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. 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.

Somatostatin Receptor Antagonism Reverses Glucagon Counterregulatory Failure in Recurrently Hypoglycemic Male Rats

Recent antecedent hypoglycemia is a known source of defective glucose counter-regulation in diabetes; the mechanisms perpetuating the cycle of progressive α-cell failure and recurrent hypoglycemia remain unknown. Somatostatin has been shown to suppress the glucagon response to acute hypoglycemia in rodent models of type 1 diabetes. We hypothesized that somatostatin receptor 2 antagonism (SSTR2a) would restore glucagon counterregulation and delay the onset of insulin-induced hypoglycemia in recurrently hypoglycemic, nondiabetic male rats. Healthy, male, Sprague–Dawley rats (n = 39) received bolus injections of insulin (10 U/kg, 8 U/kg, 5 U/kg) on 3 consecutive days to induce hypoglycemia. On day 4, animals were then treated with SSTR2a (10 mg/kg; n = 17) or vehicle (n = 12) 1 hour prior to the induction of hypoglycemia using insulin (5 U/kg). Plasma glucagon level during hypoglycemia was ~30% lower on day 3 (150 ± 75 pg/mL; P < .01), and 68% lower on day 4 in the vehicle group (70 ± 52 pg/mL; P < .001) compared with day 1 (219 ± 99 pg/mL). On day 4, SSTR2a prolonged euglycemia by 25 ± 5 minutes (P < .05) and restored the plasma glucagon response to hypoglycemia. Hepatic glycogen content of SSTR2a-treated rats was 35% lower than vehicle controls after hypoglycemia induction on day 4 (vehicle: 20 ± 7.0 vs SSTR2a: 13 ± 4.4 µmol/g; P < .01). SSTR2a treatment reverses the cumulative glucagon deficit resulting from 3 days of antecedent hypoglycemia in healthy rats. This reversal is associated with decreased hepatic glycogen content and delayed time to hypoglycemic onset. We conclude that recurrent hypoglycemia produces glucagon counterregulatory deficiency in healthy male rats, which can be improved by SSTR2a.

Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies (GLOW) Study

Objectives: To determine plasma lactate and beta-hydroxybutyrate (BHB) concentrations of healthy infants in the first 5 days and their relationships with glucose concentrations. Study design: Prospective masked observational study in Hamilton, New Zealand. Term, appropriately grown singletons had heel-prick blood samples, 4 in the first 24 hours then twice daily. Results: In 67 infants, plasma lactate concentrations were higher in the first 12 hours (median, 20; range, 10-55 mg/dL [median, 2.2 mmol/L; range, 1.1-6.2 mmol/L]), decreasing to 12 mg/dL (range, 7-29 mg/dL [median, 1.4 mmol/L; range, 0.8-3.3 mmol/L]) after 48 hours. Plasma BHB concentrations were low in the first 12 hours (median, 0.9 mg/dL; range, 0.5-5.2 mg/dL [median, 0.1 mmol/L; range, 0.05-0.5 mmol/L]), peaked at 48-72 hours (median, 7.3 mg/dL; range, 1.0-25.0 mg/dL [median, 0.7 mmol/L; range, 0.05-2.4 mmol/L]), and decreased by 96 hours (median, 0.9 mg/dL; range, 0.5-16.7 mg/dL [median, 0.1 mmol/L; range, 0.05-1.6 mmol/L]). Compared with infants with plasma glucose concentrations above the median (median, 67 mg/dL [median, 3.7 mmol/L]), those with lower glucose had lower lactate concentrations in the first 12 hours and higher BHB concentrations between 24 and 96 hours. Lower interstitial glucose concentrations were also associated with higher plasma BHB concentrations, but only if the lower glucose lasted greater than 12 hours. Glucose contributed 72%-84% of the estimated potential adenosine triphosphate throughout the 5 days, with lactate contributing 25% on day 1 and BHB 7% on days 2-3. Conclusions: Lactate on day 1 and BHB on days 2-4 may contribute to cerebral fuels in healthy infants, but are unlikely to provide neuroprotection during early or acute hypoglycemia. Trial registration: The Australian and New Zealand Clinical Trials Registry: ACTRN12615000986572.

Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies (GLOW) Study

Objectives: To determine plasma lactate and beta-hydroxybutyrate (BHB) concentrations of healthy infants in the first 5 days and their relationships with glucose concentrations. Study design: Prospective masked observational study in Hamilton, New Zealand. Term, appropriately grown singletons had heel-prick blood samples, 4 in the first 24 hours then twice daily. Results: In 67 infants, plasma lactate concentrations were higher in the first 12 hours (median, 20; range, 10-55 mg/dL [median, 2.2 mmol/L; range, 1.1-6.2 mmol/L]), decreasing to 12 mg/dL (range, 7-29 mg/dL [median, 1.4 mmol/L; range, 0.8-3.3 mmol/L]) after 48 hours. Plasma BHB concentrations were low in the first 12 hours (median, 0.9 mg/dL; range, 0.5-5.2 mg/dL [median, 0.1 mmol/L; range, 0.05-0.5 mmol/L]), peaked at 48-72 hours (median, 7.3 mg/dL; range, 1.0-25.0 mg/dL [median, 0.7 mmol/L; range, 0.05-2.4 mmol/L]), and decreased by 96 hours (median, 0.9 mg/dL; range, 0.5-16.7 mg/dL [median, 0.1 mmol/L; range, 0.05-1.6 mmol/L]). Compared with infants with plasma glucose concentrations above the median (median, 67 mg/dL [median, 3.7 mmol/L]), those with lower glucose had lower lactate concentrations in the first 12 hours and higher BHB concentrations between 24 and 96 hours. Lower interstitial glucose concentrations were also associated with higher plasma BHB concentrations, but only if the lower glucose lasted greater than 12 hours. Glucose contributed 72%-84% of the estimated potential adenosine triphosphate throughout the 5 days, with lactate contributing 25% on day 1 and BHB 7% on days 2-3. Conclusions: Lactate on day 1 and BHB on days 2-4 may contribute to cerebral fuels in healthy infants, but are unlikely to provide neuroprotection during early or acute hypoglycemia. Trial registration: The Australian and New Zealand Clinical Trials Registry: ACTRN12615000986572.

Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia

IntroductionHypoglycemia in type 2 diabetes (T2D) may increase risk for Alzheimer’s disease (AD), but no data on changes in AD-related proteins with differing degrees of hypoglycemia exist. We hypothesized that milder prolonged hypoglycemia would cause greater AD-related protein changes versus severe transient hypoglycemia.Research design and methodsTwo prospective case-control induced hypoglycemia studies were compared: study 1, hypoglycemic clamp to 2.8 mmol/L (50 mg/dL) for 1 hour in 17 subjects (T2D (n=10), controls (n=7)); study 2, hypoglycemic clamp to 2.0 mmol/L (36 mg/dL) undertaken transiently and reversed in 46 subjects (T2D (n=23), controls (n=23)). Blood sampling at baseline, hypoglycemia and 24-hour post-hypoglycemia, with proteomic analysis of amyloid-related proteins performed.ResultsIn control subjects, the percentage change from baseline to hypoglycemia differed between study 1 and study 2 for 5 of 11 proteins in the AD-related panel: serum amyloid A1 (SAA1) (p=0.009), pappalysin (PAPPA) (p=0.002), apolipoprotein E2 (p=0.02), apolipoprotein E3 (p=0.03) and apolipoprotein E4 (p=0.02). In controls, the percentage change from baseline to 24 hours differed between studies for two proteins: SAA1 (p=0.003) and PAPPA (p=0.004); however, after Bonferroni correction only SAA1 and PAPPA remain significant. In T2D, there were no differential protein changes between the studies.ConclusionsThe differential changes in AD-related proteins were seen only in control subjects in response to iatrogenic induction of hypoglycemic insults of differing length and severity and may reflect a protective response that was absent in subjects with T2D. Milder prolonged hypoglycemia caused greater AD-related protein changes than severe acute hypoglycemia in control subjects.Trial registration numbersNCT02205996, NCT03102801.

Identifying Potential Intervention Points for Acute Hypoglycemic Events in Patients With Type 2 Diabetes Using Retrospective Clinical Data

This retrospective study examined changes in medication orders as a risk factor for future acute hypoglycemic events. The investigators identified factors associated with acute hypoglycemic events resulting in emergency department visits or inpatient admissions. Non-Hispanic Black race, chronic kidney disease, insulin at baseline, and non-private insurance were associated with higher risk of an acute hypoglycemic event, whereas age, sex, and A1C were not. After adjustment for other risk factors, changes in insulin orders after A1C measurement were associated with a 1.5 times higher risk of an acute hypoglycemia (adjusted hazard ratio 1.48, 95% CI 1.08–2.03). These results further understanding of risk factors and clinical processes relevant to predicting and preventing acute hypoglycemia.

Identifying Potential Intervention Points for Acute Hypoglycemic Events in Patients With Type 2 Diabetes Using Retrospective Clinical Data

This retrospective study examined changes in medication orders as a risk factor for future acute hypoglycemic events. The investigators identified factors associated with acute hypoglycemic events resulting in emergency department visits or inpatient admissions. Non-Hispanic Black race, chronic kidney disease, insulin at baseline, and non-private insurance were associated with higher risk of an acute hypoglycemic event, whereas age, sex, and A1C were not. After adjustment for other risk factors, changes in insulin orders after A1C measurement were associated with a 1.5 times higher risk of an acute hypoglycemia (adjusted hazard ratio 1.48, 95% CI 1.08–2.03). These results further understanding of risk factors and clinical processes relevant to predicting and preventing acute hypoglycemia.

