Plasma Glucose Nadir Research Articles

Unraveling, contributing factors to the severity of postprandial hypoglycemia after gastric bypass surgery.

Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete. To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose. University Hospital (Bern, Switzerland). Twenty-five subjects with PBH following gastric bypass surgery (age, 41 ± 12 years; body mass index, 28.1 ± 6.1kg/m2) received 75g of glucose with frequent blood sampling for glucose, insulin, C-peptide, and glucagon-like peptide 1 (GLP)-1. Based on nadir plasma glucose (</≥50mg/dL), subjects were grouped into level 1 (L1) and level 2 (L2) PBH groups. Beta-cell function (BCF), GLP-1 exposure (λ), beta-cell sensitivity to GLP-1 (π), potentiation of insulin secretion by GLP-1 (PI), first-pass hepatic insulin extraction (HE), insulin sensitivity (SI), and rate of glucose appearance (Ra) were calculated using an oral model of GLP-1 action coupled with the oral minimal model. Nadir glucose was 43.3 ± 6.0mg/dL (mean ± standard deviation) and 60.1 ± 9.1mg/dL in L2- and L1-PBH, respectively. Insulin exposure was significantly higher in L2 versus L1 (P = .004). Mathematical modeling revealed higher BCF in L2 versus L1 (34.3 versus 18.8 10-9∗min-1; P = .003). Despite an increased GLP-1 exposure in L2 compared to L1 PBH (50.7 versus 31.9pmol∗L-1∗min∗102; P = .021), no significant difference in PI was observed (P = .204). No significant differences were observed for HE, Ra, and SI. Our results suggest that higher insulin exposure in PBH patients with lower postprandial nadir glucose values mainly relate to a higher responsiveness to glucose, rather than GLP-1.

Dasiglucagon Effectively Mitigates Postbariatric Postprandial Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH). In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 μg or 200 μg dasiglucagon. Compared with placebo, treatment with both 80 and 200 μg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 μg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 μg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008). Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia.

134-OR: Comparison of Glucose-Insulin Homeostasis in People with Postprandial Hypoglycemia after Gastric Bypass Surgery and Nadir Plasma Glucose &amp;lt;50 mg/dl vs. &amp;gt;50 mg/dl

Background: Mechanisms of postprandial hypoglycemia following gastric bypass (GB) surgery (PBH), remain incompletely understood. Thus, we aimed to assess the role of insulin secretion/beta-cell function (BCF), fractional hepatic insulin extraction (HE), insulin sensitivity (SI) and rate of glucose appearance (Ra) in patients with biochemically moderate and severe hypoglycemia. Methods: A total of 23 subjects with PBH (mean±SD age 41±12 years, BMI 28.1±6.1 kg/m2, 6.0±2.5 years since GB surgery) underwent an oral glucose tolerance test (75g of glucose), with frequent blood sampling for determination of glucose, insulin and C-peptide concentrations for up to 180minutes. Indices of BCF, HE, SI and Ra were calculated using the oral minimal model method and compared between subjects with nadir plasma glucose during the test below (severe hypo) and above 50mg/dL (moderate hypo). Results: Mean±SD nadir glucose was 43.3±6.0mg/dL in the severe hypo group and 60.1±9.1mg/dL in the moderate hypo group. Differences between the groups were found for indices of BCF, HE and Ra, whereas no significant differences were observed for SI (Figure 1). Conclusion: Present findings confirm three candidate mechanisms involved in PBH: increased BCF, diminished HE and faster Ra. Disclosure D. Herzig: None. M. Schiavon: None. A. Tripyla: None. V. Lehmann: None. J. Meier: None. S. Jainandunsing: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L. Bally: None. Funding Swiss National Science Foundation (PCEGP3_186978); Italian Ministry of Education, University and Research (Law 232/2016); University of Padova; Diabetes Center Berne

342-P: Effects of Sitagliptin on Hypoglycemic Episodes and Counterregulation in Type 2 Diabetic Patients Tightly Titrated with Insulin Glargine

