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Effect of Variations in Small Intestinal Glucose Delivery on Plasma Glucose, Insulin, and Incretin Hormones in Healthy Subjects and Type 2 Diabetes

Department of Medicine (D.G.O., S.D., C.F.-B., K.L.J., J.H.M., J.M.W., M.H.), University of Adelaide, Royal Adelaide Hospital; and Division of Clinical Biochemistry (H.A.M.), Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia, 5000

Address all correspondence and requests for reprints to: Professor Michael Horowitz, University of Adelaide, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia. E-mail: michael.horowitz{at}adelaide.edu.au.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The determinants of postprandial blood glycemia are controversial. We assessed the effects of variations in the initial rate of small intestinal glucose delivery on blood glucose, plasma insulin, and incretin responses in both health and type 2 diabetes. Eight controls and eight patients with type 2 diabetes managed by diet alone underwent paired studies. On both days subjects received an intraduodenal glucose infusion (t = 0–120 min); on one day the infusion rate was variable, being more rapid initially (3 kcal/min) between t = 0 and 15 min and slower (0.71 kcal/min) subsequently (t = 15–120 min), whereas on the other day, the infusion rate was constant (1 kcal/min) from t = 0 to 120 min (i.e. on both days 120 kcal of glucose were administered). Between t = 0–180 min blood glucose, plasma insulin and plasma glucose-dependent insulin-releasing polypeptide were greater with the variable, compared with the constant, infusion. Between t = 0 and 30 min the magnitude of the rise in plasma glucagon-like peptide-1 was greater with the variable, compared with the constant infusion (P < 0.01, both groups). We conclude that modest variations in the initial rate of duodenal glucose entry may have profound effects on subsequent glycemic, insulin, and incretin responses.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IT IS NOW recognized that postprandial blood glucose control is a major determinant of overall glycemia, as assessed by glycated hemoglobin (1, 2); moreover, there is increasing evidence that postprandial hyperglycemia per se has a major role in the pathogenesis of diabetic macrovascular complications (3, 4). Accordingly, pharmacological and dietary strategies to minimize postprandial glycemic excursions are receiving increasing attention (5, 6). An understanding of the determinants of postprandial blood glucose concentrations is fundamental to the effective development of such strategies.

Whereas it is widely recognized that postprandial glycemia is potentially dependent on a number of factors, including the rate of carbohydrate entry into the small intestine, small intestinal digestion and absorption, insulin secretion, peripheral insulin sensitivity, and hepatic and muscle glucose metabolism, the relative importance of these factors remains uncertain and controversial (6). It has been suggested that hepatic glucose metabolism is the major determinant of postprandial hyperglycemia in type 2 diabetes (7). However, this concept appears inconsistent with studies, which indicate that the rate of nutrient entry into the small intestine is pivotal. For example, gastric emptying of nutrient liquids, which normally approximates an overall rate of 1–3 kcal/min (8, 9, 10), has been shown in cross-sectional studies to account for approximately 35% of the variance in initial postprandial blood glucose concentrations after a 75-g oral glucose load in both healthy subjects (9) and type 2 diabetes (11). These and other observations (6) have increased interest in the potential for the modulation of gastric emptying to minimize postprandial glucose excursions and optimize glycemic control in diabetes.

In considering the potential impact of gastric emptying on postprandial glycemia, we postulated that the initial rate of glucose entry into the small intestine may be especially important. It is well recognized that postprandial secretion of insulin is prompted as much by the incretin hormones glucose-dependent insulin-releasing polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), as by entry of glucose into the blood (12). Whereas the release of these incretins is dependent on rates of nutrient entry into the small intestine, the response of GIP to nutrient loads differs from that of GLP-1 (13). Therefore, secretion of insulin follows at least three interacting time dependencies (i.e. release of GIP, release of GLP-1, and glucose entry into the blood); and the effect of secreted insulin on absorbed glucose is a further time-dependent process. The rate of change of these interacting time dependencies is greatest as the stomach begins to empty a carbohydrate-containing meal (10). Therefore, in the present study, we sought to determine how, in response to a standard enteral glucose load given over a fixed time, changing the initial rate of glucose entry into the small intestine would affect secretion of GIP, GLP-1, insulin, and, ultimately, glycemia in normal subjects and type 2 diabetes.

