover design. Sixteen inpatients with type 2 diabetes were equally allocated to 2 groups. Point of care devices provided 11 blood glucose levels used to calibrate during days 2-3 and ISO compliant glucometers provided 11 blood glucose levels used to calibrate during days 4-5 in group 1. ISO compliant glucometers provided 11 blood glucose levels used to calibrate during days 2-3 and point of care devices provided 11 blood glucose levels used to calibrate during days 4-5 in group 2. In each group 1 and group 2, point of care devices and ISO compliant glucometers were allocated from “fixed 2 point of care devices” and “fixed 2 ISO compliant glucometers” using a randomized quadruple (2 × 2) crossover design. Mean absolute relative difference (MARD) was calculated for every calibration. Results: Blood glucose levels used to calibrate obtained using point of care devices was significantly higher than blood glucose levels used to calibrate obtained using ISO compliant glucometers (173.6 ± 69.9 mg/dL vs. 158.2 ± 47.9 mg/dL, p = 0.02: unpaired t-test). MARD was significantly higher on calibration using point of care devices than on calibration using ISO compliant glucometers (7.6 ± 7.5% vs. 5.8 ± 5.8%, p = 0.01: unpaired t-test). The study patients correlated to distributions of MARD on calibration using point of care devices (η2 = 0.19, p = 0.003: correlation ratio). The study patients also correlated to distributions of MARD on calibration using ISO compliant glucometers (η2 = 0.23, p < 0.001: correlation ratio). Discussion: StatStrip Xpress Glucose/Ketone is cheaper than other point of care devices in Japan, therefore, StatStrip Xpress Glucose/Ketone should be thought to be superior in terms of being able to measure the wide range of glucose levels (10–900 mg/dL) cheaply. ISO compliant glucometers may calibrate personal CGM more accurate than StatStrip Xpress Glucose/Ketone during hospitalization. The correlation between study patients and distributions of MARD may suggest the individual differences in CGM sensor accuracy between patients.

IDF21-0425 Real-world severe hypoglycemia incidence across Canada and the United States

Background: Rate estimation of iatrogenic severe hypoglycemia (SH) in Canada and the United States has depended largely on healthcare utilization (HCU) data from electronic medical or administrative health records. However, this approach can underestimate the true magnitude of SH incidence, as it fails to account for events treated outside of the healthcare system by family members and friends. Self-reported data can help elucidate these uncaptured events, enabling a more valid understanding of real-world SH burden.

Reducing Inpatient Hypoglycemic Events: A Focus on Mealtime Insulin.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an effort to reduce iatrogenic insulin-associated hypoglycemia at the University of Chicago Medical Center in Chicago, IL.

Neural control of pancreatic peptide hormone secretion

Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.

Vulnerable Hours of the Day for Iatrogenic Hypoglycaemia

Vulnerable Hours of the Day for Iatrogenic Hypoglycaemia

Acute Hypoglycemia in Emergency Room: A Review

Hypoglycemia is frequently encountered in the emergency department (ED) and has potential for serious morbidity. The incidence and causes of iatrogenic hypoglycemia are not known. We aim to describe how often the cause of ED hypoglycemia is iatrogenic and to identify its specific causes. Adult patients with a chief complaint or ED diagnosis of hypoglycemia, or an ED glucose value of ≤70 milligrams per deciliter (mg/dL) between 2009–2014. Two independent abstractors each reviewed charts of patients with an initial glucose ≤ 50 mg/dL, or initial glucose ≥ 70 mg/dL with a subsequent glucose ≤ 50 mg/dL, to determine if the hypoglycemia was caused by iatrogenesis.&#x0D; In ED patients with hypoglycemia, iatrogenic causes are relatively common. The most frequent cause was insulin administration for hyperkalemia and uncomplicated hyperglycemia. Additionally, patients at risk of hypoglycemia in the absence of insulin, including those with alcohol intoxication or poor nutritional status, should be monitored closely in the ED.

Stakeholder Perspectives on an Inpatient Hypoglycemia Informatics Alert: Mixed Methods Study.