DPP-4 inhibitors may prevent hypoglycemic episodes in insulin-treated type 2 diabetes (T2D), but mechanisms are unclear. 20 T2D patients treated with basal insulin and metformin (± other agents) were recruited for two randomized treatments (placebo or 100 mg/d sitagliptin) in addition to insulin glargine/metformin; 17 completed (3 women, 14 men; age 57 ± 7 yrs.; BMI 28.8 ± 3.9 kg/m2; HbA1c 7.4 ± 0.7 %). After titrating fasting plasma glucose (PG) to 90-110 mg/dl, patients were observed during a 3-day (d) inpatient period with exposure to oral glucose or lipid loads, strenuous exercise and fasting, while increasing insulin doses to 110, and 120 % of the titrated dose before d 2 and 3, respectively. Hypoglycemic episodes (PG &amp;lt; 70 mg/dl) were identified by measuring venous plasma glucose or symptoms, and prompted the determination of counter-regulatory hormones at the glucose nadir and 30 and 60 min later. After titrating insulin glargine, fasting PG was 112 ± 5 and 107 ± 5 mg/dl with placebo and sitagliptin treatment, respectively. Concentrations of insulin, C-peptide and counterregulatory hormones were similar during both treatments. Hypoglycemic episodes were mainly nocturnal (10 p.m. to 7 a.m.), with a similar PG nadir (65 ± 4 mg/dl) and incidence with placebo and sitagliptin (4.5 ± 3.2 vs. 4.6 ± 3.6 episodes per patient, respectively, p = 0.96). With a similar incidence of daytime (7 a.m. to 10 p.m.) chemical hypoglycemia, the incidence of symptomatic episodes was higher with sitagliptin (0.2 ± 0.4 vs. 0.0 ± 0.0, p = 0.028). Counter-regulatory responses were suppressed by sitagliptin for cortisol (p = 0.022), unchanged for glucagon, HGH, noradrenaline and prolactin, and accentuated for adrenaline (p = 0.022). Our results suggest that sitagliptin treatment augments counter-regulatory responses of adrenaline at minimal degrees of hypoglycemia. This may increase symptoms, in particular during daytime, and may offer opportunities for earlier treatment. Disclosure M. A. Nauck: Advisory Panel; Self; Berlin-Chemie AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Consultant; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Speaker’s Bureau; Self; Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. A. Feldmann: None. J. J. Meier: Advisory Panel; Self; AstraZeneca, MSD Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, MSD Corporation, Novo Nordisk, Sanofi. M. Nauck: None. C. Kapitza: Research Support; Self; ADOCIA, Afon Technology, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Johnson &amp; Johnson, Julphar, Mylan N. V., Nestlé, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Funding Merck Sharp &amp; Dohme Corp

7-LB: Insulin and Glucagon Coadministration in Type 1 Diabetes Prevents Hypoglycemia without Worsening Hyperglycemia

