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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0513
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4489-4495
Copyright © 2005 by The Endocrine Society

Insulin-Induced Hypoglycemia Accelerates Gastric Emptying of Solids and Liquids in Long-Standing Type 1 Diabetes

Antonietta Russo, Julie E. Stevens, Richard Chen, Diana Gentilcore, Richard Burnet, Michael Horowitz and Karen L. Jones

Department of Medicine (A.R., J.E.S., R.C., D.G., M.H., K.L.J.) and Endocrine and Metabolic Unit (R.B.), Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia 5005, Australia

Address all correspondence and requests for reprints to: Dr. Karen L. Jones, University of Adelaide, Department of Medicine, Royal Adelaide Hospital, Frome Road, Adelaide, South Australia, 5005, Australia. E-mail: karen.jones{at}adelaide.edu.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The rate of gastric emptying of carbohydrate is a major determinant of postprandial glycemia. In healthy subjects and patients with uncomplicated type 1 diabetes, there is evidence that gastric emptying may be accelerated by insulin-induced hypoglycemia.

Objective: The objective was to determine the effects of acute hypoglycemia on gastric emptying in long-standing type 1 diabetes and evaluate whether the response to hypoglycemia is influenced by the rate of gastric emptying during euglycemia and/or autonomic dysfunction.

Design: Gastric emptying of a solid/liquid meal (100 g 99mTc–minced beef and 150 ml 67Ga-EDTA-labeled water) was measured by scintigraphy on 2 separate days, during hypoglycemia and euglycemia.

Setting: These studies took place at the Department of Nuclear Medicine, Positron Emission Tomography, and Bone Densitometry at the Royal Adelaide Hospital.

Patients: Twenty type 1 patients (4 female, 16 male; age, 45.9 ± 2.3 yr; duration of known diabetes, 18.0 ± 2.7 yr) were recruited from outpatient clinics and the Diabetes Centre at the Royal Adelaide Hospital.

Intervention: Hypoglycemia (~2.6 mmol/liter) was established 15 min before and maintained for 45 min after meal consumption. On one of the days, autonomic nerve function was evaluated using cardiovascular reflex tests.

Main Outcome Measure: The main outcome measure was gastric emptying during hypoglycemia when compared with euglycemia.

Results: Twelve of the 20 subjects had autonomic neuropathy. Gastric emptying of both solid (P < 0.001) and liquid (P < 0.05) was faster during hypoglycemia. The magnitude of this acceleration was greater when the rate of gastric emptying during euglycemia was slower (solid, percentage retention at 100 min, r = –0.52, P < 0.05; liquid, 50% emptying time, r = –0.82, P < 0.0001, but not influenced by autonomic nerve function).

Conclusions: Insulin-induced hypoglycemia accelerates gastric emptying of solids and liquids in long-standing type 1 diabetes, even in those patients with delayed emptying, and is likely to be an important mechanism in the counter-regulation of hypoglycemia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS NOW recognized that the rate of gastric emptying is a major determinant of the glycemic response to carbohydrate-containing meals in both type 1 and type 2 diabetes (1, 2, 3) and that gastric emptying is abnormally slow in 30–50% of patients with long-standing diabetes (4, 5, 6, 7, 8, 9, 10). The risk of gastroparesis is known to be greater in those patients with autonomic neuropathy (usually assessed by cardiovascular reflex tests), but the relationship between the delay in gastric emptying and the presence of autonomic neuropathy is not strong (4, 7, 8, 11, 12). Disordered gastric emptying in diabetes may also result from acute changes in the blood glucose concentration (3, 13, 14, 15, 16, 17, 18, 19).

Although it is well established that acute hyperglycemia slows gastric emptying in both normal subjects (3, 17) and type 1 diabetic patients (13, 18, 19), there is relatively little information about the effects of hypoglycemia on gastric emptying (14, 15), and only one study has hitherto evaluated patients with diabetes (14). The initial report by Schvarcz et al. (14) involved eight young adult patients with uncomplicated type 1 diabetes of short duration; during acute hypoglycemia, gastric emptying was apparently much faster. The observations were subsequently confirmed in a study of eight healthy young adults (15). A substantial methodological limitation of both studies (14, 15) is that they were not randomized: gastric emptying was always measured initially during euglycemia and, subsequently, during hypoglycemia. Furthermore, although a dual-isotope technique was used to measure gastric emptying of solids and liquids concurrently, the labeling was demonstrably imprecise, because solid and liquid meals were reported to empty from the stomach at about the same rate during euglycemia, whereas solids are known to empty from the stomach much more slowly than low-nutrient liquids (20). Hence, the conclusions derived from these studies (14, 15) may not be valid. There is no information about the effects of acute hypoglycemia on gastric emptying in patients with long-standing type 1 diabetes, nor is it known whether the response to hypoglycemia is influenced by the rate of gastric emptying during euglycemia or the presence of gastroparesis. Schvarcz et al. (21) reported in healthy subjects that the acceleration of gastric emptying induced by hypoglycemia is blocked by concurrent administration of atropine, indicating that cholinergic stimulation is important in mediating the effect. It is, however, not known whether the gastric emptying response to hypoglycemia is modified by the presence of autonomic neuropathy.

