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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2017 Jul 26;102(11):3953–3960. doi: 10.1210/jc.2017-00051

Antecedent Hypoglycemia Does Not Attenuate the Acceleration of Gastric Emptying by Hypoglycemia

Palash Kar 1,2,✉, Karen L Jones 3,4, Mark P Plummer 1,2, Yasmine Ali Abdelhamid 1,2, Emma J Giersch 2, Matthew J Summers 2, Seva Hatzinikolas 3, Simon Heller 5, Michael Horowitz 3,4, Adam M Deane 1,6
PMCID: PMC5673277  PMID: 28973430

Abstract

Context:

Acute hypoglycemia accelerates gastric emptying and increases cardiac contractility. However, antecedent hypoglycemia attenuates counterregulatory hormonal responses to subsequent hypoglycemia.

Objective:

To determine the effect of antecedent hypoglycemia on gastric and cardiac responses to subsequent hypoglycemia in health.

Design:

A prospective, single-blind, randomized, crossover study (performed at the Royal Adelaide Hospital, Adelaide, South Australia, Australia).

Patients:

Ten healthy young men 18 to 35 years of age were studied for 36 hours on two occasions.

Interventions:

Participants were randomly assigned to either antecedent hypoglycemia [three 45-minute periods of strict hypoglycemia (2.8 mmol/L] or control [three 45-minute periods of strict euglycemia (6 mmol/L)] during the initial 12-hour period. Participants were monitored overnight, and the following morning blood glucose was clamped at 2.8 mmol/L for 60 minutes and then at 6 mmol/L for 120 minutes. At least 6 weeks later participants returned for the alternative intervention. Gastric emptying and cardiac fractional shortening were measured with scintigraphy and two-dimensional echocardiography, respectively, on the morning of all 4 study days.

Results:

A single, acute episode of hypoglycemia accelerated gastric emptying (P = 0.01) and augmented fractional shortening (P < 0.01). Gastric emptying was unaffected by antecedent hypoglycemia (P = 0.74) whereas fractional shortening showed a trend to attenuation (P = 0.06). The adrenaline response was diminished (P < 0.05) by antecedent hypoglycemia

Conclusions:

In health, the acceleration of gastric emptying during hypoglycemia is unaffected by antecedent hypoglycemia, whereas the increase in cardiac contractility may be attenuated.

We studied antecedent hypoglycemia effects on gastric and cardiac responses to subsequent hypoglycemia, finding gastric emptying unaffected but that cardiac contractility may be attenuated.

Hypoglycemia is associated with considerable morbidity, as well as an increased risk of death among ambulant and hospitalized patients with diabetes (1, 2). In both health and diabetes, hypoglycemia triggers profound physiological responses, in part due to autonomic activation, including increases in catecholamine and cortisol secretion (3). However, antecedent hypoglycemia, even one episode, attenuates the catecholamine response and diminishes patient recognition to subsequent hypoglycemia (4). This effect is also noted with an increased number and differing duration of antecedent hypoglycemia (5–7).

The rate of gastric emptying (GE) is now recognized as a major determinant of the postprandial glycemic response in health and diabetes (8–10). The relationship between GE and glycemia is complex and bidirectional, as acute changes in the blood glucose concentration also have major effects on the rate of GE (11–13). In particular, in both healthy subjects and patients with type 1 diabetes, GE is accelerated markedly during acute hypoglycemia (11, 14, 15). This acute response, known to be blocked by intravenous atropine (16) and attenuated by exogenous administration of GLP-1 (12), is an important counterregulatory mechanism leading to an increased delivery of carbohydrate to the small intestinal and a consequent prompt increment in blood glucose (17).

Acute hypoglycemia also has major effects on the cardiovascular system. Sympathoadrenal activation and counterregulatory hormonal secretion results in an increase in blood pressure and left ventricular ejection fraction (EF); the latter changes are sustained for some time after resolution of hypoglycemia. However, changes in heart rate are inconsistent, probably because parasympathetic activation has the capacity to prevent much of the sympathetic-associated increase (3, 18, 19). Cardiac electrophysiological abnormalities may also occur, increasing the risk of arrhythmia (20).

