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Effect of Lipase Inhibition on Gastric Emptying of, and the Glycemic and Incretin Responses to, an Oil/Aqueous Drink in Type 2 Diabetes Mellitus

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.

	Abstract

Top Abstract Introduction Subjects and Methods Results Blood glucose, plasma insulin,... Discussion References

 
This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 ± 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq ^99mTc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq ⁶⁷Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a 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

Top Abstract Introduction Subjects and Methods Results Blood glucose, plasma insulin,... Discussion References

 
IT IS NOW ESTABLISHED that there is a close association between both the development and progression of diabetic microvascular (and possibly macrovascular) complications and average glycemic control, as assessed by glycated hemoglobin (1, 2). The latter is dependent on both fasting and postprandial blood glucose concentrations. Although their relative contributions have not been defined precisely (3), diabetes is characterized initially by changes in postprandial, and subsequently, fasting blood glucose concentrations, and it is clear that improved glycemic control can be achieved by lowering postprandial blood glucose concentrations, even at the expense of a higher fasting glucose (4). There is also increasing evidence that postprandial hyperglycemia, per se, may have a distinct role in the pathogenesis of diabetic macrovascular complications (5, 6). Accordingly, optimization of postprandial blood glucose concentrations represents a specific target for treatment (4).

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.

	Subjects and Methods

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Subjects

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.

	Results

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All subjects tolerated the study well; six out of seven subjects experienced transient side effects after orlistat treatment, all occurring after the completion (i.e. after 210 min) of the study day. These included loose and oily stools, and in all cases resolved spontaneously. No subject had evidence of autonomic nerve damage (mean score, 0.9 ± 0.3; range, 0–2)

Gastric emptying and intragastric distribution

Total stomach (Fig. 1A). 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.

View larger version (30K): [in this window] [in a new window]   FIG. 1. Total (A), proximal (B), and distal (C) stomach retention of oil and glucose components of a liquid meal containing orlistat (black circles) vs. control (white circles). Data are expressed as mean values ± SEM (n = 7).

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.

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

Top Abstract Introduction Subjects and Methods Results Blood glucose, plasma insulin,... Discussion References

 
Blood glucose (Fig. 2A).

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).

View larger version (32K): [in this window] [in a new window]   FIG. 2. Blood glucose (A), plasma insulin (B), plasma GLP-1 (C), and plasma GIP (D) concentrations immediately before and after ingestion of an oil/glucose liquid meal containing orlistat (black circles) vs. control (white circles). Arrow represents liquid meal ingestion. Time of completion of liquid meal, defined as t = 0 min. BL, Mean baseline blood glucose concentrations. Data are expressed as mean values ± SEM (n = 7).

Plasma insulin (Fig. 2B).

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.

	Discussion

Top Abstract Introduction Subjects and Methods Results Blood glucose, plasma insulin,... Discussion References

 
This study demonstrates that in patients with type 2 diabetes the incorporation of orlistat to a liquid meal containing oil and glucose consumed in the left lateral decubitus position: 1) accelerates gastric emptying of fat and glucose; 2) potentiates the postprandial rises in blood glucose and plasma insulin; and 3) attenuates the plasma GLP-1 and GIP responses, when compared with a meal containing fat and glucose alone.

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.

	Acknowledgments

 
We acknowledge Ms. Antonietta Russo and Miss Julie Stevens for technical support and the Department of Nuclear Medicine, Royal Adelaide Hospital for allowing the studies to be conducted in their department.

	Footnotes

 
This study was supported by project grants from the Royal Adelaide Hospital and the National Health and Medical Research Council (NH&MRC) of Australia. Salary of K.L.J. is derived from a Fellowship jointly awarded by the NH&MRC and Diabetes Australia. Salary of C.F. is provided by the Florey Research Fellowship of the Royal Adelaide Hospital.

Abbreviations: GIP, Glucose-dependent insulintropic polypeptide; GLP-1, glucagon-like peptide-1.

Received February 7, 2003.

