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University of Adelaide, Department of Medicine, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
Address all correspondence and requests for reprints to: Dr. Karen L. Jones, National Health and Medical Research Council/Diabetes Australia Senior Research Fellow, Department of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. E-mail: karen.jones{at}adelaide.edu.au.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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Postprandial blood glucose concentrations are 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 glucose release (7). Gastric emptying accounts for approximately 35% of the variance in initial postprandial blood glucose concentrations after a 75-g oral glucose load in both healthy subjects (8) and type 2 diabetes (9). Hence, there is substantial interest in the potential for the modulation of gastric emptying, by dietary or pharmacological means, to minimize postprandial glucose excursions and optimize glycemic control (7). In type 2 diabetes, which is associated with a diminished and delayed insulin response (7), strategies that slow gastric emptying are likely to benefit postprandial glycemia (7, 10). In healthy subjects, when fat is ingested with carbohydrate (11) or infused directly into the small intestine (12), gastric emptying is slowed and the glycemic and insulinemic responses attenuated (11, 12). The addition of relatively small quantities of fat to a carbohydrate-containing meal may, therefore, have a beneficial effect on glycemic control in patients with type 2 diabetes. The effects of fat on gastric emptying are known to be dependent on posture (13, 14) and the interaction of its digestive products (free fatty acids) with receptors in the small intestine (14, 15)—a lack of lipase activity, for example in cystic fibrosis (16), results in an acceleration of gastric emptying due to a reduction in feedback inhibition from lipolytic products in the small intestine (14, 15, 17). In the left lateral decubitus position, the pylorus is positioned vertically above the distal and proximal stomach (13). Hence, after ingestion of a drink containing oil and aqueous phases, oil floats to the top of the aqueous phase due to its lower density and is retained in the distal stomach close to the pylorus (13). Consequently, the oil phase empties first and triggers motor mechanisms that retard emptying of the remainder (aqueous phase) of the drink (13). Accordingly, the effect of oil on gastric emptying and postprandial blood glucose concentrations is likely to be most marked in this posture.
Modest weight loss has a significant impact on the glycemic control in type 2 diabetes (18). In view of this, the introduction of agents such as the lipase inhibitor, orlistat (Xenical, Hoffman-LaRoche, Basel, Switzerland), which is known to induce weight loss (19), have been advocated. Orlistat is a potent, specific, and reversible inhibitor of gastric and pancreatic lipases, reducing fat absorption by approximately 30% (19, 20). In combination with a calorie-restricted diet, orlistat has been shown to induce weight loss in obese subjects with (20, 21, 22, 23), and without (19), type 2 diabetes.
The effects of orlistat on glycemic control in type 2 diabetes has been reported in four studies (20, 21, 22, 23). In the majority of these studies, the primary endpoints to evaluate effects on glycemic control were fasting blood glucose concentrations and glycated hemoglobin (20, 21, 23). In all of these studies, there was an improvement in glycated hemoglobin with orlistat that was greater than that seen in response to placebo, and potentially attributable to weight loss (18), rather than an effect of orlistat per se. However, it appears that the magnitude of the reduction in glycated hemoglobin with orlistat was less than would be anticipated from the fall in fasting glucose (3). This suggests that orlistat may exacerbate postprandial glycemia. Only one study has hitherto evaluated the effect of orlistat on postprandial blood glucose concentrations (22). Although no effect was evident, postprandial blood glucose concentrations were only evaluated at 2 h, and the nature of the meal was not stated (22). As inhibition of lipolysis by orlistat is known to accelerate gastric emptying of meals containing fat in healthy subjects (15, 24), orlistat has the potential to affect the glycemic response adversely.
The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulintropic polypeptide (GIP), play an important role in the stimulation of postprandial insulin secretion (25). It was initially believed that the release of GLP-1 was triggered by carbohydrate only (25). However, animal studies have demonstrated that fat releases GLP-1 on contact with the ileum (26) and more recently it has been established in humans that fat is at least as potent as carbohydrate in stimulating GLP-1 release (27, 28) and that the latter is dependent on the products of fat digestion (29, 30). The effects of orlistat on incretin release after a fatty meal, have not been studied in either healthy subjects or patients with diabetes.