Despite pharmacological and technical advances, risk of hypoglycemia remains the greatest impediment to optimal glycemia in type 1 diabetes (T1D) and there is increasing interest in how the opposing actions of insulin and glucagon (Gn) may be harnessed to optimize glycemic control. We studied T1D subjects (n=11; age 36±4y, gender M:F 5:6, BMI 25.0±0.7 kg/m2, disease duration 23±3y, A1C 7.0±0.3%, daily insulin dose 43±3u) on two occasions, under meal challenge conditions (liquid mixed meal, 100g carbohydrate) during a phased 6h IV regular insulin infusion with (+Gn) and without (-Gn) IV glucagon. On both occasions, subjects were treated overnight with low dose IV insulin prior to the morning meal to prevent antecedent nocturnal hypoglycemia and to attain near-normal fasting glycemia. Insulin dosing was designed to control the early rise in plasma glucose (PG) but also to elicit hypoglycemia in the later phase. During +Gn, glucagon was co-administered with insulin at a fixed molar ratio. At the two visits, fasting PG was similar (-Gn 121±5, +Gn 119±6 mg/dl) and the initial meal-induced PG elevation (0-3h) was indistinguishable whether glucagon was present or not (peak PG -Gn 224±18, +Gn 228±15 mg/dl; ΔPG 0-180AUC -Gn 10501±3014, +Gn 11537±1778 mg.min/dl). During the latter phase (3-6h), 7/11 -Gn subjects experienced an excessive fall in PG to &amp;lt;80mg/dl with 5/11 dropping to 50mg/dl requiring IV glucose rescue (by protocol). During +Gn, the fall in PG was attenuated in all cases with a significant difference observed in PG nadir (-Gn 51.1±4.0, +Gn100.5±11.0 mg/dl; p=0.007). Appropriate elevations in plasma insulin and glucagon were observed in keeping with study design. To conclude, it is feasible that insulin and glucagon can be co-administered under specific conditions allowing protection against insulin-induced hypoglycemia without impeding hyperglycemic control. This unique observation offers insight into novel approaches to glucose control in diabetes. Disclosure B.W. Bode: Advisory Panel; Self; Medtronic, Novo Nordisk A/S. Consultant; Self; Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Abbott, Advance, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, National Institutes of Health, Nova Biomedical, Novo Nordisk A/S, Provention Bio, Inc., Sanofi, Senseonics. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., MannKind Corporation, Medtronic, Novo Nordisk A/S, Sanofi, Senseonics. Stock/Shareholder; Self; Aseko. J. Boyd: None. A. Shah: Consultant; Self; Abvance Therapeutics. Stock/Shareholder; Spouse/Partner; Fractyl Laboratories, Inc. D. Parkes: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Prolynx, ProSciento. S. Ghosh: Consultant; Self; Abvance Therapeutics, Fractyl Laboratories, Inc., Takeda Pharmaceutical Company Limited. A.D. Cherrington: Advisory Panel; Self; Biocon, Fractyl Laboratories, Inc., Metavention, Sekkei Bio, Sensulin, LLC., vTv Therapeutics, Zafgen, Inc. Consultant; Self; Thetis Pharmaceuticals LLC. Research Support; Self; Diasome Pharmaceuticals, Inc. Other Relationship; Self; Abvance Therapeutics, Novo Nordisk Inc.

Hypoglycaemia and cardiac arrhythmias in diabetes.

Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called ‘dead-in-bed syndrome’. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.

A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia.

Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 μg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. NCT03255629.

22-OR: Nasal Glucagon: A Viable Alternative to Treat Insulin-Induced Hypoglycemia in Japanese Patients with Type 1 and Type 2 Diabetes

Background/Objective: Currently available glucagon products for rescue treatment of severe hypoglycemia require cumbersome multistep reconstitution and injection procedures in an emergency situation. Nasal glucagon (NG) is a nasally administered, single-use, drug-device combination containing 3 mg glucagon dry powder. We aimed to evaluate noninferiority of NG to intramuscular glucagon (IMG) for treatment of insulin-induced hypoglycemia in patients with type 1 and type 2 diabetes (T1D/T2D) (NCT03421379). Methods: This was a randomized, two-period, crossover trial with NG and IMG. Hypoglycemia was induced by an intravenous insulin infusion; insulin was stopped once plasma glucose (PG) reached &amp;lt;60 mg/dL. Approximately 5 minutes (min) after stopping insulin either 3 mg NG or 1 mg IMG was administered followed by PG measurements up to 4 hours. Treatment success was defined as an increase in PG to ≥70 mg/dL or an increase of ≥20 mg/dL from the PG nadir within 30 min after receiving glucagon. Spontaneously reported adverse events (AEs) and a Nasal and Non-Nasal Symptom Questionnaire (NNSQ) assessed local tolerability of NG. Results: Of the 68 evaluable patients (T1D 32, T2D 36) who received both NG and IMG, all patients achieved treatment success with a mean time of 12.0 min (NG) and 11.0 min (IMG). Noninferiority of NG to IMG was demonstrated. PG responses were similar between T1D and T2D. During the treatment period 26 treatment-emergent AEs (TEAEs) occurred with NG and 13 with IMG. Most TEAEs were mild in severity and none was severe. TEAEs with an incidence ≥5% were rhinalgia (NG 8.5%, IMG 0%), nausea (NG 5.6%, IMG 11.4%), and blood pressure increase (NG 5.6%, IMG 0%). With NG, very common (≥10%) symptoms from NNSQ were watery eyes and nasal congestion. Conclusion: NG was noninferior compared to IMG for the treatment of insulin-induced hypoglycemia in Japanese patients with T1D/T2D supporting the use of NG as a rescue treatment for severe hypoglycemia. Disclosure M. Matsuhisa: Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Y. Takita: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Nasu: None. K. Ohwaki: Employee; Self; Eli Lilly and Company. H. Nagashima: None.