No studies have evaluated whether antecedent hypoglycemia affects the rate of GE and cardiac responses to subsequent hypoglycemia. Because oral carbohydrate is the preferred treatment of the conscious individual with hypoglycemia (17), any attenuation of the protective response to accelerate GE may undermine management of the condition.

The primary and secondary hypotheses of this study were that compared with an initial hypoglycemic episode, antecedent hypoglycemia would (1) attenuate the acceleration of GE, and (2) attenuate the augmentation of cardiac fractional shortening (FS).

Materials and Methods

This was a prospective, single-blind, randomized, crossover study.

Study participants

Healthy young men aged 18 to 35 years of age were recruited, with written informed consent obtained prior to their participation. A young, healthy, relatively homogeneous cohort was chosen given that advancing age is a risk factor for autonomic neuropathy, which can affect both GE and the response to hypoglycemia (21). Exclusion criteria included a history of diabetes, hemoglobin A1c > 6.0%, impaired renal function, use of medication known to effect gastrointestinal function, and previous stomach or small intestinal surgery. The protocol was approved by the Human Research Ethics Committee of the Royal Adelaide Hospital and prospectively registered with the Australian New Zealand Clinical Trial Registry (ACTRN12614000986673).

Protocol

Each participant attended the hospital after an overnight fast on two occasions for ∼30 hours comprising a day 1 and day 2 on each occasion, separated by at least 6 weeks. The order of the two studies, that is, control or antecedent hypoglycemia, was randomized. Randomization was performed by the Department of Pharmacy at the Royal Adelaide Hospital. Allocation concealment was performed with study investigators notified of the intervention for participants on the morning of the study. Once enrolled, participants were unaware of the glycemic clamp that they had been allocated to on each study day (i.e., euglycemia or antecedent hypoglycemia). On arrival, an intravenous catheter was inserted into the antecubital veins of both arms for intravenous infusion of insulin/glucose and blood sampling, respectively. Each participant was given the same meals during both study periods (13). The protocol is summarized in Fig. 1.

Figure 1.

Figure 1.

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Protocol of the study outlining euglycemia (control) and antecedent hypoglycemia interventions. To compare effects of antecedent hypoglycemia, the primary comparison was between measurements made during hypoglycemia after 24 hours of euglycemia in hospital (C2) with measurements made during hypoglycemia after three periods of hypoglycemia in the hospital in the preceding 24 hours (AH2).

Clamp techniques have been described (12). In brief, insulin (Actrapid; Novo Nordisk Pharmaceuticals) was commenced at 125 mU/m2 per minute and then titrated to a maintenance rate of 40 mU/m2 per minute for 10 minutes. During each clamp, 25% glucose was administered intravenously concurrently with insulin. Blood was sampled intravenously and the blood glucose concentration was measured using a portable glucose meter (Optium Xceed; Abbott Laboratories). During the longer 3-hour clamps, blood glucose was measured every 5 minutes for 90 minutes (i.e., during the 45-minute period of hypoglycemia/euglycemia, followed by 45 minutes of stabilization) then every 15 minutes for the remaining 90 minutes. During the shorter 60-minute clamps, blood glucose was measured every 5 minutes for 90 minutes (i.e., during the 60-minute clamp and for 30 minutes after clamp). Using these measurements, intravenous glucose infusion was varied to maintain the desired blood glucose target (12).