BackgroundIatrogenic hypoglycemia is a common occurrence among hospitalized patients and is associated with poor clinical outcomes and increased mortality. Clinical decision support systems can be used to reduce the incidence of this potentially avoidable adverse event.ObjectiveThis study aims to determine the desired features and functionality of a real-time informatics alert to prevent iatrogenic hypoglycemia in a hospital setting.MethodsUsing the Agency for Healthcare Research and Quality Five Rights of Effective Clinical Decision Support Framework, we conducted a mixed methods study using an electronic survey and focus group sessions of hospital-based providers. The goal was to elicit stakeholder input to inform the future development of a real-time informatics alert to target iatrogenic hypoglycemia. In addition to perceptions about the importance of the problem and existing barriers, we sought input regarding the content, format, channel, timing, and recipient for the alert (ie, the Five Rights). Thematic analysis of focus group sessions was conducted using deductive and inductive approaches.ResultsA 21-item electronic survey was completed by 102 inpatient-based providers, followed by 2 focus group sessions (6 providers per session). Respondents universally agreed or strongly agreed that inpatient iatrogenic hypoglycemia is an important problem that can be addressed with an informatics alert. Stakeholders expressed a preference for an alert that is nonintrusive, accurate, communicated in near real time to the ordering provider, and provides actionable treatment recommendations. Several electronic medical record tools, including alert indicators in the patient header, glucose management report, and laboratory results section, were deemed acceptable formats for consideration. Concerns regarding alert fatigue were prevalent among both survey respondents and focus group participants.ConclusionsThe design preferences identified in this study will provide the framework needed for an informatics team to develop a prototype alert for pilot testing and evaluation. This alert will help meet the needs of hospital-based clinicians caring for patients with diabetes who are at a high risk of treatment-related hypoglycemia.

Spontaneous and iatrogenic hypoglycemia in cystic fibrosis

Spontaneous episodes of hypoglycemia can occur in people with cystic fibrosis (CF) without diabetes, who are not on glucose lowering medications. Spontaneous hypoglycemia in CF could occur both in the fasting or postprandial state (reactive hypoglycemia). The pathophysiology of fasting hypoglycemia is thought to be related to malnutrition and increased energy expenditure in the setting of inflammation and acute infections. Reactive hypoglycemia is thought to be due to impaired first phase insulin release in response to a glucose load, followed by a delayed and extended second phase insulin secretion; ineffective counterregulatory response to dropping glucose levels may also play a role. The overall prevalence of spontaneous hypoglycemia varies from 7 to 69% as examined with oral glucose tolerance test (OGTT) or with continuous glucose monitoring (CGM) under free living conditions. Spontaneous hypoglycemia in CF is associated with worse lung function, higher hospitalization rates, and worse clinical status. In addition, patients with CF related diabetes on glucose-lowering therapies are at risk for iatrogenic hypoglycemia. In this article, we will review the pathophysiology, prevalence, risk factors, clinical implications, and management of spontaneous and iatrogenic hypoglycemia in patients with CF.

24-hr observation unit is safe location for rapid glucose control in uncomplicated severe hyperglycaemia

BackgroundUncomplicated hyperglycaemia is a common presentation in the emergency department (ED). Rapid glucose control is associated with the risk of iatrogenic hypoglycaemia. We sought to determine the safety of a rapid glucose control protocol delivered in a 24-h emergency department observation unit (OU).MethodsThis is a retrospective chart review of patients admitted to the OU for hyperglycaemia where the assessing clinician deemed there was no other reason for medical admission apart from hyperglycaemia; and that the patient could be safely discharged provided their hyperglycaemia was adequately treated. The rapid glucose control protocol consists of 4–6 hourly glucose monitoring and insulin injections according to a sliding scale. We report the demographics, reduction in glucose values and the incidence of hypoglycaemia in the OU. We also determine the rate of discharge from OU and the rate of hospital admission at 30 days.ResultsWe included 101 patients. The mean age was 53.5 years (95% CI 50.4–56.6) and 64% of patients were male. The mean HbA1c value was 12.8% (95% CI 12.3–13.3). The mean admission and discharge glucose values were 27.2 (95% CI 26.3–28.1) and 13.9 (95% CI 13.2–14.6) mmols/l respectively. There was no incidence of hypoglycaemia in the OU. We successfully discharged 90.1% of the patients from the OU, of which 3 (3.3%) patients were admitted to the hospital within 30 days of discharge.ConclusionED OU is a safe location to deliver effective management for patients presented with uncomplicated severe hyperglycaemia.