The aims of this study were to determine the effects of acute hypoglycemia on gastric emptying and evaluate whether the response to hypoglycemia is influenced by the rate of gastric emptying during euglycemia or autonomic dysfunction, in long-standing type 1 patients.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Twenty type 1 patients (4 female, 16 male; age, 45.9 ± 2.3 yr, mean ± SE; body mass index, 26.3 ± 0.7 kg/m2; duration of diabetes, 18.0 ± 2.7 yr) were recruited from outpatient clinics and the Diabetes Centre at the Royal Adelaide Hospital. Glycated hemoglobin was 8.1 ± 0.3% (normal, <6%). Severe cardiac or respiratory disease, previous gastrointestinal surgery (apart from uncomplicated appendectomy), and the use of medication known to affect gastrointestinal motility represented exclusion criteria. The plasma creatinine was also required to be within the normal range (≤0.12 mmol/liter). Patients were not selected on the basis of gastrointestinal symptoms, gastric emptying status, or autonomic nerve function.

A physical examination was performed to assess diabetic microvascular complications. Retinopathy was graded on a recent ophthalmological assessment. Peripheral neuropathy was diagnosed when absent ankle reflexes were associated with either motor or sensory changes (4). Written, informed consent was obtained from each patient before enrollment in the study in accordance with the Declaration of Helsinki, and the protocol was approved by the Human Ethics Committee of the Royal Adelaide Hospital.

Protocol

Each subject attended the Department of Nuclear Medicine, Positron Emission Tomography, and Bone Densitometry at about 0900 h after an overnight fast (12 h for solids, 10 h for liquids) on two separate occasions for measurement of gastric emptying. Smoking was prohibited for 24 h before each gastric emptying measurement. On one day, the blood glucose concentration was maintained in the euglycemic range (~6 mmol/liter) for the duration of the gastric emptying measurement, whereas on the other day, hypoglycemia (~2.6 mmol/liter) was induced and maintained for 60 min, followed by euglycemia. The studies were performed in a single-blind, randomized manner, and the two study days were separated by a minimum of 4 d. Two iv cannulae were inserted, one in an antecubital vein of the right arm for infusion of glucose and insulin, and the other retrogradely on the dorsum of the left hand for blood sampling. The left hand was heated with an electric pad to "arterialize" the venous blood. A blood pressure cuff (DINAMAP; Johnson & Johnson, Tampa, FL) was placed around the left arm for measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR).

The blood glucose concentration was stabilized at the desired level using a glucose-insulin clamp. The rate of insulin infusion (Actrapid; Novo Nordisk Pharmaceuticals, Auckland, New Zealand) based on a standard rate of 80 mU/m2·min was initially variable (0–10 min) according to the subject’s body surface area and then constant for the remainder of the study (22, 23), whereas the glucose (25%) infusion was varied to maintain the blood glucose at the desired level (23). When venous blood glucose was stabilized at either 6 mmol/liter (euglycemia) or 2.6 mmol/liter (hypoglycemia) for 15 min, subjects ingested the meal. On the hypoglycemic day, the blood glucose concentration was maintained at approximately 2.6 mmol/liter for 60 min [i.e. t = –15–45 min, returned to euglycemic levels (i.e. 6 mmol/liter) between t = 45 and 75 min, and maintained at that level for the remainder of the study (i.e. t = 75–120 min]. On the euglycemic day, the blood glucose was maintained at approximately 6.0 mmol/liter from t = –15–120 min. Blood glucose concentrations were measured every 5 min throughout each study using a portable glucose meter (Medisense Precision QID; Abbott Laboratories, Bedford, MA). Plasma glucose was measured using the hexokinase method on the venous blood samples (~20 ml) obtained at t = –15, 0, 15, 30, 45, 60, 75, 90, 105, and 120 min.

