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Orlistat Augments Postprandial Increases in Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients: Response to Damci Et Al./ Orlistat Augments Postprandial Increases In Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients: Response to Horowitz Et

Posted on: Thursday, 18 November 2004, 03:00 CST

COMMENTS AND RESPONSES

Orlistat Augments Postprandial Increases in Glucagon-Like Peptide- 1 in Obese Type 2 Diabetic Patients

Response to Damci et al.

Damci et al. (1) suggest that the lipase inhibitor, orlistat, stimulates the postprandial secretion of glucagon-like peplide-1 (GLP-1) after meals containing fat and speculate that this may lead lo reductions in both postprandial glycemia and energy intake. The authors observed (in a cohort of 29 type 2 diabetic patients) that after ingestion of a 600 kcal breakfast (comprising 38% fat, 50% carbohydrate, and 12% protein), the increases from baseline in plasma GLP-1 and serum C-peptide were slightly greater and that of serum glucose slightly less, as measured in a single blood sample taken 60 min after commencement of the meal. The authors have apparently failed to appreciate the following: 1) While fat is a potent stimulant of GLP-1 secretion, the latter appears to be dependent on the digestion of fat to fatly acids (2,3), e.g., in healthy subjects, the stimulation of GLP-1 by intraduodenal triglyceride is abolished by concomitant administration of orlistat (2). 2) As ihe regulation of gastric emptying of fat is also dependent on lipolysis (4,5), orlistat may accelerate gastric emptying of meals containing fat (4). If the meal also contains carbohydrate, orlistat has the capacity to exacerbate overall postprandial glycemic excursions in type 2 diabetic patients by this mechanism (3). Even relatively minor variations in gastric emptying of carbohydrate are now known to potentially have a major effect on postprandial glycemia and insulin responses in both healthy subjects and type 2 diabetic patients (6,7). 3) In healthy subjects, acute lipase inhibition with orlistat attenuates rather than increases the inhibitory effects of fat on subsequent energy intake (2,8).

The effects of orlistat on glycemic, insulin, and incretin responses to a meal, including the time course of these effects, are likely to be critically dependent on both the macronutrient composition and energy content of a meal, perhaps particularly the ratio of fat to carbohydrate. It should also be recognized that in patients with type 2 diabetes, gastric emptying is frequently abnormal and may influence these responses (7). In relation to the study by Damci et al. (1), we would offer an alternative interpretation, i.e., after administration of orlistat, the carbohydrate, fat, and protein components of their meal (the type of meal is not described) initially emptied from the stomach more rapidly, and this was reflected in a relative increase in C-peptide and GLP-1 at 60 min and a slight reduction in plasma glucose at that time. The stimulation of GLP-1 would reflect the greater small intestinal carbohydrate load during this lime as well as the presence of fatty acids that escaped lipase inhibition. We would anticipate that the overall GLP-1 response to the meal would be less and initial postprandial glycemia worse. It would require more frequent blood sampling over a longer period of time to fully interpret the action of orlistat on incretin and insulin secretion and to draw conclusions about GLP-1 as a mediator of the effects of orlistat on body weight in obesity.

MICHAEL HOROWITZ, MB, BS, PHD1

CHRISTINE FEINLE-BISSET, PHD1

KAREN JONES, PHD1

MICHAEL NAUCK, MD2

From ihe 1 Department of Medicine, University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia; and 2 Diabeteszentrum, Bad Lauterberg im Harz, Germany.

Address correspondence 10 Professor Michael Horowitz, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia, 5000. E-mail: michael.horowitz@ adelaide.edu.au.

2004 by the American Diabetes Association.