Ventrolateral ventromedial hypothalamic nucleus GABA neuron adaptation to recurring Hypoglycemia correlates with up-regulated 5′-AMP-activated protein kinase activity

<abstract> <p>Gamma-aminobutyric acid (GABA) acts on ventromedial hypothalamic targets to suppress counter-regulatory hormone release, thereby lowering blood glucose. Maladaptive up-regulation of GABA signaling is implicated in impaired counter-regulatory outflow during recurring insulin-induced hypoglycemia (RIIH). Ventromedial hypothalamic nucleus (VMN) GABAergic neurons express the sensitive energy gauge 5′-AMP-activated protein kinase (AMPK). Current research used high-neuroanatomical resolution single-cell microdissection tools to address the premise that GABAergic cells in the VMNvl, the primary location of ‘glucose-excited’ metabolic-sensory neurons in the VMN, exhibit attenuated sensor activation during RIIH. Data show that during acute hypoglycemia, VMNvl glutamate decarboxylase_65/67 (GAD)-immunoreactive neurons maintain energy stability, yet a regional subset of this population exhibited decreased GAD content. GABA neurons located along the rostrocaudal length of the VMNvl acclimated to RIIH through a shift to negative energy imbalance, e.g. increased phosphoAMPK expression, alongside amplification/gain of inhibition of GAD profiles. Acquisition of negative GAD sensitivity may involve altered cellular receptivity to noradrenergic input via α₂-AR and/or β₁-AR. Suppression of VMNvl GABA nerve cell signaling during RIIH may differentiate this neuroanatomical population from other, possibly non-metabolic-sensory GABA neurons in the MBH. Data here also provide novel evidence that VMNvl GABA neurons are direct targets of glucocorticoid control, and show that glucocorticoid receptors may inhibit RIIH-associated GAD expression in rostral VMNvl GABAergic cells through AMPK-independent mechanisms.</p> </abstract>

Dual self-regulated delivery of insulin and glucagon by a hybrid patch

Reduced β-cell function and insulin deficiency are hallmarks of diabetes mellitus, which is often accompanied by the malfunction of glucagon-secreting α-cells. While insulin therapy has been developed to treat insulin deficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains inadequate. Here, we describe a transdermal patch that mimics the inherent counterregulatory effects of β-cells and α-cells for blood glucose management by dynamically releasing insulin or glucagon. The two modules share a copolymerized matrix but comprise different ratios of the key monomers to be “dually responsive” to both hyper- and hypoglycemic conditions. In a type 1 diabetic mouse model, the hybrid patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy with simulated delayed meal or insulin overdose.

Sustained impact of real-time continuous glucose monitoring in adults with type 1 diabetes on insulin pump therapy: Results after 24 months RESCUE study

<b>Objective:</b> In recent years, a growing number of people with type 1 diabetes have access to real-time continuous glucose monitoring (rtCGM). Long-term benefits of rtCGM are unclear due to lack of large studies of long duration. We evaluated whether real-world rtCGM-use up to 24 months offered benefits, in particular to those living with impaired awareness of hypoglycemia (IAH). <p><b>Research Design and Methods:</b> This 24-month, prospective, observational, cohort study followed 441<b> </b>adults with insulin pumps receiving full reimbursement for rtCGM. Forty-two percent had IAH. Primary endpoint was evolution of HbA_1c, with secondary endpoints change in acute hypoglycemia complications, diabetes-related work absenteeism, and quality of life (QOL) scores. Additionally, we evaluated if people could achieve glycemic consensus targets during follow-up.</p> <p><b>Results:</b> After 24 months, HbA_1c remained significantly lower compared to baseline (7.64% [60 mmol/mol] vs 7.37% [57 mmol/mol], p<0.0001). Sustained benefits were also observed for the score on the hypoglycemia fear survey and hypoglycemia-related acute complications irrespective of hypoglycemia awareness level. People with IAH had the strongest improvement, especially for severe hypoglycemia (862 events year before vs 119 events per 100 patient-years in second year, p<0.0001). Over 24 months, more people were able to meet hypoglycemia consensus targets at the expense of slightly less people achieving hyperglycemia consensus targets. Furthermore, the number of people with HbA_1c <7% (<53 mmol/mol) without severe hypoglycemia events more than doubled (11.0% vs 25.4%, p<0.0001).</p> <p><b>Conclusion:</b> Use of rtCGM led to sustained improvements in hypoglycemia-related glucose control over 24 months. Lower fear of hypoglycemia, less acute hypoglycemia-related events and diabetes-related days off work were observed, particularly in those with IAH.</p>