Measurements

Gastric emptying. Gastric emptying was measured using a dual-isotope scintigraphic technique (20, 24). The test meal comprised 100 g lean minced beef labeled with 20 MBq 99mTc-sulfur colloid chicken liver and 150 ml water labeled with 7 MBq 67Ga-EDTA (2). The solid meal was eaten within 5 min, followed by the water, which was consumed within 1 min. Radioisotopic data were acquired with the subject seated with their back against a gamma camera (Siemens, Chicago, IL) at 1 min frames for the first hour and 3 min frames thereafter. Time zero (t = 0) was defined as the time of meal completion, and gastric emptying was monitored for 120 min. Data were corrected for radionuclide decay, {gamma} ray attenuation, and subject movement, using previously described methods (20, 25). Regions of interest were drawn for the total stomach, which was subsequently divided into proximal and distal stomach regions. Gastric emptying curves for total, proximal, and distal stomach regions, expressed as percentage retention over time, were then derived (25). For the solid component of the meal, the lag phase (Tlag, defined as the time at which activity was first seen in the proximal small intestine) and the percentage of the solid meal remaining in the stomach at 100 min (T100) were determined; for the liquid component, the time for 50% emptying (T50) was derived (24, 26). Delayed gastric emptying was defined as a T100 of more than 66% and a T50 more than 35 min based on an established normal range (20).

Upper gastrointestinal and hypoglycemic symptoms. Before the commencement of the first study, the following upper gastrointestinal symptoms were assessed: lack of appetite, nausea, early satiation, vomiting, upper abdominal discomfort or distension, abdominal pain ("gastric symptoms"), dysphagia, heartburn, and acid regurgitation ("esophageal symptoms") using a validated questionnaire (2, 4). The severity of each symptom was graded as follows: 0, none; 1, mild; 2, moderate; 3, severe, for a maximum total score of 27.

Hypoglycemic symptoms were evaluated on each day at –30, –15, –10, –5, 0, 15, 30, 45, 60, 75, 90, and 120 min, and subjects were asked to score the following symptoms: pounding heart, shakiness, sweating, headache, difficulty thinking, and slowed thinking, on a scale of 1–7, in which 1 indicated that the subject did not have the symptom and 7 indicated that the symptom was experienced in the extreme; the maximum possible score was 42 (23).

Blood pressure and HR. SBP, DBP, and HR were measured at –30, –15, 0, 15, 30, 45, 60, 75, 90, 105, and 120 min using the automated device (DINAMAP).

Autonomic nerve function. Autonomic nerve function was measured at the end of the second visit, approximately 2 h after the completion of the gastric emptying measurement, using standardized cardiovascular reflex tests (4, 24, 27). Parasympathetic function was evaluated by the variation (R-R interval) of the HR during deep breathing and in response to standing (30:15 ratio). Sympathetic function was assessed by the fall in SBP in response to standing. The result of each test was scored as follows: 0, normal; 1, borderline; 2, abnormal. A score equal to or more than 3 was considered to indicate definite autonomic dysfunction (2, 4, 24).

Statistical analysis

Individual comparisons between the two "treatment" groups (hypoglycemia vs. euglycemia) were performed using Student’s t test. Data were analyzed using repeated-measures ANOVA with treatment and time as variables. In the case of a treatment x time interaction, contrasts were used to compare individual time points between the two treatment groups to examine preplanned hypotheses. Relationships between gastric emptying and other parameters were assessed by linear regression analysis. Data are shown as mean ± SEM unless stated otherwise. A P value of <0.05 was considered significant in all analyses.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
No serious untoward effects occurred on either of the test days. Although some subjects experienced mild neuroglycopenic symptoms, all were able to cooperate and eat the test meal. Twelve of the 20 patients had definite evidence of autonomic neuropathy, with a mean score of 3.0 ± 0.3. Five subjects had proliferative retinopathy, and five (25%) had evidence of peripheral neuropathy. Blood glucose concentrations closely approximated the desired levels; during hypoglycemia, the blood glucose between t = –15 and 45 min was 2.6 ± 0.1 mmol/liter (Fig. 1Go). There was no difference in the blood glucose concentration between the 2 d after 75 min.



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  		FIG. 1. Plasma glucose concentrations in studies conducted during hypoglycemia (black circles) and euglycemia (white circles). Blood glucose concentrations were maintained using a sliding scale glucose-insulin clamp technique based on a standardized insulin infusion at 80 mU/m2·min. Gastric emptying was measured between t = 0 and 120 min. Data are mean ± SEM. *, P < 0.05; #, P < 0.0001 compared with euglycemia (ANOVA).