References

1. Damci T, Yalin S, Bald H, Oser Z, Korugan U, Ozyazar M, Illkova H: Orlistal augments post prandial increases in glucagonlike peptide-1 in obese type 2 diabetic patients. Diabetes Care 27:1077- 1080, 2004

2. Feinle C, O'Donovan D, Doran S, Andrews JM, Wish art J, Chapman I, Horowitz M: Effects of fat digestion on appetite, APD motility, and gut hormones in response to duodenal fat infusion in humans. Am J Physiol Gastrointest Liver Physiol 284:G798-G807, 2003

3. Pilichiewicz A, O'Donovan D, Feinle C, Lei Y, Wishart JM, Bryant L, Meyer JH, Horowitz M, Jones KL: Effect of lipase inhibition on gastric emptying of, and the glycemic increiin responses to, an oil/ aqueous drink in type 2 diabetes mellitus. J Clin Endocrinol Metab 88:1829-3834, 2003

4. Schwizer W, Asal K, Kreiss C, Mettraux C, Berovicka J, Remy B, Guzelhan C, Hartmann D, Fried M: Role of lipase in the regulation of upper gastrointestinal function in humans. Am J Physiol 273:G612G620, 1995

5. Carney BI, Jones KL, Horowitz M, Sun WM, Penagini R, Meyer JH: Gastric emptying of oil and aqueous meal components in pancreatic insufficiency: effects of posture and on appetite. Am J Physiol 268: G925-G932, 1995

6. O'Donovan DG, Doran S, Feinle-Bisset C, Jones KL, Meyer JH, Wishart JM, Morris HA, Horowitz M: Effect of variations in small intestinal glucose delivery on plasma glucose, insulin and increiin hormones in healthy subjects and type 2 diabetes. J Clin Endocrinol Metab 89:34313435, 2004

7. Rayner CK, Samsom M, Jones KL, Horowitz M: Relationships of upper gastrointestinal motor and sensory function with glycaemic control. Diabetes Care 24:371381, 2001

8. O'Donovan D, Feinle-Bisset C, Wishart J, Horowitz M: Lipase inhibition attenuates the acute inhibitory elfecis of oral fat on food intake in healthy subjects. Br J Nutr 90:849-852, 2003

Orlistat Augments Postprandial Increases In Glucagon-Like Peptide- 1 in Obese Type 2 Diabetic Patients

Response to Horowitz et al.

We thank Horowilz et al. (1) for their comments on our article (2) on the effect of orlistat on postprandial glucose, insulin, and incretin levels. They raise criticisms regarding the increase in postprandial GLP-1 levels, asserting that it is a result of fat digestion rather than the fat content of the meal. They also state that to draw more definitive conclusions, more Irequent blood sampling over a longer period of time is required rather than a single sample at 60 min after the mixed meal. Ours was an observatory pilot study that tested the effect of this drug on postprandial incretin levels. Putative mechanisms of action will be addressed in further studies in which we will take these criticisms into account. Horowitz et al. also state that orlistat would be expected to worsen postprandial hyperglycemia since this drug accelerates gastric emptying. Apart from our study, orlistat was previously shown to ameliorate postprandial blood glucose levels in long-term studies (3).

TANER DAMCI, MD1

SERAP YALIN, MD1

HURIYE BALCI, PHD2

ZEYNEP OSAR, MD1

USTUN KORUGAN, MD1

MUCAHIT OZYAZAR, MD1

HASAN ILKOVA, MD2

From the 1 Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey; and the 2 Central Laboratories, Istanbul University Cerrahpasa Medical School, Istanbul, Turkey.

Address correspondence to Taner Damci, MD, Atakoy 4, Kisim O-67 D:7, 34750 Alakoy, Istanbul, Turkey. E-mail: idamci@superonline.com.

T.D. is an advisory board member for Aventis and has received honoraria from Roche, Avenus, and Pfizer. H.I. is an advisory board member for Aveulis and has received honoraria from Roche, Novo Nordisk, Pfizer, and GlaxoSmithKline.

2004 by the American Diabetes Association.

References

1. Horowilz M, Feinle-Bisset C, Jones K, Nauck M: Orlislai augments postprandial increases in glucagon-likc peptide-1 in obese type 2 diabetic patients (Letter). Diabetes Care 27:2770, 2004

2. Damci T, Yalta S, Balci H, Osar Z, Korugan U, Ozyazar M, Ilkova H: Orlistat augments postprandial increasesin glucagonlike peptide I in obese type 2 diabetic patiems. Diabetes Care 27:1077- 1080, 2004

3. Holander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T: Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care 21:12881294, 1998

Copyright American Diabetes Association Nov 2004

Source: Diabetes Care

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