Hypoglycemia Impairs Baroreflex Sensitivity: Implications for Autonomic Control of Cardiovascular Function in Diabetes

Background: Iatrogenic hypoglycemia is an unintended, though common, occurrence in individuals with diabetes. There is a clear association between hypoglycemia exposure and an increase in mortality in individuals with type 2 diabetes (T2DM). It is well-established that recurrent hypoglycemic episodes impair the counterregulatory hormone responses; however, it is yet to be determined if in T2DM there are more global effects of hypoglycemia on autonomic control of cardiovascular function (baroreflex sensitivity, BRS), as has been shown in healthy individuals. This is a clinically relevant knowledge gap as decreases in BRS are pro-arrhythmogenic and associated with decreases in mortality in individuals with diabetes. Objective: We tested the hypothesis that in individuals with T2DM, hypoglycemia impairs baroreflex sensitivity (BRS), a robust measure of cardiovascular autonomic control. Methods: Individuals with well-controlled T2DM and without known cardiovascular disease were exposed to two 90-minute episodes of experimental hypoglycemia (50 mg/dl) in the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). BRS was assessed using the modified Oxford method (sequential administration of nitroprusside and phenylephrine) before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 minutes of hypoglycemia, and the following day. Results: The study included 16 individuals with a diagnosis of T2DM (6 men and 10 women) with the following characteristics (mean ± SD): age 45 ± 11 years, BMI 32 ± 6 kg/m2, hemoglobin A1c 6.4 ± 0.9%, and diabetes duration 8 ± 5 years. At baseline, individuals with T2DM had a BRS of 7.7 ± 3.6 ms/mmHg, which is reduced compared to a BRS of 21.3 ± 13.8 ms/mmHg in a historical healthy control group of 54 subjects (p<0.001). A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on BRS (p=0.008). Pairwise comparisons revealed a significant decrease in BRS during the PM clamp as compared with BRS assessed at baseline (5.5 ± 5.0 vs 7.7 ± 3.6 ms/mmHg, p=0.045), during the AM clamp (5.5 ± 5.0 vs 10.5 ± 5.6 ms/mmHg, p=0.43), and the following day (5.5 ± 5.0 vs 8.6 ± 3.8 ms/mmHg, p=0.33). Of note, there was no significant difference between BRS at baseline and during the AM clamp (p=0.44). Additionally, insulin levels positively and strongly correlated with BRS at baseline (R2 0.52) and during the AM clamp (R2 0.67). Discussion: Insulin may have a stimulatory effect on BRS during a hyperinsulinemic hypoglycemic clamp that counters the inhibitory effect of hypoglycemia during the first episode of hypoglycemia. However, with exposure to a second hypoglycemic clamp, BRS decreases. Conclusion: Individuals with T2DM have low BRS at baseline, which is further reduced after 2 episodes of hypoglycemia.

Iatrogenic Hypoglycemia Induced by Valproic Acid in an Adult Patient

Literature on antiepileptic induced iatrogenic hypoglycemia is scanty. Due to its broad spectrum of activity and mechanisms of action, valproic acid (VPA), a fatty acid, is the most widely prescribed epilepsy treatment worldwide.Herein, we describe an adult epileptic patient, where persistent, otherwise unexplained hypoglycemia, was most likely induced by VPA, as suggested by the VPA time course and glucose blood levels. Indeed, no further hypoglycemic episodes occurred after VPA discontinuation and the diagnostic work-up ruled out other possible causes of hypoglycemia.This case supports the hypothesis that VPA may induce hypoglycemia, due to still not well-defined metabolic mechanisms of action. Moreover, it emphasizes the fact that an iatrogenic pathogenesis should be considered if an apparently unexplained hypoglycemia occurs in a patient on chronic therapy with antiepileptics, even at a therapeutical dosage.

Liver glycogen-induced enhancements in hypoglycemic counterregulation require neuroglucopenia.

Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; n = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain.NEW & NOTEWORTHY It is well known that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in patients with diabetes. Our data confirm that increasing liver glycogen content 75% above fasting levels enhances hormonal responses to insulin-induced hypoglycemia and demonstrate that this enhanced hormonal response does not occur in the absence of hypoglycemia in the brain. These data demonstrate that information from the liver regarding glycogen availability is integrated in the brain to optimize the counterregulatory response.

The promising future of insulin therapy in diabetes mellitus.

The first therapeutic use of insulin by Frederick Banting and Charles Best in 1921 revolutionized the management of type 1 diabetes and considerably changed the lives of many patients with other types of diabetes. In the past 100 years, significant pharmacological advances took place in the field of insulin therapy, bringing closer the goal of optimal glycemic control along with decreased diabetes-related complications. Despite these developments, several challenges remain, such as increasing treatment flexibility, reducing iatrogenic hypoglycemia, and optimizing patient quality of life. Ongoing innovations in insulin therapy (e.g., new insulin analogs, alternative routes of insulin administration, and closed-loop technology) endeavor to overcome these hurdles and change the landscape of diabetes mellitus management. This report highlights recent advances made in the field of insulin therapy and discusses future perspectives.