 
Gastric emptying (Fig. 2Go)

Five of the 20 subjects had delayed solid and 7 delayed liquid emptying during euglycemia. In two subjects, gastric emptying of solid was markedly delayed (solid T100 ≥ 3 SDs outside the normal range). There was no significant difference in gastric emptying of solids (solid T100) or liquids (liquid T50) during euglycemia in patients with autonomic neuropathy when compared with the remainder of the group (data not shown).



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  		FIG. 2. Gastric emptying and intragastric distribution of the solid (left) and liquid (right) components of the meal during hypoglycemia (black circles) and euglycemia (white circles). Data are mean ± SEM. *, P < 0.05; #, P < 0.01 compared with euglycemia (ANOVA).

 
There was a significant treatment x time interaction (P < 0.0001) for solid gastric emptying; gastric emptying was faster (P < 0.001) during hypoglycemia from 60 min (Fig. 2AGo). The Tlag phase (hypoglycemia vs. euglycemia) was 16.8 ± 4.3 vs. 22.7 ± 6.0 min (P = 0.2), and the retention at solid T100 was 35.7 ± 5.4 vs. 48.6 ± 5.2% (P = 0.04). There was also a treatment x time interaction for liquid emptying (P < 0.05); gastric emptying was faster (P < 0.05) during hypoglycemia when compared with euglycemia from 15 min (Fig. 2BGo). The liquid T50 also tended to be less during hypoglycemia (26.4 ± 4.8 vs. 41.2 ± 7.6 min; P = 0.09). Of the 20 patients, three had delayed emptying for solid and two for liquid on the hypoglycemic day.

There was no significant difference between euglycemia and hypoglycemia in the retention of solid in the proximal stomach (Fig. 2CGo). However, there was a treatment x time interaction for the retention of liquid in the proximal stomach (P < 0.01), so that retention was less (P < 0.05) on the hypoglycemic day (Fig. 2DGo). There was a significant treatment x time interaction (P < 0.01) for gastric emptying of solid from the distal stomach, so that retention in the distal stomach was less (P < 0.05) during hypoglycemia when compared with euglycemia (Fig. 2EGo). There was no significant difference in distal stomach retention of liquid between the 2 d (Fig. 2FGo).

When the cohort was divided according to whether their gastric emptying was normal or delayed during euglycemia (i.e. solid and/or liquid emptying), the magnitude of the acceleration of gastric emptying of liquids during hypoglycemia was greater (change in T50, 38.9 ± 21.1 vs. 1.8 ± 2.6 min; P < 0.05) in those with delayed emptying of liquid; for solid emptying, this was not quite significant (change in T100, 30.0 ± 19.8 vs. 7.3 ± 3.6%; P = 0.09). In the two subjects with markedly delayed gastric emptying of solids, gastric emptying was faster during hypoglycemia. When the cohort was divided into those with and without cardiovascular autonomic neuropathy, there was no significant difference in the magnitude of the change in gastric emptying of either solid (change in T100, 8.9 ± 4.1 vs. 19.0 ± 13.3%; P = 0.40) or liquid (change in T50, 4.6 ± 9.5 vs. 30.0 ± 14.1 min; P = 0.14), nor were there any relationships between either the total score for autonomic neuropathy or the 30:15 ratio for the HR response to standing between the change in gastric emptying of solids or liquids during euglycemia and hypoglycemia.

There was a significant relationship between the magnitude of the acceleration of gastric emptying in response to hypoglycemia and the rate of gastric emptying during euglycemia for both the solid T100 (r = –0.52; P < 0.05) and liquid T50 (r = –0.82; P < 0.0001) (Fig. 3Go), i.e. hypoglycemia had a greater effect when gastric emptying was relatively more slow.



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  		FIG. 3. The relationship between the magnitude of the change in gastric emptying for the solid retention at 100 min (T100) and liquid 50% emptying time (T50) between hypoglycemia and euglycemia and the rate of gastric emptying during euglycemia. Individual data for the 20 subjects are shown.

 
Upper gastrointestinal and hypoglycemic symptoms

Upper gastrointestinal symptoms were present in 13 of the 20 subjects; the total score was 3.0 ± 0.83 (gastric symptoms, 2.2 ± 0.7; esophageal symptoms, 0.9 ± 0.3). There was no significant relationship between the total symptom score and either the solid T100 (r = –0.17; P = 0.47) or the liquid T50 (r = –0.31; P = 0.18) during euglycemia.