OR22-3 Closed-Loop Glucagon Pump: A Novel and Effective Strategy for Post-Bariatric Hypoglycemia

Current therapies for post-bariatric hypoglycemia (PBH) are incompletely effective. We previously reported feasibility of an open-loop glucagon system for this challenging syndrome. In this study, patients with PBH were enrolled in a double-masked, placebo-controlled, crossover trial to determine the efficacy of a closed-loop mini-dose glucagon delivery system to reduce severe hypoglycemia after a mixed meal. A novel hypoglycemia detection & mitigation algorithm was embedded in the Artificial Pancreas System connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with study drug (Xeris liquid glucagon or vehicle). After screening and enrollment, CGM were placed; participants returned after an overnight fast for the 1st of 2 study visits. A liquid mixed meal (Ensure Compact: 64 g CHO, 18 g protein, 236 mL) was consumed, and sensor/plasma glucose were measured serially. The system autonomously delivered up to 2 doses of study drug (300/150 mcg of glucagon or equal volume vehicle) if triggered by the hypoglycemia mitigation algorithm. If plasma glucose fell to <55 mg/dL or neuroglycopenia occurred, rescue IV dextrose was given per protocol. During a 2nd study visit, the protocol was repeated, with pump filled with the other study drug. Twelve participants (11F/1M, age 52+2, postoperative duration 8+1 years, mean+SEM) completed all study visits. In an additional 3 participants, the mixed meal did not trigger either alarm or hypoglycemia, so study drug was not administered, and a second visit was not conducted. For the 12 participants receiving glucagon vs. vehicle during 2 study visits, predictive hypoglycemia alerts prompted automated drug delivery at mean 94+6 vs. 89+5 (p=0.41) minutes post meal, when sensor glucose was 114+7 vs. 121+5 mg/dL (p=0.39). Four participants did not require rescue during either visit; 1 participant required rescue during both visits. Seven participants required rescue glucose after vehicle but not after glucagon (p=0.0082). Similarly, 5 participants had severe hypoglycemia (plasma glucose <55 mg/dL) after vehicle but not after glucagon (p=0.03). Nadir plasma glucose was higher in study visits with glucagon vs. vehicle delivery (67.4±2.7 vs. 58.5±1.9 mg/dL, p=0.004). Glucagon levels were not elevated at time of alert (14.6±1.4 pg/mL) but rose after glucagon delivery (1231±187 vs. vehicle 16 ±1.4 pg/mL at 30 minutes, p = 0.001). No rebound hyperglycemia occurred. Emesis occurred before study drug delivery in 2 visits. Transient pain at infusion site was reported during both glucagon (n=11 of 12) and vehicle (n=10 of 12) study visits. No other adverse advents were observed. Our data demonstrate that a CGM-guided glucagon closed-loop system can detect imminent hypoglycemia and deliver mini-dose glucagon, yielding improvements in post-meal glucose and reducing severe hypoglycemia in patients with PBH.