Control

During day 1 of the control period (C1), each participant underwent three euglycemic clamps at a blood glucose of 6 mmol/L (12). The initial clamp was 3 hours in duration, allowing measurement of GE (described here), with each subsequent clamp lasting 60 minutes. There were 2-hour periods between each clamp, during which the clamp was ceased and blood glucose concentrations reflected endogenous concentrations (i.e., euglycemia). The following morning [day 2 of the control period (C2)], each participant underwent a hypoglycemic clamp with blood glucose stabilized at 2.8 mmol/L for 45 minutes, followed by a period of 15 minutes to return to euglycemia, then titration to 6 mmol/L for the remaining 2 hours (Fig. 1). This hypoglycemic clamp was predefined as the “control acute hypoglycemic clamp (C2),” as it followed 24 hours in hospital under controlled euglycemic study conditions.

Antecedent hypoglycemia

During day 1 of the antecedent hypoglycemia period (AH1), each participant underwent three hypoglycemic clamps at a blood glucose of 2.8 mmol/L. For each clamp period at least 15 minutes was allowed to reach a blood glucose of 2.8 mmol/L, and then another 15 minutes to achieve euglycemia at the end of each clamp. The initial clamp consisted of strict hypoglycemia (2.8 mmol/L) for 45 minutes, followed by a period of 15 minutes to return to euglycemia, and then 2 hours at 6 mmol/L (total clamp time of 3 hours). This initial hypoglycemic clamp allowed quantification of the effects of acute hypoglycemia without the confounder of study conditions or hospitalization for 24 hours. The following two clamps were each of 45 minutes in duration at 2.8 mmol/L, followed by 15 minutes to return to euglycemia (total clamp time of 60 minutes). There were 2-hour periods of euglycemia, with cessation of the insulin infusion, between each clamp. The following morning [day 2 of the antecedent hypoglycemia period (AH2)] each participant underwent a hypoglycemic clamp with blood glucose stabilized at 2.8 mmol/L for 45 minutes, followed by 15 minutes to return to euglycemia, and then maintained at 6 mmol/L for the subsequent 2 hours with measurement of GE. The period of strict hypoglycemia totaled 3 hours during the intervention period, which was based on previous studies that have established major effects of antecedent hypoglycemia with clamps lasting at least 30 minutes (7) and the total hypoglycemic time equaling 3 hours (5). A priori we defined that the primary period of interest as data from the antecedent hypoglycemic clamp (AH2) when compared with data from control acute hypoglycemic clamp (C2), as the period of time in the hospital, meals, and exertion were standardized, with the only difference between the two periods being three antecedent hypoglycemic clamp periods in the previous 24 hours (Fig. 1).

GE

GE was measured by scintigraphy during the first clamp of day 1 and day 2 of both the control (GEC1 and GEC2) and antecedent hypoglycemia (GEAH1 and GEAH2) periods. The test meal consisted of 100 g of minced beef (25 g of protein, 21 g of fat, ∼270 kcal) labeled with 20 MBq 99mtechnetium-sulfur colloid (22). It was administered once the target blood glucose concentration was achieved. Radioisotopic data were acquired in dynamic mode every minute for 180 minutes using a gamma camera (DigiRad 2020tc, Gammasonics) with the patient lying in the semirecumbent position. Data were corrected for subject movement, radionuclide decay, and gamma ray attenuation (23). GE curves were derived for the total stomach and expressed as percentage retention over time. Data were analyzed by the same individual (K.L.J.) blinded to the study conditions.

Cardiac function

During each visit, a four-chamber view echocardiography was performed using an ultrasound machine (SonoSite X-Porte, SonoSite Australasia) via parasternal long axis view by a single, unblinded, operator (P.K.) on day 1 and day 2 of both the control (FSC1 and FSC2) and antecedent hypoglycemia (FSAH1 and FSAH2) periods. Left ventricular end diastolic diameter (LVEDD) and end systolic diameter (LVESD) were measured, with FS calculated via a standardized formula [(LVEDD − LVESD)/LVEDD × 100] (24). Echocardiography was performed at the commencement of the clamp, 15 minutes after reaching and maintaining the target blood glucose concentration and then 45 minutes after maintaining target blood glucose to quantify FS. EF and stroke volume were calculated via the Teichholz equation (25).