Development and Validation of a Machine Learning Model to Predict Near-Term Risk of Iatrogenic Hypoglycemia in Hospitalized Patients

Accurate clinical decision support tools are needed to identify patients at risk for iatrogenic hypoglycemia, a potentially serious adverse event, throughout hospitalization. To predict the risk of iatrogenic hypoglycemia within 24 hours after each blood glucose (BG) measurement during hospitalization using a machine learning model. This retrospective cohort study, conducted at 5 hospitals within the Johns Hopkins Health System, included 54 978 admissions of 35 147 inpatients who had at least 4 BG measurements and received at least 1 U of insulin during hospitalization between December 1, 2014, and July 31, 2018. Data from the largest hospital were split into a 70% training set and 30% test set. A stochastic gradient boosting machine learning model was developed using the training set and validated on internal and external validation. A total of 43 clinical predictors of iatrogenic hypoglycemia were extracted from the electronic medical record, including demographic characteristics, diagnoses, procedures, laboratory data, medications, orders, anthropomorphometric data, and vital signs. Iatrogenic hypoglycemia was defined as a BG measurement less than or equal to 70 mg/dL occurring within the pharmacologic duration of action of administered insulin, sulfonylurea, or meglitinide. This cohort study included 54 978 admissions (35 147 inpatients; median [interquartile range] age, 66.0 [56.0-75.0] years; 27 781 [50.5%] male; 30 429 [55.3%] White) from 5 hospitals. Of 1 612 425 index BG measurements, 50 354 (3.1%) were followed by iatrogenic hypoglycemia in the subsequent 24 hours. On internal validation, the model achieved a C statistic of 0.90 (95% CI, 0.89-0.90), a positive predictive value of 0.09 (95% CI, 0.08-0.09), a positive likelihood ratio of 4.67 (95% CI, 4.59-4.74), a negative predictive value of 1.00 (95% CI, 1.00-1.00), and a negative likelihood ratio of 0.22 (95% CI, 0.21-0.23). On external validation, the model achieved C statistics ranging from 0.86 to 0.88, positive predictive values ranging from 0.12 to 0.13, negative predictive values of 0.99, positive likelihood ratios ranging from 3.09 to 3.89, and negative likelihood ratios ranging from 0.23 to 0.25. Basal insulin dose, coefficient of variation of BG, and previous hypoglycemic episodes were the strongest predictors. These findings suggest that iatrogenic hypoglycemia can be predicted in a short-term prediction horizon after each BG measurement during hospitalization. Further studies are needed to translate this model into a real-time informatics alert and evaluate its effectiveness in reducing the incidence of inpatient iatrogenic hypoglycemia.

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/β-MHC) during insulin-induced hypoglycaemia: Role of oxidative stress.

Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycaemia and iatrogenic hypoglycaemia exacerbate several pathogenic mechanisms underlying hypertension and heart diseases. Carnitine is a potent endogenous antioxidant and cellular fatty acid transporter for antioxidative stress and energy production in the cardiovascular system. The current study aimed to find the role of carnitine in the regulation of hypoglycaemia-induced hypertension and cardiac hypertrophy. Male rats received insulin glargine (InG) to induce hypoglycaemia followed by D-carnitine or acetyl-L-carnitine for carnitine depletion or carnitine supplementation, respectively. The obtained results showed that carnitine deficiency provoked hypoglycaemia-induced hypertension. Mean arterial pressure was elevated from 78.16±11.4 to 100±5.11mmHg in InG treated group, and from 78.2±8.5 to 123.4±28.2mmHg in InG+D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycaemic animals and kept it within the normal values (68.33±6.7mmHg). Acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycaemia-induced oxidative stress, which was evaluated through measurement of the oxidative stress biomarkers such as inducible nitric oxide synthase, NAD(P)H quinone dehydrogenase-1, heme oxygenase-I, and glutathione S-transferase. Moreover, acetyl-L-carnitine prevented induction of gene expression of cardiac hypertrophy markers during hypoglycaemic conditions, which was assessed via the evaluation of mRNA expression of α-myosin heavy chain and β-myosin heavy chain. These findings demonstrate that carnitine might play an essential role in prevention of hypoglycaemia-induced hypertension and cardiac hypertrophy through providing energy and antioxidants to the cardiovascular system.