OR05-2 Targeted Inhibition of Glutamate Dehydrogenase by Alpha-Tocopherol: A Potential Novel Treatment for Hyperinsulinism Hyperammonemia Syndrome

Congenital hyperinsulinism is a rare genetic disorder that causes severe hypoglycemia and can lead to permanent brain damage if inadequately controlled. Gain of function mutations in glutamate dehydrogenase (GDH) result in hyperinsulinism hyperammonemia (HI/HA) syndrome, the second most common cause of congenital hyperinsulinism. Current therapies inhibit insulin secretion but do not target GDH overactivity directly and thus fail to treat the spectrum of clinical manifestations observed, which in addition to hyperinsulinism and hyperammonemia, include seizures and developmental delays. The neurological symptoms are profound and occur independent of the hypoglycemia. We investigated the efficacy of alpha-tocopherol as a targeted GDH inhibitor in vitro and in vivo models of HI/HA syndrome. Human embryonic kidney (HEK293T) cells were transduced with lentivirus to overexpress either wild-type GDH or H454Y GDH, a well-characterized disease-causing mutant. GDH enzyme kinetics were determined spectrophotometrically in cell homogenates perfused with escalating concentrations of alpha-tocopherol on a background of 10mM glutamine. To evaluate the inhibitory effect of alpha-tocopherol on GDH in vivo, wild-type (WT, n=10) and H454Y GDH transgenic (Tg, n=13) adult mice were treated with oral alpha-tocopherol (75 μg/g body weight/dose) or vehicle twice daily for 3 doses and then fasted for 6 hours. Nadir fasting plasma glucoses were measured as a clinical correlate of GDH activity and compared between alpha-tocopherol and vehicle-treated wild-type and transgenic mice, respectively. Alpha-tocopherol effectively inhibited activity of wild-type and H454Y mutant GDH in HEK293T cells with 50% inhibitory concentration (IC50) of 4.1 and 3.1 μM, respectively. In vivo, nadir fasting plasma glucose was significantly higher in alpha-tocopherol-treated versus vehicle-treated WT and Tg mice (WT: mean nadir plasma glucose 94.3 ± 9.6 mg/dl v. 80.1 ± 9.6 mg/dl, p=0.003; Tg: mean nadir plasma glucose 71.9± 11.3 mg/dl v. 57.2 ± 12.6 mg/dl, p=0.002). Alpha-tocopherol effectively inhibits GDH in vitro and ameliorates fasting hypoglycemia in vivo in a mouse model of HI/HA syndrome. Based upon these findings, alpha-tocopherol is a promising potential treatment for HI/HA syndrome. Our next step will be to study the safety and efficacy of oral alpha-tocopherol supplementation in human subjects with HI/HA syndrome.

Newborn Plasma Glucose Concentration Nadirs by Gestational-Age Group

Background: The glucose concentrations and times to nadir for newborns of all gestational ages when intrapartum glucose-containing solutions are not routinely provided are unknown. Objective: To characterize and compare patterns of initial glucose concentration nadirs by gestational-age groups. Methods: A cross-sectional cohort study of 1,366 newborns born in 1998 at the University of Arkansas for Medical Sciences, appropriate for gestational age, nonasphyxiated, nonpolycythemic, and not infants of diabetic mothers, were included. Initial plasma glucose concentrations, before intravenous fluids or feedings, were plotted against time after birth for 4 gestational-age groups (full term [FT], ≥37–42 weeks; late preterm [LPT], ≥34 and < 37 weeks; preterm [PT], ≥28 and < 34 weeks; and extremely low gestational age newborns [ELGAN], 23 and < 28 weeks of gestation). Results: ELGAN had the earliest nadir at 61 ± 4 min, followed by PT newborns (71 ± 2 min), and then LPT and FT newborns at 92–93 min. The time to nadir for ELGAN and PT newborns was significantly earlier than for FT newborns. Glucose nadir concentrations for ELGAN, PT, and LPT newborns were significantly lower than for FT newborns. LPT newborns’ pattern of glucose paralleled those of FT newborns, with values approximately 5–6 mg/dL lower during the first 3 h. Conclusion: Plasma glucose nadirs occurred at different times among gestational-age groups during the early postnatal period as follows: ELGAN < PT < LPT ≈ FT. In order to potentially prevent low glucose concentrations at the time of the nadir, exogenous glucose should be provided to all newborns as soon as possible after birth.