Catecholamines and pancreatic polypeptide

Plasma samples were collected at the commencement of the clamp, 15 minutes after reaching the target blood glucose concentration and then 45 minutes after maintaining target blood glucose for the measurement of catecholamines (adrenaline and noradrenaline) and pancreatic polypeptide. Catecholamine samples were collected into chilled lithium heparin tubes containing 2 mg of sodium metabisulfite (Sigma-Aldrich). Pancreatic polypeptide samples were collected into chilled EDTA tubes. All samples were separated by centrifugation (3200 rpm for 15 minutes at 4°C) within 30 minutes of collection and then stored at −70°C until assayed (26). Catecholamine concentrations were measured via reverse phase isocratic high-performance liquid chromatography coupled with electrochemical detection. The sensitivity of the assay was 0.1 nmol/L with intrarun and interrun coefficient of variation of <6% and <9%, respectively. Pancreatic polypeptide was measured via an enzyme-linked immunosorbent assay kit with assay sensitivity of 12.3 pg/mL and the coefficient of variation 9.5% within assays and 8.9% between assays.

Symptoms of hypoglycemia

Symptoms of hypoglycemia were recorded using a previously described Likert scale (27), every 30 minutes (i.e., starting at clamp commencement, ending 45 minutes after achieving target blood glucose concentration), from 1 (none) to 7 (very severe) for each symptom. These questionnaires were completed during the 3-hour clamp on day 2 of each study period. Additionally, a visual analog scale was used to quantify appetite and nausea (28).

Statistical analysis

The sample size was determined on the basis of mean and standard deviation of previous GE data [area under the curve (AUC) during 0 to 180 minutes] (12). Ten participants completing both study periods provided 80% power to detect a 63% difference in GE (quantified as AUC from 0 to 180 minutes) when comparing the predefined, primary outcome of a single episode of hypoglycemia (control day 2) vs antecedent hypoglycemia (intervention day 2) at a two-sided significance level of 0.05. Only data from participants completing both study days were retained and analyzed. The primary outcome of GE (AUC from baseline to 180 minutes) was derived using the trapezoidal rule (12, 13, 29). Catecholamine and pancreatic polypeptide levels were compared using incremental AUC (iAUC0–60). Data were analyzed using paired sample t tests, Wilcoxon signed ranks tests, or McNemar tests as appropriate. Data were also tested for period and carryover effects. To test the robustness of observations of the primary outcome during the longer time period (AUC0–180), a priori secondary analyses of GE data were also performed for the time period of strict hypoglycemia (i.e., GE AUC0–45) (12, 29). Statistical analyses were performed using SPSS version 22.0 with statistical significance set at P < 0.05.

Results

Thirteen participants were enrolled with 10 completing both study periods. All studies were well tolerated. Three participants did not return for the second visit, two because of personal reasons and one withdrew consent. GE data from the 10 participants who completed both study periods were included [age, 22.5 (3.1) years; body mass index, 23.8 (1.7) kg/m2; hemoglobin A1c, 5.2% (0.2%)]. Echocardiography images were inadequate in one study participant and these data are limited to nine participants.

Blood glucose

Blood glucose concentrations were clamped effectively at the desired hypoglycemic and euglycemic targets (Supplemental Fig. 1 (652.9KB, pdf) ).

GE

Acute hypoglycemia accelerated GE substantially during the total measured GE period (Fig. 2; AUC0–180: GEC1 vs GEC2, P = 0.01). Moreover, this acceleration was not affected by antecedent episodes of hypoglycemia (Fig. 2; AUC0–180: GEAH2 vs GEC2, P = 0.74). When evaluating only the time period of strict hypoglycemia, there was no significant difference with either acute hypoglycemia when compared with normoglycemia (Fig. 2; AUC0–45: GEC1 vs GEC2, P = 0.08) or antecedent episodes of hypoglycemia compared with the first episode of hypoglycemia (Fig. 2; AUC0–45: GEAH2 vs GEC2, P = 0.85).