Accepted May 2, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Blood glucose, plasma insulin,... Discussion References

 

1. UK Prospective Diabetes Study (UKPDS) Group 1998 Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853[CrossRef][Medline]
2. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986[Abstract/Free Full Text]
3. American Diabetes Association 2001 Postprandial blood glucose. Diabetes Care 24:775–778[Free Full Text]
4. Bastyr 3rd EJ, Stuart CA, Brodows RG, Schwartz S, Graf CJ, Zagar A, Robertson KE 2000 Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group. Diabetes Care 23:1236–1241[Abstract/Free Full Text]
5. Saydah SH, Miret M, Sung J, Varas C, Gause D, Brancati FL 2001 Postchallenge hyperglycemia and mortality in a national sample of U. S. adults. Diabetes Care 24:1397–1402[Abstract/Free Full Text]
6. Del Prato S 2002 In search of normoglycaemia in diabetes: controlling postprandial glucose. Int J Obes Relat Metab Disord 26(Suppl 3):S9–S17
7. Rayner CK, Samsom M, Jones KL, Horowitz M 2001 Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 24:371–381[Abstract/Free Full Text]
8. Horowitz M, Edelbroek MA, Wishart JM, Straathof JW 1993 Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 36:857–862[CrossRef][Medline]
9. Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L 1996 Gastric emptying in early noninsulin-dependent diabetes mellitus. J Nucl Med 37:1643–1648[Abstract/Free Full Text]
10. Jones KL, MacIntosh C, Su YC, Wells F, Chapman IM, Tonkin A, Horowitz M 2001 Guar gum reduces postprandial hypotension in older people. J Am Geriatr Soc 49:162–167[CrossRef][Medline]
11. Cunningham KM, Read NW 1989 The effect of incorporating fat into different components of a meal on gastric emptying and postprandial blood glucose and insulin responses. Br J Nutr 61:285–290[CrossRef][Medline]
12. Welch IM, Bruce C, Hill SE, Read NW 1987 Duodenal and ileal lipid suppresses postprandial blood glucose and insulin responses in man: possible implications for the dietary management of diabetes mellitus. Clin Sci (Lond) 72:209–216[Medline]
13. Horowitz M, Jones K, Edelbroek MA, Smout AJ, Read NW 1993 The effect of posture on gastric emptying and intragastric distribution of oil and aqueous meal components and appetite. Gastroenterology 105:382–390[Medline]
14. Meyer JH, Elashoff JD, Domeck M, Levy A, Jehn D, Hlinka M, Lake R, Graham LS, Gu YG 1994 Control of canine gastric emptying of fat by lipolytic products. Am J Physiol 266:G1017–G1035
15. Schwizer W, Asal K, Kreiss C, Mettraux C, Borovicka J, Remy B, Guzelhan C, Hartmann D, Fried M 1997 Role of lipase in the regulation of upper gastrointestinal function in humans. Am J Physiol 273:G612–G620
16. Carney BI, Jones KL, Horowitz M, Sun WM, Penagini R, Meyer JH 1995 Gastric emptying of oil and aqueous meal components in pancreatic insufficiency: effects of posture and on appetite. Am J Physiol 268:G925–G932
17. Long WB, Weiss JB 1974 Rapid gastric emptying of fatty meals in pancreatic insufficiency. Gastroenterology 67:920–925[Medline]
18. Williams G 1999 Obesity and type 2 diabetes: a conflict of interests? Int J Obes Relat Metab Disord 23(Suppl 7):S2–S4
19. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB 1999 Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 281:235–242[Abstract/Free Full Text]
20. Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J 1998 Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 21:1288–1294[Abstract]
21. Miles JM, Leiter L, Hollander P, Wadden T, Anderson JW, Doyle M, Foreyt J, Aronne L, Klein S 2002 Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetes Care 25:1123–1128[Abstract/Free Full Text]
22. Hanefeld M, Sachse G 2002 The effects of orlistat on body weight and glycaemic control in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes Metab 4:415–423[CrossRef][Medline]
23. Kelley DE, Bray GA, Pi-Sunyer FX, Klein S, Hill J, Miles J, Hollander P 2002 Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 25:1033–1041[Abstract/Free Full Text]
24. Borovicka J, Schwizer W, Guttmann G, Hartmann D, Kosinski M, Wastiel C, Bischof-Delaloye A, Fried M 2000 Role of lipase in the regulation of postprandial gastric acid secretion and emptying of fat in humans: a study with orlistat, a highly specific lipase inhibitor. Gut 46:774–781[Abstract/Free Full Text]
25. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B 1995 Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 56:117–126[Medline]
26. Wen J, Phillips SF, Sarr MG, Kost LJ, Holst JJ 1995 PYY and GLP-1 contribute to feedback inhibition from the canine ileum and colon. Am J Physiol 269:G945–G952
27. MacIntosh CG, Horowitz M, Verhagen MA, Smout AJ, Wishart J, Morris H, Goble E, Morley JE, Chapman IM 2001 Effect of small intestinal nutrient infusion on appetite, gastrointestinal hormone release, and gastric myoelectrical activity in young and older men. Am J Gastroenterol 96:997–1007[CrossRef][Medline]
28. Feinle C, Chapman IM, Wishart J, Horowitz M 2002 Plasma glucagon-like peptide-1 (GLP-1) responses to duodenal fat and glucose infusions in lean and obese men. Peptides 23:1491–1495[CrossRef][Medline]
29. Beysen C, Karpe F, Fielding BA, Clark A, Levy JC, Frayn KN 2002 Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Diabetologia 45:1533–1541[CrossRef][Medline]
30. Feinle C, O’Donovan D, Doran S, Andrews J, Wishart J, Chapman IM, Horowitz M 2003 Effects of fat digestion on appetite, antropyloroduodenal motility, and gut hormones in response to duodenal fat infusion in humans. Am J Physiol Gastrointest Liver Physiol 284:G798–G807
31. Horowitz M, Maddox AF, Wishart JM, Harding PE, Chatterton BE, Shearman DJ 1991 Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur J Nucl Med 18:229–234[Medline]
32. Ewing DJ, Clarke BF 1982 Diagnosis and management of diabetic autonomic neuropathy. BMJ 285:916–918
33. Cunningham KM, Baker RJ, Horowitz M, Maddox AF, Edelbroek MA, Chatterton BE 1991 Use of technetium-99m(V)thiocyanate to measure gastric emptying of fat. J Nucl Med 32:878–881[Abstract/Free Full Text]
34. Bellen JC, Chatterton BE, Penglis S, Tsopelas C 1995 Gallium-67 complexes as radioactive markers to assess gastric and colonic transit. J Nucl Med 36:513–517[Abstract/Free Full Text]
35. Collins PJ, Horowitz M, Cook DJ, Harding PE, Shearman DJ 1983 Gastric emptying in normal subjects—a reproducible technique using a single scintillation camera and computer system. Gut 24:1117–1125[Abstract/Free Full Text]
36. Horowitz M, Cunningham KM, Wishart JM, Jones KL, Read NW 1996 The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects. Diabetologia 39:481–486[Medline]
37. Wishart JM, Horowitz M, Morris HA, Jones KL, Nauck MA 1998 Relation between gastric emptying of glucose and plasma concentrations of glucagon-like peptide-1. Peptides 19:1049–1053[CrossRef][Medline]
38. Orskov C, Jeppesen J, Madsbad S, Holst JJ 1991 Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest 87:415–423
39. Wishart J, Morris HA, Horowitz M 1992 Radioimmunoassay of gastric inhibitory polypeptide in plasma. Clin Chem 38:2156–2157[Medline]
40. Piha SJ 1991 Cardiovascular autonomic reflex tests: normal responses and age-related reference values. Clin Physiol 11:277–290[Medline]
41. Berry MK, Russo A, Wishart JM, Tonkin A, Horowitz M, Jones KL 2003 Effect of a solid meal on gastric emptying of, and the glycemic and cardiovascular responses to, liquid glucose in older subjects. Am J Physiol Gastrointest Liver Physiol 284:G655–G662
42. MacGregor IL, Gueller R, Watts HD, Meyer JH 1976 The effect of acute hyperglycemia on gastric emptying in man. Gastroenterology 70:190–196[Medline]
43. Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, Dent J 1990 Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33:675–680[CrossRef][Medline]
44. Schvarcz E, Palmer M, Aman J, Berne C 1995 Hypoglycemia increases the gastric emptying rate in healthy subjects. Diabetes Care 18:674–676[Abstract]
45. Schvarcz E, Palmer M, Aman J, Lindkvist B, Beckman KW 1993 Hypoglycaemia increases the gastric emptying rate in patients with type 1 diabetes mellitus. Diabet Med 10:660–663[Medline]
46. Holst JJ, Orskov C 2001 Incretin hormones—an update. Scand J Clin Lab Invest Suppl 234:75–85[Medline]
47. Schirra J, Katschinski M, Weidmann C, Schafer T, Wank U, Arnold R, Goke B 1996 Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97:92–103[Medline]

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