Hypoglycemia during oral glucose tolerance test among post–bariatric surgery pregnant patients: incidence and perinatal significance

BackgroundWhile hypoglycemia during an oral glucose tolerance test (OGTT) has been shown to occur in a considerable portion of nonpregnant post–bariatric surgery (BS) patients, its incidence among pregnant post-BS patients evaluated for gestational diabetes has only been sparsely studied. ObjectivesWe investigated OGTT results and pregnancy outcomes in pregnant women who underwent 3 types of bariatric procedures before pregnancy. SettingA university hospital. MethodsFrom medical records, data were collected on glucose measurements during a 100-g, 3-hour OGTT, as well as maternal and fetal outcomes. ResultsOf 119 post-BS pregnant patients included in the study, 55 underwent laparoscopic sleeve gastrectomy, 34 laparoscopic adjustable gastric banding, and 30 laparoscopic Roux-en-Y gastric bypass surgery. Hypoglycemia (<55 mg/dL) was encountered in 59 (49.6%) patients during the OGTT. Among them, the nadir plasma glucose levels occurred 2 hours after glucose ingestion in 25 (42.4%) and after 3 hours in 34 (57.6%), with a median value of 47 (44–52) mg/dL. The risk of hypoglycemia was higher among women with prior laparoscopic Roux-en-Y gastric bypass surgery (83.3%) than among those with prior laparoscopic sleeve gastrectomy (54.5%; P = .009) or laparoscopic adjustable gastric banding (11.8%; P<.0001). Time from surgery to conception was significantly shorter among women with evidence of hypoglycemia during OGTT (median 711 versus 1246 days, P = .002). Compared with patients without evidence of hypoglycemia, patients who experienced hypoglycemia had lower rates of gestational diabetes (P = .03) but higher proportions of low birth weight (P = .01) and small for gestational age infants (P = .03). ConclusionsBecause hypoglycemia is common during OGTT among post-BS parturients, other diagnostic methods should be considered in this setting. The association found between hypoglycemia and poor fetal growth warrants investigation as to whether interventions to prevent hypoglycemia will improve fetal outcome.

QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals.

Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. 119 individuals (69 males, age 47.5±13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. QTc increased from 415.1±21.9ms (mean±standard deviation) at baseline to 444.9±26.5ms during hypoglycaemia (plasma glucose nadir, 1.6±0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0±22.7ms to 64.1±40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ⩾460ms in females and ⩾450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K+ ⩽3.6mmol/L), and plasma epinephrine increased from 220.4±169.5pmol/L at baseline to 2945.6±2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc.

Association of aerobic fitness level with exercise-induced hypoglycaemia in Type 1 diabetes.

To determine the impact of physical fitness level on hypoglycaemia risk during exercise in people with Type 1 diabetes. A total of 44 patients [34 adults (aged 22-70 years) and 10 adolescents (aged 12-18 years)] with Type 1 diabetes, treated with insulin pump therapy, underwent a standardized exercise session. Cardiorespiratory fitness (maximum oxygen uptake) was measured and classified, based on established norms for age and sex, into either poor (< 25th percentile) or good fitness level (> 25th percentile). Plasma glucose levels were measured every 10 min, each patient performed physical activity at 60% maximum oxygen uptake either on a treadmill for 1 h or on a bicycle for 30 min. Frequency of hypoglycaemia (plasma glucose < 4 mmol/l) and decline in plasma glucose levels during exercise were assessed. In all, 23 patients had a good exercise fitness level. Hypoglycaemic events occurred in 17/23 patients (74.0%) in the good fitness level group compared with 8/21 patients (38.0%) in the poor fitness level group (P = 0.02). Both groups had similar pre-exercise plasma glucose levels. The plasma glucose values during exercise in the good fitness level group compared with the poor fitness level group were: plasma glucose nadir 3.9 ± 1.6 vs 5.5 ± 2.4 mmol/l (P = 0.01) and plasma glucose change -4.6 ± 3.4 vs. -2.1 ± 3.1 mmol/l (P = 0.01). The correlation between the plasma glucose nadir and maximum oxygen uptake was r = -0.38 (P = 0.01). Patients with good fitness level seem to be more prone to hypoglycaemia during exercise. This could be the result of better insulin sensitivity and the fact that they tend to exercise at greater work thresholds. These results are a step toward a better understanding of the association between physical fitness and exercise-induced hypoglycaemia.