Figure 2.

Figure 2.

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GE curves during control (C1, black circles; C2, striped circles) and antecedent hypoglycemia (AH1, dark gray squares; AH2, light gray squares) study periods. The control period underwent a clamp at 6 mmol/L for 180 minutes. The antecedent hypoglycemia period underwent an initial clamp at 2.8 mmol/L for 45 minutes, followed by 15 minutes to achieve euglycemia, then another 120 minutes at 6 mmol/L (total 180 minutes). Data are mean (standard deviation).

Cardiac function

When compared with euglycemia, acute hypoglycemia increased FS at the end of the strict hypoglycemic period (Table 1; Supplemental Fig. 2 (652.9KB, pdf) ; FSC2 vs FSC1, P < 0.01). Mean FS was less after antecedent hypoglycemia, but the difference did not achieve the predefined level of significance (FSAH2 vs FSC2, P = 0.06).

Table 1.

FS at the End of the Period of Strict Hypoglycemia During Control and Antecedent Hypoglycemia Study Periods

FS (%)
C1 28.4 (5.7)
C2 36.8 (8.1)
AH1 33.9 (11.0)
AH2 31.7 (8.4)
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Data are mean (standard deviation).

Acute hypoglycemia also increased the EF [EFC2 65.8% (3.5%) vs EFC1 54.3% (3.1%), P < 0.01] and stroke volume [SVC2 70.4 (7.1) mL per beat vs SVC1 62.4 (6.5) mL per beat, P = 0.03]. The increase in EF was attenuated by antecedent hypoglycemia [EFAH2 58.6% (4.0%) vs EFC2 65.8% (3.5%), P = 0.04] without any effect on stroke volume [SVAH2 70.8 (8.0) mL vs SVC2 70.4 (7.1) mL, P = 0.90].

Catecholamines and pancreatic polypeptide

There was a significant rise in adrenaline levels on both the control (P = 0.01) and antecedent hypoglycemia days (P < 0.01). However, when compared with acute hypoglycemia, antecedent episodes of hypoglycemia resulted in a smaller rise in the concentration of adrenaline (Fig. 3; iAUC60, AH2 vs C2, P < 0.05). No differences were observed with noradrenaline concentrations (P = 0.61). When compared with baseline, pancreatic polypeptide concentrations increased during the postprandial phase of the control (P = 0.02) and antecedent hypoglycemia days (P < 0.01); mean values were not significantly less after antecedent hypoglycemeia.

Figure 3.

Figure 3.

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Plasma adrenaline iAUC60 comparing day 2 of control and antecedent hypoglycemia study periods. Data are mean (standard deviation).

Neurologic symptoms and hunger ratings

No significant differences were noted between the groups in autonomic and neuroglycopenic questionnaire scores (Supplemental Table 1 (652.9KB, pdf) ). Patients reported greater hunger during C2 when compared with the AH2 (P = 0.04; Supplemental Table 2 (652.9KB, pdf) ). No other significant differences were noted.

Discussion

This study in healthy subjects confirms that acute hypoglycemia accelerates GE and that antecedent hypoglycemia attenuated the adrenaline response to subsequent hypoglycemia. The key finding is that the marked acceleration of GE rate is not modified by antecedent episodes of hypoglycemia. Accordingly, the primary hypothesis that acceleration of GE would diminish with antecedent hypoglycemia was rejected. The major secondary finding is that antecedent episodes of hypoglycemia may attenuate the increase in FS of the left ventricle in response to acute hypoglycemia.