The aims of this study were to investigate in patients with type 2 diabetes the acute effects of orlistat on gastric emptying, and the glycemic and incretin hormone responses to, a meal containing fat and carbohydrate components.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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Seven subjects (four males and three females; age, 58 ± 5 yr; body mass index, 28.2 ± 1.9 kg/m2) with type 2 diabetes mellitus, managed by diet alone, were included in the study. The mean duration of known diabetes was 3 ± 1 yr, and glycated hemoglobin was 7.1 ± 0.6% (normal range, 4–6%) at the time of study. The subjects were randomly selected from outpatients attending the Diabetes Centre at the Royal Adelaide Hospital. No subject had any significant gastrointestinal symptoms (mean score 1.5 ± 0.5 from a total possible score of 27) as assessed by a validated questionnaire (31), a past history of gastrointestinal disease or surgery, or was taking medication known to affect appetite, body weight or gastrointestinal motor function. Only one subject smoked (a maximum of 10 cigarettes/d), and no subject habitually consumed more than 20 g alcohol/d. The study protocol was approved by the Royal Adelaide Hospital Research Ethics Committee and conducted in accordance with the guidelines in The Declaration of Helsinki. All subjects gave written informed consent before inclusion into the study.
Study protocol
Each subject attended the Department of Nuclear Medicine at approximately 0930 h on two occasions, separated by at least 3 d, after an overnight fast (14 h for solids, 12 h for liquids). An iv cannula was inserted into an antecubital vein for subsequent blood sampling. The subjects were then positioned in the left lateral decubitus posture on a bed with their back against a camera (Siemens, Hoffmann Estates, IL) (10). Each subject then consumed a drink containing oil and glucose over approximately 3 min. On one of the 2 d, 120 mg of orlistat (Xenical, Hoffmann-La Roche, Basel, Switzerland) was mixed into the oil in double-blind, randomized fashion. Gastric emptying was then assessed for 210 min following ingestion of the drink. Blood samples, for measurements of blood glucose and plasma insulin, GLP-1 and GIP concentrations, were taken immediately before ingestion of the drink (two baseline samples) and then at 15-min intervals for the first 120 min and at 30-min intervals for the remaining 90 min. Cardiovascular autonomic nerve function was evaluated on one of the study days, after completion of the gastric emptying measurement (31, 32). Subjects were requested to report any side effects experienced following each study.
Gastric emptying and intragastric distribution
The drink comprised 60 ml olive oil (Faulding Pty. Ltd., Adelaide, South Australia) labeled with 20 MBq 99mTechnetium-V-thiocyanate (13, 16, 33) mixed with 75 g glucose dissolved in 300 ml water labeled with 6 MBq 67Gallium-EDTA (67Ga-EDTA) (34). The energy content of the drink was 840 kcal (300 kcal from glucose, 540 kcal from oil). The time of completion of the drink was defined as t = 0 min. Radioisotopic data were acquired in 1-min frames for the first 60 min and in 3-min frames for the remaining 150 min. Data were corrected for subject movement, radionuclide decay and -ray attenuation, as described previously (35). A region-of-interest was drawn for the total stomach, which was subsequently divided into proximal and distal stomach regions, with the proximal region corresponding to the fundus and proximal corpus and the distal region corresponding to the distal corpus and antrum (35). Gastric emptying curves were derived for total, proximal, and distal regions and expressed as percent retention over time. The content of the total, proximal, and distal stomach at 15-min intervals was taken from these curves. For the total stomach, the duration of the lag phase (determined visually as the time before any radioactivity appeared in the proximal small intestine) was also derived (35).
Blood glucose, plasma insulin, plasma GLP-1, and plasma 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)/ml blood. Plasma was separated by centrifugation (3200 rpm, 15 min, 4 C) and stored at -70 C for later analysis.
Blood glucose concentrations (millimoles/liter) were determined immediately by the glucose oxidase method 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 (31).
Plasma insulin concentrations (milliunits/liter) 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 was 6.2% (36).
Plasma GLP-1 concentrations (pmol/liter) were measured by RIA using an adaptation (37) of a previously published method (38). Standards were prepared in charcoal-stripped plasma and extracted in 66% ethanol along with the samples. Extracts were dried down under N2 and resuspended in assay buffer [0.1 M phosphate, 3.9 g/liter EDTA, 1 g/liter human serum albumin, 0.6 mM thimmerosol, 1.3 g/liter aminocaproic acid (pH 7.4)]. 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 and has been demonstrated by chromatography to measure intact GLP-1(7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36) amide. 125I-labeled GLP-1 was prepared using the lactoperoxidase method and purified by HPLC for use as tracer. Incubation was for 48 h at 4 C. The antibody bound fraction was separated by the addition of dextran-coated charcoal containing gelatin (0.015 g gelatin, 0.09 g dextran, and 0.15 g charcoal in 30 ml assay buffer) and the radioactivity determined in the supernatants following centrifugation. 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 this technique have been published previously (39). The minimum detectable limit was 2 pmol/liter and both intraassay and interassay coefficient of variation was 15%.