Role of the Entero-Insular Axis in the Pathogenesis of Idiopathic Reactive Hypoglycemia: A Pilot Study.

Idiopathic reactive hypoglycemia (IRH) is characterized by recurrent episodes of symptomatic hypoglycemia occurring within 4 hours after meals. The underlying mechanisms remain obscure. This study aimed to investigate the response of the glucoregulatory and gastrointestinal hormones to an oral glucose load (OGTT) in individuals with documented IRH. This was a cross-sectional study composed of outpatients referred to "Federico II" University of Naples. We enrolled subjects with IRH documented by a mixed meal under ordinary life conditions and healthy subjects as controls. We measured plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), GIP, and glucagon response to a 75-g OGTT in cases and controls. Ten IRH and eight control subjects were enrolled. During the OGTT, mean plasma glucose tended to be lower in IRH than in control subjects, reaching a statistically significant difference at 240 minutes (T240) (43 ± 1.6 vs 72 ± 0.3 mg/dL; P = .001). Accordingly, the insulin response was higher in IRH than in control subjects (P < .019) with a statistically significant difference (46%) at T90 (P = .045) and was associated with significantly lower glucagon levels in the late phase of the OGTT: at T120 (P = .031) and T180 (P = .048) in IRH than in control subjects. A greater GLP-1 response was found among IRH compared with control subjects (P = .005); GLP-1 peak was 2-fold higher in IRH individuals (9.77 ± 2.52 pmol/L) than in the control group (4.19 ± 0.53 pmol/L; P = .041). In the IRH group, GLP-1 peak inversely correlated with the nadir of plasma glucose (r = -0.66; P = .039). A multivariate analysis confirmed that GLP-1 peak independently predicted the plasma glucose nadir (β = -0.593; P = .026). GLP-1 may play a significant role in the pathogenesis of idiopathic IRH.

Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo-controlled, double-blind, crossover trial.

To investigate the effect of glucagon-like peptide 1 receptor agonist liraglutide on the counter-regulatory hormone response to hypoglycaemia in type 1 diabetes. We conducted a randomized, double-blind, placebo-controlled, single-centre trial, in which a total of 45 adults with type 1 diabetes [mean ± standard deviation age 34.5 ± 11.2 years, BMI 23.9 ± 2.4 kg/m(2) , glycated haemoglobin (HbA1c) 7.6 ± 0.8%, diabetes duration 16.6 ± 9.4 years] underwent a hypoglycaemic clamp after 4 weeks' crossover treatment with once-daily liraglutide/placebo added to insulin in one of three liraglutide dose groups: 0.6 mg (n = 15); 1.2 mg (n = 14); and 1.8 mg (n = 16). The main outcome measure was glucagon concentration at nadir plasma glucose (2.5 mmol/l). Clinical outcomes were also evaluated. Five participants were withdrawn from the trial; three because of adverse events. All participants were included in the analysis. Glucagon concentration at nadir plasma glucose was modest, trending towards lower concentrations at increasing liraglutide dose versus placebo: 34.7 versus 38.1 pg/ml, p = 0.555 (0.6 mg); 28.8 versus 37.2 pg/ml, p = 0.126 (1.2 mg); and 28.4 versus 37.5 pg/ml, p = 0.092 (1.8 mg). There was no difference, however, between liraglutide and placebo in incremental change in glucagon during hypoglycaemia. Other counter-regulatory hormone levels increased during hypoglycaemia with no systematic differences between groups. Glucose infusion rates were significantly lower with liraglutide versus placebo during the clamp. After 4 weeks' treatment, HbA1c remained unchanged in the liraglutide and placebo groups. Greater reductions in insulin dose and body weight were seen with liraglutide versus placebo. Liraglutide did not compromise hypoglycaemic responses in type 1 diabetes after 4 weeks' treatment.