The mechanisms underlying acceleration of GE by a single episode of acute hypoglycemia are poorly defined. In rats the acceleration of GE during hypoglycemia is suppressed by intravenous administration of fructose (a monosaccharide that does not cross the blood–brain barrier), but suppression is eliminated by hepatic vagotomy (30). These data suggest that hypoglycemia-induced acceleration of GE may be inhibited by signals from the periphery via increased calorie delivery to the liver. That this inhibition is abolished with hepatic vagotomy suggests that the hepatic branch of the vagus nerve may modulate this effect on GE. Hypoglycemia also completely overrides the slowing of GE by exogenous amylin in rats (31). Furthermore, glucose-sensitive neurons in rodents may compete with, or take precedence over, amylin receptors, which are both found in the area postrema and the nucleus tractus solitarius (32).

In humans, acute hypoglycemia accelerates the rate of GE (14), but cholinergic blockade with atropine inhibits this response (16). The results from this study therefore suggest that vagal cholinergic mechanisms may be more important than adrenergic mechanisms in modulating GE rate at differing blood glucose concentrations. However, this hypothesis is highly speculative, as no animal or human studies have previously evaluated the effect of, and mechanisms underlying, antecedent hypoglycemia on GE or cardiac contractility. Previous data related to counterregulatory hormones and GE suggest that exogenous, and endogenous, noradrenaline and adrenaline may slow GE via β-adrenoreceptor stimulation (33, 34), but the magnitude of effect is less than with cholinergic blockade, which may explain, at least in part, why the rate of GE during hypoglycemia did not appear to be affected by antecedent hypoglycemic episodes even though the adrenaline rise was diminished.

Consistent with the demonstrated effect on adrenaline concentrations, it appears that the sympathetic nervous system is attenuated following repeated hypoglycemia. In contrast, pancreatic polypeptide, which may be indicative of the central parasympathetic response, was unaffected. However, pancreatic polypeptide may also be influenced by the rate of GE per se, possibly negating an effect of antecedent hypoglycemia (35). It is also possible that antecedent hypoglycemia has differing effects on the sympathetic and parasympathetic nervous systems, consistent with the concept that blunted physiological responses to antecedent hypoglycemia occur in a hierarchal order, as previously noted (7).

In contrast to GE, antecedent episodes of hypoglycemia attenuated the augmentation of FS and EF. The effect of antecedent hypoglycemia on cardiac function is not well studied. Adler et al. (36) explored its effect on cardiovascular autonomic function in humans and reported that baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after antecedent episodes of hypoglycemia.

The diminished endogenous counterregulatory hormones during antecedent hypoglycemic episodes (5, 7) may explain the observations related to FS. The mechanisms underlying the attenuation of counterregulator hormone secretion in the setting of repeated hypoglycemia are uncertain (37), with possibilities including increased levels of cortisol (38), an increase in alternative sources of metabolic fuel (lactate and ketone bodies) (39), and changes in brain glucose uptake (40). The potential mechanisms are described in detail elsewhere (41).

Strengths of the present study include novelty and the clinical relevance of the primary outcome, GE. The methodology ensured that the GE studies were performed after a prolonged period of stabilization and monitoring, thereby reducing bias and potential confounders. The blood glucose targets for hypoglycemia were based on previous studies (5, 6, 37, 42), and the insulin/glucose algorithm was established (12) and ensured precise glycemic clamping. Moreover the depth, duration, and frequency of hypoglycemia were chosen based on previous studies (7, 43, 44) and ensured a potent antecedent hypoglycemic stimulus. Scintigraphy was used to quantify GE, which is the gold standard for the measurement of GE and allows small, but clinically important, differences to be detected using similar sample sizes (9, 13, 22), with analysis performed by an investigator blinded to the blood glucose concentration. Additionally, no significant period effects and carryover effects were evident.