	Subjects and Methods

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Subjects

Eight healthy subjects (age 48 ± 10 yr, body mass index 27 ± 3 kg/m²) and eight patients with type 2 diabetes managed by diet alone (age 58 ± 6 yr, body mass index 32 ± 2 kg/m²) were recruited by advertisement. In the diabetic group, the mean duration of known diabetes was 5 ± 1 yr and glycated hemoglobin 7.3 ± 0.7% (normal range 4–6%) at the time of study. No subject had a history of gastrointestinal disease or surgery, significant respiratory or cardiac disease, alcohol abuse, or epilepsy. No subject smoked more than 10 cigarettes/d or was taking medication known to affect gastrointestinal function. All the type 2 patients met World Health Organization criteria for the diagnosis of diabetes.

The protocol was approved by the Research Ethics Committee of the Royal Adelaide Hospital, and each subject gave written, informed consent before the commencement of the study.

Protocol

Each subject underwent paired studies, separated by an interval of 5–9 d. The two studies were performed in randomized order. On each study day, the subject attended the laboratory at 0900 h after an overnight fast (12 h for solids and 10 h for liquids). On arrival, a silicone rubber catheter (diameter 4 mm) (Dentsleeve, Wayville, South Australia) was inserted into the stomach via an anesthetized nostril and allowed to pass into the duodenum by peristalsis, which took between 20 and 120 min. The catheter included two channels to facilitate measurement of antroduodenal transmucosal potential difference (TMPD) (14) and an additional channel 11.75 cm distal to the pylorus for intraduodenal infusion. TMPD was monitored continuously using a 20-gauge saline-filled cannula placed sc in the left forearm as a reference electrode. The two channels used for TMPD measurement were perfused with degassed normal saline at a rate of 0.08 ml/min. An iv cannula was positioned in the right antecubital vein for blood sampling. The subject was then allowed to rest comfortably in the recumbent position for 10 min.

At time t = 0 min, an intraduodenal infusion of 25% glucose (Baxter Health Care, Old Toongabbie, NSW, Australia) or a mixture of 25% glucose and 0.9% saline was infused at a rate of 3 ml/min between t = 0 and120 min. On one day the rate of energy delivery was variable (3 kcal/min between 0 and 15 min and 0.71 kcal/min from 15 to 120 min); on the other day, the rate of energy delivery was constant (1 kcal/min from 0 to 120 min) (i.e. on both days a total of 360 ml containing 120 kcal of glucose was infused intraduodenally). At t = 120 min, the catheter was removed and the subject allowed to rest comfortably until t = 180 min. Venous blood samples (10 ml) were obtained immediately before (t = 0 min) the commencement of the intraduodenal infusions and subsequently at t = 2, 4, 6, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, and 180 min for measurement of blood glucose, plasma insulin, GLP-1 (15), and GIP (16) using established methods. Cardiovascular autonomic function (17, 18) was evaluated on one of the study days, after t = 180 min.

Blood glucose, plasma insulin, GLP-1, and GIP concentrations

Blood samples for determination of plasma insulin, GLP-1, and GIP were collected in ice-chilled EDTA-treated tubes containing 400 kIU aprotinin (Trasylol; Bayer Australia Ltd., Pymple, Australia) per liter blood. Plasma was separated by centrifugation (3200 rpm, 15 min, 4 C) and stored at –70 C for later analysis.

Blood glucose concentrations were determined immediately using a portable glucose meter (Medisense Precision QID, Abbott Laboratories, Bedford, MA). The accuracy of this method has been confirmed in our laboratory using the hexokinase technique (9).

Plasma insulin concentrations were measured by ELISA immunoassay (Diagnostics Systems Laboratories Inc., Webster, TX). The sensitivity of the assay was 0.26 mU/liter; the intraassay coefficient of variation was 2.6% and the interassay coefficient of variation 6.2% (19).

Plasma GLP-1 concentrations were measured by RIA using an adaptation (15) of a previously published method (20). Antibody was supplied by Professor S. R. Bloom (Hammersmith Hospital, London, UK) and did not cross-react with glucagon, GIP, or other gut or pancreatic peptides. The intraassay coefficient of variation was 17%, and the interassay coefficient of variation was 18%. Sensitivity was 1.5 pmol/liter.

Plasma GIP was measured by RIA, the details of which have been published previously (16). The minimum detectable limit was 2 pmol/liter and both intra- and interassay coefficients of variation were 15%.

