Mechanisms behind the immediate effects of Roux-en-Y gastric bypass surgery on type 2 diabetes

Roland E. Allen, Tyler D. Hughes, Jia Lerd Ng, Roberto D. Ortiz, Michel Abou Ghantous, Othmane Bouhali, Philippe Froguel, Abdelilah Arredouani

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: The most common bariatric surgery, Roux-en-Y gastric bypass, leads to glycemia normalization in most patients long before there is any appreciable weight loss. This effect is too large to be attributed purely to caloric restriction, so a number of other mechanisms have been proposed. The most popular hypothesis is enhanced production of an incretin, active glucagon-like peptide-1 (GLP-1), in the lower intestine. We therefore set out to test this hypothesis with a model which is simple enough to be robust and credible. Method. Our method involves (1) setting up a set of time-dependent equations for the concentrations of the most relevant species, (2) considering an "adiabatic" (or quasi-equilibrium) state in which the concentrations are slowly varying compared to reaction rates (and which in the present case is a postprandial state), and (3) solving for the dependent concentrations (of e.g. insulin and glucose) as an independent concentration (of e.g. GLP-1) is varied. Results: Even in the most favorable scenario, with maximal values for (i) the increase in active GLP-1 concentration and (ii) the effect of GLP-1 on insulin production, enhancement of GLP-1 alone cannot account for the observations. I.e., the largest possible decrease in glucose predicted by the model is smaller than reported decreases, and the model predicts no decrease whatsoever in glucose ×insulin, in contrast to large observed decreases in homeostatic model assessment insulin resistance (HOMA-IR). On the other hand, both effects can be accounted for if the surgery leads to a substantial increase in some substance that opens an alternative insulin-independent pathway for glucose transport into muscle cells, which perhaps uses the same intracellular pool of GLUT-4 that is employed in an established insulin-independent pathway stimulated by muscle contraction during exercise. Conclusions: Glycemia normalization following Roux-en-Y gastric bypass is undoubtedly caused by a variety of mechanisms, which may include caloric restriction, enhanced GLP-1, and perhaps others proposed in earlier papers on this subject. However, the present results suggest that another possible mechanism should be added to the list of candidates: enhanced production in the lower intestine of a substance which opens an alternative insulin-independent pathway for glucose transport.

Original languageEnglish
Article number45
JournalTheoretical Biology and Medical Modelling
Volume10
Issue number1
DOIs
Publication statusPublished - 18 Jul 2013

Fingerprint

Glucagon-Like Peptide 1
Gastric Bypass
Insulin
Diabetes
Medical problems
Surgery
Type 2 Diabetes Mellitus
Peptides
Glucose
Caloric Restriction
Pathway
Decrease
Intestines
Muscle
Normalization
Incretins
Bariatric Surgery
Restriction
Muscle Contraction
Alternatives

ASJC Scopus subject areas

  • Health Informatics
  • Modelling and Simulation
  • Medicine(all)

Cite this

Mechanisms behind the immediate effects of Roux-en-Y gastric bypass surgery on type 2 diabetes. / Allen, Roland E.; Hughes, Tyler D.; Ng, Jia Lerd; Ortiz, Roberto D.; Ghantous, Michel Abou; Bouhali, Othmane; Froguel, Philippe; Arredouani, Abdelilah.

In: Theoretical Biology and Medical Modelling, Vol. 10, No. 1, 45, 18.07.2013.

Research output: Contribution to journalArticle

Allen, Roland E. ; Hughes, Tyler D. ; Ng, Jia Lerd ; Ortiz, Roberto D. ; Ghantous, Michel Abou ; Bouhali, Othmane ; Froguel, Philippe ; Arredouani, Abdelilah. / Mechanisms behind the immediate effects of Roux-en-Y gastric bypass surgery on type 2 diabetes. In: Theoretical Biology and Medical Modelling. 2013 ; Vol. 10, No. 1.
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AU - Ghantous, Michel Abou

AU - Bouhali, Othmane

AU - Froguel, Philippe

AU - Arredouani, Abdelilah

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N2 - Background: The most common bariatric surgery, Roux-en-Y gastric bypass, leads to glycemia normalization in most patients long before there is any appreciable weight loss. This effect is too large to be attributed purely to caloric restriction, so a number of other mechanisms have been proposed. The most popular hypothesis is enhanced production of an incretin, active glucagon-like peptide-1 (GLP-1), in the lower intestine. We therefore set out to test this hypothesis with a model which is simple enough to be robust and credible. Method. Our method involves (1) setting up a set of time-dependent equations for the concentrations of the most relevant species, (2) considering an "adiabatic" (or quasi-equilibrium) state in which the concentrations are slowly varying compared to reaction rates (and which in the present case is a postprandial state), and (3) solving for the dependent concentrations (of e.g. insulin and glucose) as an independent concentration (of e.g. GLP-1) is varied. Results: Even in the most favorable scenario, with maximal values for (i) the increase in active GLP-1 concentration and (ii) the effect of GLP-1 on insulin production, enhancement of GLP-1 alone cannot account for the observations. I.e., the largest possible decrease in glucose predicted by the model is smaller than reported decreases, and the model predicts no decrease whatsoever in glucose ×insulin, in contrast to large observed decreases in homeostatic model assessment insulin resistance (HOMA-IR). On the other hand, both effects can be accounted for if the surgery leads to a substantial increase in some substance that opens an alternative insulin-independent pathway for glucose transport into muscle cells, which perhaps uses the same intracellular pool of GLUT-4 that is employed in an established insulin-independent pathway stimulated by muscle contraction during exercise. Conclusions: Glycemia normalization following Roux-en-Y gastric bypass is undoubtedly caused by a variety of mechanisms, which may include caloric restriction, enhanced GLP-1, and perhaps others proposed in earlier papers on this subject. However, the present results suggest that another possible mechanism should be added to the list of candidates: enhanced production in the lower intestine of a substance which opens an alternative insulin-independent pathway for glucose transport.

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