Cardiovascular autonomic nerve function
Autonomic nerve function was evaluated using standardized cardiovascular reflex tests (31, 32, 40). 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 3 or more was considered to indicate definite evidence of autonomic dysfunction (31).
Statistical analysis
Gastric emptying, blood glucose, plasma insulin, plasma GLP-1, and plasma GIP concentrations were evaluated using repeated measures ANOVA with treatment and time as factors. Student’s paired t tests were used to compare maximum (peak) concentration and baseline measurements. Statistical significance was accepted at P < 0.05, and data are presented as mean values ± SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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Gastric emptying and intragastric distribution
Total stomach (Fig. 1A
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Under both study conditions [orlistat (P < 0.001); control (P < 0.005)], the glucose emptied more slowly than the oil, as a result of layering of the oil on top of the aqueous glucose in the left lateral decubitus (pylorus up) position. Orlistat treatment accelerated gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) compared with control (no orlistat). There were no significant differences in the lag phase of oil (orlistat, 3.9 ± 0.9 min vs. control, 5.9 ± 2.1 min; not significant) or glucose (orlistat, 3.6 ± 1.2 min vs. control, 8.7 ± 4.4 min; not significant), between the two treatments.
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Less oil (P < 0.005) and glucose (P < 0.001) was retained in the proximal stomach after orlistat when compared with control (Fig. 1B
). There was also less retention of both oil (P < 0.05) and glucose (P < 0.05) (Fig. 1C) in the distal stomach following orlistat compared with control, i.e. although the oil floated on top of the aqueous layer, accumulation in the distal antrum was less as a result of more rapid gastric emptying.
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Blood glucose, plasma insulin, plasma GLP-1, and plasma GIP concentrations |
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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).There were no differences in baseline blood glucose concentrations between the two study days. There was a rise (P < 0.0005) in blood glucose concentrations after the drink on both study days; however, postprandial blood glucose concentrations were higher (P < 0.0005) after orlistat compared with control. Peak blood glucose concentration was also higher after orlistat compared with control (orlistat, 16.4 ± 1.4 mmol/liter vs. control, 12.1 ± 1.8 mmol/liter; P < 0.005).
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).There were no differences in baseline plasma insulin concentrations between the two study days. There was a rise (P < 0.0005) in plasma insulin concentrations after the drink on both study days; however, plasma insulin concentrations were higher (P < 0.05) after orlistat compared with control. Peak plasma insulin concentration was also higher after orlistat (orlistat, 40.4 ± 9.7 mU/liter vs. control, 24.3 ± 6.2 mU/liter; P < 0.05).
Plasma GLP-1 (Fig. 2C).
There were no differences in baseline plasma GLP-1 concentrations and plasma GLP-1 concentrations increased (P < 0.0005) on the two study days. Plasma GLP-1 concentrations were lower (P < 0.005) following orlistat treatment when compared with control. Peak plasma GLP-1 concentration was also less after orlistat compared with control (orlistat, 30.2 ± 8.2 pmol/liter vs. control, 60.6 ± 8.7 pmol/liter; P < 0.005).
Plasma GIP (Fig. 2D).
There were no differences in baseline plasma GIP concentrations and plasma GIP concentrations increased (P < 0.01) on the two study days. Plasma GIP concentrations were lower (P < 0.05) following orlistat treatment compared with control.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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Previous studies have shown improvements in fasting glucose concentrations, glycated hemoglobin, and weight loss after treatment with orlistat (20, 21, 22, 23), hence promoting its use in type 2 diabetes. This is the first study to report rises in glycemic and insulinemic responses after incorporation of orlistat into a glucose drink containing fat. Postprandial blood glucose and plasma insulin concentrations were substantially greater following orlistat compared with control. These observations are in contrast to those reported by Hanefeld et al. (22) in patients with type 2 diabetes, which demonstrated a modest improvement in postprandial blood glucose concentrations after orlistat compared with control. Postprandial blood glucose concentrations were, however, only assessed at one time point, 2 h after a test meal, and the mean postprandial rise in blood glucose concentrations from baseline was in fact greater, rather than less, after orlistat compared with placebo. Moreover, the type of meal (350 kcal containing 10% protein, 40% fat, and 50% carbohydrate) was not specified (22). Although this study (22) and others (20, 21, 23) have demonstrated modest improvements in both glycated hemoglobin and fasting blood glucose concentrations following treatment with orlistat, it remains to be established whether the magnitude of the fall in glycated hemoglobin is consistent with the observed reduction in fasting glucose. The improvement in glycated hemoglobin observed during treatment with orlistat may well be attributable to the effects of weight loss and dietary restriction per se, and the potential for orlistat to affect postprandial glycemia adversely cannot be discounted.