Cardiovascular autonomic nerve function

Autonomic nerve function was evaluated using standardized cardiovascular reflex tests (17, 18, 21). Parasympathetic function was evaluated by the variation (R-R interval) of the heart rate during deep breathing and the immediate heart rate response to standing (30:15 ratio). Sympathetic function was assessed by the fall in systolic blood pressure in response to standing. Each test result was scored, according to age-adjusted predefined criteria, as 0 = normal, 1 = borderline, or 2 = abnormal for a total maximum score of 6. A score of 3 or more was considered to indicate definite evidence of autonomic dysfunction (17).

Statistical analysis

Data were analyzed for the time periods 0–30 min (arbitrarily defined as the early response) and 0–180 min. To assess changes in the magnitude of response between healthy subjects and type 2 patients, data were assessed as change from baseline. Blood glucose, plasma insulin, plasma GLP-1, and plasma GIP concentrations were evaluated using repeated-measures ANOVA within each subject group with treatment and time as factors and between-subject groups using treatment, time, and subject group as factors. Peak blood glucose and hormone concentrations were compared within subject groups using Student’s paired t test. Statistical significance was accepted at P < 0.05, and data are presented as mean values ± SEM.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All subjects tolerated the study well. No subject had definite evidence of autonomic nerve damage (mean score, healthy subjects: 0.7 ± 0.3, range 0–1; type 2 patients: 1.1 ± 0.4, range 0–2).

Fasting blood concentrations of glucose and hormones did not differ between test days within each group of subjects. The type 2 patients had significantly higher fasting glucose (P = 0.001) and insulin levels (P = 0.03) than the control subjects and also had generally higher glucose and insulin levels after each infusion. Also, as expected, rises in plasma insulin were less in the type 2 patients relative to changes in plasma glucose than in the normal subjects.

Blood glucose (Fig. 1A)

In both groups blood glucose concentrations increased on both study days (P = 0.001 for both), but the magnitude of the rise from baseline between 0 and 30 min was greater during the variable, compared with the constant, infusion (P = 0.0001 for both). Overall, between 0 and 180 min (i.e. ANOVA over 0–180 min), blood glucose concentrations were greater during the variable, compared with the constant, infusion (control: P = 0.0001; type 2: P = 0.0003). However, in the control group at 120 min, the blood glucose concentration during the variable, compared with the constant, infusion was significantly less (P = 0.02). Between 75 and 180 min for controls and 135 and 180 min for type 2 patients, there was no difference in blood glucose concentrations between the two study days.

View larger version (32K): [in this window] [in a new window]   FIG. 1. Effect of a variable intraduodenal glucose infusion (3 kcal/min between t = 0 and 15 min and 0.71 kcal/min between t = 15 and 120 min) (closed symbols) or a constant infusion (1 kcal/min between t = 0 and 120 min) (open symbols) in control subjects (triangles) and patients with diabetes (circles) on blood glucose (A), plasma insulin (B), plasma GLP-1 (C), and plasma GIP (D). The intraduodenal infusions were given between 0 and 120 min. Data are mean values ± SEM. *, P < 0.05, difference between variable and constant infusions between 0 and 30 min.

Plasma insulin (Fig. 1B)

In both groups plasma insulin increased during each infusion (control: P = 0.0001; type 2: P = 0.001), but the magnitude of the rise from baseline between 0 and 30 min was greater during the variable, compared with the constant, infusion (control: P = 0.0001; type 2: P = 0.007). Between 0 and 180 min, plasma insulin was higher during the variable, compared with the constant, infusion in controls (P = 0.0001) and type 2 patients between 0 and 60 min (P = 0.007). Between 60 and 180 min for controls and 45 and 180 min for type 2 patients, there was no difference in plasma insulin between the two study days.

Plasma GLP-1 (Fig. 1C)

In both control and type 2 patients, plasma GLP-1 increased during both infusions (P = 0.0001 for both), but the magnitude of the rise from baseline between 0 and 30 min was greater during the variable, compared with the constant, infusion (control: P = 0.05; type 2: P = 0.001). Between 0 and 180 min, however, there was no overall difference in plasma GLP-1 during the variable, compared with the constant, infusion (control: P = 0.24; type 2: P = 0.13).