There was a significant treatment x time interaction for pounding heart (P < 0.0001), shakiness (P < 0.0001), and sweating (P < 0.0001). The symptom of pounding heart was greater on the hypoglycemic day between t = –30 and 15 min (P < 0.01); shakiness was greater during hypoglycemia from t = –30 to 45 min (P < 0.01); sweating was greater during hypoglycemia between t= –15 and 15 min (P < 0.01), when compared with euglycemia (data not shown). There was a treatment x time interaction for total symptoms (P < 0.05); symptoms of hypoglycemia were greater from t = –15 to 15 min (P < 0.01) when compared with the euglycemic day (Fig. 4Go). When the cohort was divided into those with and without cardiovascular autonomic neuropathy, there was no significant difference in the total score for hypoglycemic symptoms during the hypoglycemic study day (data not shown).



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  		FIG. 4. Symptoms of hypoglycemia during hypoglycemia (black circles) and euglycemia (white circles). Data are mean ± SEM. #, P < 0.01 compared with euglycemia (ANOVA).

 
Blood pressure and HR

There was no difference in baseline SBP or DBP or HR between the 2 d: (SBP, hypoglycemia, 122.1 ± 3.4 mm Hg vs. euglycemia, 121.1 ± 3.6 mm Hg; DBP, 68.2 ± 2.2 vs. 69.8 ± 2.2 mm Hg; and HR, 77.4 ± 3.1 vs. 73.6 ± 2.5 beats/min). There was also no significant difference in SBP or DBP during the gastric emptying measurements between the two treatments. There was, however, a treatment x time interaction for HR (P < 0.05), so that HR was greater (P < 0.05) from t = –15 to 15 min during hypoglycemia (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our study evaluated the acute effects of insulin-induced hypoglycemia on gastric emptying in a heterogeneous group of patients with long-standing type 1 diabetes. Only one study has hitherto evaluated the effects of hypoglycemia on gastric emptying in type 1 diabetes (14); this study only included eight subjects, all of whom had uncomplicated diabetes, and interpretation is hampered by methodological limitations. Our study was randomized, and gastric emptying of both solid and liquid meal components was evaluated with a precise scintigraphic technique (20, 24). We have demonstrated the following in long-standing type 1 diabetes: 1) that hypoglycemia accelerates gastric emptying of both solid and liquid meal components and 2) that the magnitude of this acceleration is greater in those patients who have slower gastric emptying during euglycemia.

It is now well established that acute elevations in blood glucose concentrations have a major, reversible effect on gastric emptying (3, 13, 17, 19), as well as motility in other regions of the gastrointestinal tract (28, 29, 30) in both healthy subjects and diabetic patients. Even elevations in the blood glucose concentration that are within the normal postprandial range influence gastric emptying; in both healthy subjects and uncomplicated type 1 patients, emptying of solids and liquids is slower at a blood glucose concentration of 8 vs. 4 mmol/liter (16). Aylett (31) was the first to report that gastric emptying of water was accelerated by insulin-induced hypoglycemia in a group of patients with duodenal ulceration. Schvarcz et al. subsequently performed studies relating to the effects of acute hypoglycemia (blood glucose, ~1.9 mmol/liter) on gastric emptying in uncomplicated type 1 patients (14) and healthy subjects (15). Although the radioisotopic labeling was imprecise, and the studies were not randomized, the apparent acceleration of gastric emptying was substantial, with a reduction in the 50% emptying times of solids and liquids of ~50% (14, 15). These studies, like ours, was not designed to discriminate between the potential effects of hypoglycemia and hyperinsulinemia on gastric emptying. However, subsequent studies indicate that hyperinsulinemia per se has no effect on either gastric motility or gastric emptying. In particular, euglycemic hyperinsulinemia has no effect on postprandial antral motility in healthy subjects (32) or on gastric emptying of solids or liquids in patients with uncomplicated type 1 and type 2 diabetes (33). Hence, the effects of hyperglycemia on gastric emptying are most unlikely to be attributable to hyperinsulinemia.