There are, however, a number of limitations. This study was performed on healthy young men who do not normally experience hypoglycemia. Accordingly, relevance to older persons, patients with diabetes, those with autonomic neuropathy, and those taking medications that affect the gastrointestinal tract can only be inferred. Only a specific blood glucose concentration and defined period of hypoglycemia were tested (7). Blood glucose was measured on venous samples using a portable glucometer for practical reasons, with inherent limitations in precision, but the differences in blood glucose between euglycemia and hypoglycemia were substantial. Furthermore, the acceleration in GE that occurred during hypoglycemia was marked. The methodology used to evaluate secondary outcomes, including the use of echocardiography to measure FS and EF, was chosen because the technique is minimally invasive, does not involve radiation, and could, accordingly, be performed without compromising the assessment of the primary outcome. Nonetheless, echocardiography is operator-dependent, which could potentially bias toward a positive result. Other changes in cardiovascular physiology are known to occur with hypoglycemia, as described elsewhere (3, 18, 19). Unmeasured confounders must also be considered. The overnight stay in the hospital may affect the regulation of gastrointestinal function (45, 46), but was chosen based on our previous study that demonstrated a positive result (13). Symptoms that have been shown to be affected by antecedent hypoglycemia were not a major focus. Lastly, given the relatively small number of study participants, a β-type error cannot be excluded, i.e., it is possible that antecedent hypoglycemia has a minor effect on GE that was not detected. The effects of antecedent hypoglycemia on FS “borders on significance,” which may represent an insufficient sample size, but overinterpretation of P values should be avoided (47).

This study provides important inferences for clinical care. Hypoglycemia occurs repeatedly in a proportion of patients with diabetes, it may be accompanied by unawareness, and it is causally associated with increased morbidity and mortality (48, 49). The cornerstone of management involves the administration of an oral carbohydrate. The observations from this study suggest that, at least in health, the rate of GE is maintained in the face of repeated hypoglycemic events. This represents an important safety factor in treating recurrent events with oral carbohydrate.

In conclusion, the acceleration of GE during acute hypoglycemia in health does not appear to be affected by antecedent hypoglycemia, whereas the increase in cardiac contractility may be attenuated. Accordingly, if similar gastric responses are observed in individuals with type 1 and 2 diabetes, management of hypoglycemia with oral carbohydrate should remain effective in patients with recurrent hypoglycemia.

Acknowledgments

The authors thank Kylie Lange for statistical expertise and all patients who kindly gave their time toward this study.

Financial Support: P.K. is supported by a Royal Adelaide Hospital A.R. Clarkson Scholarship, K.L.J. is supported by a National Health and Medical Research Council Senior Clinical Career Development Award Fellowship, and A.M.D. is supported by a National Health and Medical Research Council Early Career Fellowship.

Clinical Trial Information: Australian New Zealand Clinical Trial Registry no. ACTRN12614000986673 (registered 9 December 2014).

Author Contributions: P.K. was involved in the conception and design of the study, acquiring data, analysis and interpretation of data, and drafting and revising the manuscript for final submission. K.L.J. was involved in design of the study, analysis of the scintigraphic data, and revising the manuscript. M.P.P. was involved in the conception, design, and coordination of the study along with acquiring data and revising the manuscript. E.J.G. and M.J.S. assisted with collecting data and reviewed the manuscript. S.H. collected the scintigraphic data and revised the manuscript. S.H. was involved in design of the study and edited and redrafted the manuscript. M.H. helped conceive and design the study and assisted in revising the manuscript. A.M.D. supervised P.K. and was involved in the conception and design of the study, analysis and interpretation of data, and drafting and revising the manuscript for final submission. All authors read and approved the final manuscript. P.K. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Current Affiliation: Y. Ali Abdelhamid’s current affiliation is Intensive Care Unit, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.

Acknowledgments

Disclosure Summary: The authors have nothing to disclose.

Footnotes

Abbreviations:
AH1
day 1 of the antecedent hypoglycemia period
AH2
day 2 of the antecedent hypoglycemia period
AUC
area under the curve
C1
day 1 of the control period
C2
day 2 of the control period
EF
ejection fraction
FS
fractional shortening
GE
gastric emptying
iAUC
incremental area under the curve
SV
stroke volume.

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