Plasma GIP (Fig. 1D)

Plasma GIP increased in both control and type 2 subjects during both infusions (control: P = 0.001; type 2: P = 0.0001), but the magnitude of the rise from baseline between 0 and 30 min was greater during the variable, compared with the constant, infusion (control: P = 0.0001, type 2: P = 0001). Between 0 and 180 min, plasma GIP was higher during the variable, compared with the constant, infusion (control: P = 0.0001; type 2 P = 0.0001). Between 60 and 180 min, there was no difference in plasma GIP between infusions for either group.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To our knowledge this study represents, perhaps surprisingly, the first formal evaluation of the effect of minor variations in the pattern of small intestinal delivery of glucose on glycemic, insulinemic, and incretin responses in healthy subjects and patients with diet-controlled type 2 diabetes. On both study days, subjects received a relatively small glucose load of 120 kcal intraduodenally over a period of 2 h; on one day the initial (between 0 and 15 min) rate of the glucose infusion was relatively more rapid at 3 kcal/min, whereas on the other day, a constant infusion of 1 kcal/min was used. The observations in healthy and type 2 diabetic subjects were generally comparable; the variable intraduodenal glucose infusion was associated with substantially greater early (i.e. between 0 and 30 min) glucose and hormonal responses. Moreover, the overall (i.e. 0–180 min) blood glucose, plasma insulin, and plasma GIP responses were significantly greater with the variable infusion. These observations establish that minor variations in duodenal delivery of glucose, which are within the physiological range of gastric emptying (8, 10), may have major effects on the glycemic, insulinemic, and incretin hormonal responses in both healthy subjects and patients with type 2 diabetes.

We elected to administer glucose directly into the duodenum to assess the effect of perturbations in gastric emptying more directly [the rates of duodenal glucose infusion used (between 0.71 and 3 kcal/min) fall within the normal physiological range of gastric emptying of glucose observed in healthy subjects (8, 9, 10, 19)]. Gastric emptying of nutrient-containing liquids, such as glucose, generally approximates an overall linear pattern, after an initial emptying phase that may be slightly faster (22). Whereas gastric emptying of nutrient liquids and solids may be delayed in 30–50% of patients with longstanding type 2 diabetes (23, 24), the type 2 cohort studied is more representative of so-called early type 2 diabetes (i.e. the mean duration of known diabetes was relatively short and all patients were managed by diet alone) in which gastric emptying of glucose may be unchanged (11) or, possibly, more rapid than normal (25, 26, 27).

The concept that gastric emptying is a major determinant of postprandial glycemia in both health (9) and type 2 diabetes (11) is supported by the observed relationships between blood glucose excursions and gastric emptying and the effects of dietary and pharmacological modulations of gastric emptying on postprandial blood glucose and insulin concentrations (6, 28, 29, 30). For example, Phillips et al. (28) observed in patients with type 2 diabetes that plasma glucose levels after a 50-g glucose drink could be suppressed by giving cholecystokinin-8 iv to slow gastric emptying and that a marked reduction in plasma glucose was evident even within 15 min of giving cholecystokinin, when as little as 6 g (instead of about 12 g in control tests) of glucose had entered the small intestine. Hence, our observations, although novel, are not altogether surprising: it is clear that in both healthy subjects and type 2 patients even minor variations in the initial rate of gastric emptying of glucose may affect glycemic excursions.

It could be anticipated that the glycemic and insulinemic responses to an initially faster rate of gastric emptying of glucose would be greater (i.e. during the first 30 min, the subjects received approximately 56 kcal with the variable, compared with 30 kcal with the constant, infusion). However, the subsequent responses (i.e. after 30 min) are much more difficult to predict because a number of factors may potentially influence blood glucose concentrations later in the postprandial period (6). The plasma insulin response to iv, and probably oral, carbohydrate is biphasic (31). Potentially an early surge in insulin release induced by relative hyperglycemia may result in lower blood glucose concentrations subsequently and an overall improvement in the glycemic profile (32, 33). For example, in healthy subjects, whereas the area under the curve of blood glucose between 0 and 30 min is directly related to gastric emptying of a 75-g oral glucose load, the blood glucose concentration at 120 min is inversely related to gastric emptying (9). Beckoff et al. (34) reported, in healthy older subjects, that dietary supplementation with glucose for 10 d resulted in a modest acceleration in the rate of gastric emptying of 75 g glucose, which was associated with an earlier rise in serum insulin (within 15 min) and subsequently (between 75 and 120 min) lower glucose levels when compared with a nonsupplemented diet. However, in our study there was limited compensation, i.e. at only one time point was blood glucose lower (at 120 min) with the variable, when compared with the constant, glucose infusion and this was only evident in the healthy subjects. This relative lack of compensation may reflect a greater glucose load being delivered into the small intestine in our study (variable infusion), compared with the study by Beckoff et al. (34) in the first 15 min (11 vs. 5 g). Hence, it is likely that the overall glycemic and insulinemic effects of oral glucose will be critically dependent on the initial rate of delivery into the small intestine, and that there is a threshold of glucose delivery (which is < 3 kcal/min) into the small intestine above which the insulin and other counterregulatory responses are less adequate to compensate for the rise in blood glucose. Further studies are indicated to address these issues.