Performance of a predictive algorithm in sensor-augmented pump therapy in the prevention of hypoglycaemia

The Predictive Low Glucose Management (PLGM) system consists of a Medtronic Veo pump, Enlite sensor, MiniLink REAL-Time transmitter, Bluetooth-RF translator and a predictive algorithm operating from a Blackberry smartphone. The system suspended insulin delivery when the pre-set hypoglycaemic threshold of 4.4mmol/L was predicted to be reached in 30 minutes. The aim of this study was to determine the plasma glucose profile with the PLGM system when hypoglycaemia was induced by (a) moderate-intensity exercise, (b) subcutaneous insulin bolus and (c) increasing the overnight basal infusion rate in individuals with type 1 diabetes. The primary outcome was the plasma glucose nadir following each hypoglycaemic stimulus with and without PLGM. Participants performed 30-60 minutes of moderate-intensity exercise or were administered a subcutaneous insulin bolus following a glucose stabilisation period on basal continuous subcutaneous insulin infusion. In participants studied with increased overnight basal rates, hypoglycaemia was induced by increasing basal rates by 180%. They were randomised and studied on 2 separate days; with PLGM off and with PLGM on. On both days, participants were observed until plasma glucose dropped to 2.8mmol/L or were symptomatic.

Depth and duration of hypoglycaemia achieved during the insulin tolerance test

The insulin tolerance test (ITT) is the gold standard for assessment of the pituitary adrenal axis but its use is limited because of concerns relating to the risk of hypoglycaemia. This study examined the depth and duration of hypoglycaemia achieved during the test in a large cohort of patients. Two hundred and twenty ITTs were performed from 2005 to 2010. A 1200-bed University Teaching Hospital. Two hundred and twenty ITTs were carried out in patients with suspected or known pituitary disorders. Intravenous insulin was administered to achieve nadir plasma glucose (NPG) of 2.2 mmol/l (39.6 mg/dl). Blood chemistry to show the cortisol and GH response to hypoglycaemic stress was measured. Predictors of depth and duration of hypoglycaemia, adverse events and within-subject variability of nadir glucose, peak cortisol and peak GH were studied. Thirty percent of the cohort achieved a nadir glucose of <2.0 mmol/l (36 mg/dl) that lasted for 60 min or more. The NPG correlated positively with fasting plasma glucose (FPG; r=0:56; P<0.0005), insulin dose (r=0.27; P<0.0005) and weight (r=0.21; P<0.004). The within subject variability of nadir glucose was 15.2%, peak cortisol was 11.7% and peak GH was 6.4%. The factors determining nadir blood glucose were FPG (b=0.56, P<0.0005, 20% contribution) and weight (b=0.14, P<0.05, 2% contribution). The five patients with adverse events had NPG and insulin dose comparable with the rest of the population. The hypoglycaemia achieved during the ITT is much lower than the target required. However, adverse events are few and do not relate to the depth of hypoglycaemia.

Blunted Counterregulatory Hormone Responses to Hypoglycemia in Young Children and Adolescents With Well-Controlled Type 1 Diabetes

We thank Graveling et al. (1) for their thoughtful comments regarding our article (2). In their letter, they argue that our conclusion was not supported by the study data because the achieved level of hypoglycemia was not adequate. They point out that the mean nadir plasma glucose level in our subjects was ∼60 mg/dl, whereas plasma glucose concentrations <60 mg/dl are often required to elicit …

Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity

In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus—9 with high and 9 with low RAS activity—underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group ( P = .004) and from 76 to 109 pg/L in the low-RAS group ( P = .01), with no difference between RAS groups ( P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.