We used a double-isotope radionuclide technique, which has been used extensively by our group to evaluate gastric emptying in diabetes (4, 24): both solid and liquid meal components were labeled precisely (20). The cohort studied had long-standing type 1 diabetes (mean duration, 18 yr). Five had delayed solid emptying, 7 of 20 had delayed liquid emptying during euglycemia, and 60% had autonomic neuropathy; these prevalences are comparable with those reported previously (4, 6, 7, 9). The magnitude of the observed acceleration of gastric emptying of solids and liquids during hypoglycemia was substantial and consistent with the reports by Schvarcz et al. (14, 15). Because it is now established that even minor changes in the rate of small intestinal delivery of carbohydrate may have a major effect on glycemia (3, 34), the observed acceleration of gastric emptying is likely to represent an important counter-regulatory mechanism to hypoglycemia. It is of interest that the acceleration of gastric emptying of liquids was evident very soon after meal ingestion, whereas the acceleration of solid emptying was not apparent until approximately 60 min, and hypoglycemia had no effect on the lag phase for solid emptying. During the lag phase, solids are ground into small particles by the antrum before emptying commences (20, 35). Hence, it appears that hypoglycemia does not affect this component of gastric mechanics and that solids must be "liquefied" for their emptying to be accelerated. The acceleration of gastric emptying by hypoglycemia was associated with changes in intragastric meal distribution, as would be expected: during hypoglycemia, the retention of liquid in the proximal stomach, and that of solid in the distal stomach, were decreased.

Issues of clinical relevance that could be addressed by our study because of heterogeneity of the cohort were whether the effect of hypoglycemia on gastric emptying was influenced by the rate of emptying during euglycemia and/or autonomic nerve function. The magnitude of the acceleration of gastric emptying was shown to be inversely related to the rate of gastric emptying during euglycemia for both solid and liquid meal components; when gastric emptying was relatively slower, the response was greater. Hence, there is no evidence to suggest that the response to hypoglycemia may be impaired by gastroparesis; rather, as has been shown to be the case with many gastrokinetic drugs, the response is in general more marked when gastric emptying is delayed (35). It should, however, be recognized that solid gastric emptying was markedly delayed in only two subjects. Although acceleration of gastric emptying by hypoglycemia was observed in both of these subjects, this group may potentially respond differently. Schvarcz et al. (21) reported that the acceleration of gastric emptying induced by hypoglycemia in healthy subjects was blocked by atropine. Hence, it would not have been surprising if the response to hypoglycemia proved to be dependent on autonomic (particularly parasympathetic) function. There was, however, no clear evidence to support this concept, although there was perhaps a trend for the acceleration of liquid emptying to be less in those patients with autonomic neuropathy, and the possibility of a type 2 statistical error must be acknowledged. Autonomic nerve function was evaluated, as in previous studies using standardized cardiovascular reflex tests (2, 7, 8, 12), which are probably a reasonable surrogate for (36), but are certainly not sophisticated or a direct measure of, gastrointestinal autonomic function. Hence, our observations relating to the effect of autonomic function should be viewed circumspectly. It remains possible that drugs with anticholinergic activity could influence the gastric emptying response to hypoglycemia, as suggested by Schvarcz et al. (21).

Our study does not provide additional insights into either the mechanism(s) by which hypoglycemia accelerates gastric emptying or the gastroduodenal motor correlates of this effect. In relation to the former, stimulation of both sympathetic and parasympathetic activity (21, 37) may be important. The rate of gastric emptying is dependent on the integration of motor activity in the proximal stomach, antrum, pylorus, and proximal small intestine (38), and the motor dysfunctions in type 1 patients with gastroparesis are heterogeneous (19, 39). Studies are indicated to evaluate the effects of insulin-induced hypoglycemia on postprandial gastric motility in healthy subjects and type 1 patients. The effects of hypoglycemia on fasting antropyloric motility in normals are apparently unremarkable (40, 41). We have also not determined whether there is a "threshold" at which hypoglycemia accelerates emptying or whether the response is continuous [there appears to be a direct relationship between changes in gastric emptying/gastric motility and the magnitude of acute elevations in blood glucose concentrations (32, 42)]; the degree of hypoglycemia induced in our study (~2.6 mmol/liter) was less than that used by Schvarcz et al. (14, 15) (~1.9 mmol/liter).


   Acknowledgments
 
We thank the staff of the Department of Nuclear Medicine, Positron Emission Tomography, and Bone Densitometry (Royal Adelaide Hospital) for providing radiopharmaceuticals and gamma camera time and Mr. Justin Lokhorst (Department of Public Health, University of Adelaide) for statistical advice.


   Footnotes
 
This work was supported by a grant from the National Health and Medical Research Council of Australia. The salary of K.L.J. is funded jointly by Diabetes Australia and the National Health and Medical Research Council of Australia.

First Published Online May 17, 2005

Abbreviations: DBP, Diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.

Received March 8, 2005.

Accepted May 5, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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