GLP-1 and GIP, the so-called incretin hormones, stimulate insulin release after enteral carbohydrate ingestion (12). GLP-1 also suppresses glucagon release, stimulates insulin-independent glucose disposal in the periphery, and slows gastric emptying (35). In both healthy and type 2 patients, there was an early increase in GLP-1 and GIP in response to the variable infusion and a smaller response to the constant infusion. Plasma GIP concentrations are known to reflect the rate of nutrient entry into the small intestine (13); hence, a greater response to the variable infusion was to be expected. Although it has been suggested that plasma GLP-1 requires a threshold of caloric delivery to be exceeded (1.8 kcal/min) to stimulate its release (13), a small increase in GLP-1 was evident during the constant (1 kcal/min) infusion.

Our cohort of type 2 patients was older and more overweight than the healthy subjects, although we attempted to minimize these differences; hence, comparisons between the two groups should be circumspect. However, there were only minor differences in the responses between the two groups. Type 2 diabetes is known to be associated with a reduced early, and frequently increased late, postprandial insulin response, which may precede the occurrence of insulin resistance (36). Studies relating to incretin hormone responses in type 2 diabetes have yielded inconsistent observations (20, 37), which may in part reflect differences in hormone assays and blood glucose concentrations during experiments. In our study the GLP-1 and GIP responses were comparable in the healthy and type 2 subjects. However, as expected, blood glucose concentrations were consistently higher in the type 2 patients, which suggests that there may be a relative deficiency in both GIP and GLP-1 secretion in this group.

As discussed, other factors apart from gastric emptying contribute to postprandial hyperglycemia (6). There appears to be no difference in glucose absorption in type 2 diabetes, compared with healthy subjects (38). Studies using radiolabeled glucose isotopes have suggested that excessive hepatic glucose release is a major mechanism of postprandial hyperglycemia in type 2 diabetes; however, these methods may be more suited to evaluation of the late postprandial period, as opposed to the immediate response to a meal (6). The relative contribution of gastric emptying and hepatic glucose metabolism to postprandial blood glucose concentrations is also likely to vary over time after a meal and be dependent on the carbohydrate load. Hepatic glucose metabolism may be the predominant factor after the first 60 min, whereas gastric emptying appears to be dominant in the early postprandial period (6).

Our observations confirm that the rate of small intestinal glucose delivery is a critical determinant of glucose tolerance (9, 19) and indicate that interventions that result in a modest and early slowing of gastric emptying may optimize postprandial glycemic responses in healthy subjects and type 2 diabetes (9, 28). The use of agents, whether dietary, e.g. fat (39), soluble fiber (40), or pharmacologic, e.g. GLP-1 agonists (41), may prove useful in the management of type 2 diabetes by reducing the rate of carbohydrate entry into the small intestine and thereby facilitating metabolic compensation minimizing glycemic excursions.

	Footnotes

 
This work was supported by project grants from the Royal Adelaide Hospital and the National Health and Medical Research Council (NH&MRC) of Australia. K.L.J.’s salary is derived from a fellowship jointly awarded by the NH&MRC and Diabetes Australia. C.F.-B.’s salary is provided by a Career Development Award from the NH&MRC.

Abbreviations: GIP, Glucose-dependent insulin-releasing polypeptide; GLP-1, glucagon-like peptide-1; TMPD, transmucosal potential difference.

Received February 20, 2004.

Accepted April 1, 2004.

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