Previous studies have shown that glucose absorption is dependent on the rate of gastric emptying (10). Even minor accelerations in the initial (first 30–60 min after meal ingestion) rates of gastric emptying have profound effects on postprandial glycemia in both normal subjects and type 2 patients (8, 9, 41). Previous studies, in which fat was incorporated into a carbohydrate meal (11) or infused directly into the small intestine (12), resulted in the slowing of gastric emptying and blunting of postprandial glucose and insulin responses (11, 12). Because there was an initial acceleration in gastric emptying of glucose by orlistat, it is not surprising that the magnitude of the rise in blood glucose and plasma insulin concentrations was substantially greater. In normal subjects, lipase inhibition with orlistat is known to be associated with acceleration of the rate of gastric emptying of a mixed protein/fat meal (24); in patients with cystic fibrosis (16), gastric emptying of fat and aqueous components in both the sitting and, particularly, in the left lateral decubitus position, is abnormally fast (16). However, blood glucose concentrations were not measured in these studies (16, 24).
While postprandial blood glucose concentrations are dependent on the rate of small intestinal nutrient delivery, the blood glucose concentration itself has a major, reversible effect on gastric emptying. Acute hyperglycemia slows gastric emptying in both normal subjects (42) and patients with type 1 diabetes (43), whereas hypoglycemia accelerates gastric emptying (44, 45). In this study, orlistat accelerated gastric emptying of oil and glucose, despite hyperglycemia; the effects of orlistat on gastric emptying, however, could potentially be influenced by the blood glucose concentration at the time of administration. It should also be recognized that we studied patients with uncomplicated type 2 diabetes; long-standing type 2 diabetes is associated with a high prevalence of both gastroparesis (7) and autonomic neuropathy that may potentially affect the response to orlistat.
Oral ingestion of glucose stimulates the incretin hormones, GLP-1 and GIP, about 50% of the increase in plasma insulin after oral glucose is mediated by the incretin response (37, 46). We have recently reported in normal subjects that the increase in GLP-1 concentrations following a duodenal fat infusion is abolished by lipase inhibition with orlistat (30). In accordance with these findings, we have now demonstrated that in patients with type 2 diabetes, both GLP-1 and GIP secretion in response to a mixed glucose/fat drink is attenuated by orlistat, suggesting that the generation of free fatty acids may mediate the release of both incretin hormones. Furthermore, Beyson et al. (29) have recently demonstrated differential stimulation of GLP-1 release by different types of oral fat (monounsaturated, olive oil; polyunsaturated, safflower oil; saturated, palm stearin); the greatest increase in GLP-1 was observed after fat containing monounsaturated fatty acid. In this current study, the steep rise in plasma GLP-1 occurred over the first 90 min during control (when approximately 20 g of fat and 8 g of glucose had emptied); whereas after treatment with orlistat, the rise in GLP-1 was less than one third as much in the first 90 min (when about 40 g of fat and 45 g of glucose had emptied). In the previous study by our group (30), addition of orlistat to a direct intraduodenal infusion of a triglyceride emulsion, abolished the release of GLP-1 by the infused fat. The results of this current study and that of our previous study (30) suggest that GLP-1 may be released predominantly by the products of fat digestion, rather than by glucose (25). The reduction in GLP-1 may also have in part been due to the effects of hyperglycemia; a recent study in healthy subjects demonstrated that the rise in GLP-1 concentrations resulting from monounsaturated free fatty acids is attenuated by hyperglycemia (29). Furthermore, decreased GLP-1 release may favor more rapid gastric emptying (37, 47), potentially exacerbating postprandial glycemic control.
In interpreting our results, some methodological issues require consideration. This was an acute study designed to define mechanisms, and for this reason, the meal and posture, were unphysiological. Further studies using more physiological test meals and study conditions (e.g. seated, rather than lateral decubitus, position) are now warranted. In addition, the effects of chronic administration of orlistat on glycemic control needs to be assessed. Future studies assessing the effects of orlistat in type 2 patients should certainly evaluate postprandial glycemia. This acute study indicates that lipase inhibition by orlistat of a mixed carbohydrate/fat meal exacerbates postprandial glycemic excursions due to more rapid gastric emptying of glucose and a diminished incretin response.
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Acknowledgments |
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Footnotes |
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Abbreviations: GIP, Glucose-dependent insulintropic polypeptide; GLP-1, glucagon-like peptide-1.
Received February 7, 2003.
Accepted May 2, 2003.
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TopAbstractIntroductionSubjects and MethodsResultsBlood glucose, plasma insulin,...DiscussionReferences |
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