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Cited by 323Bariatric Surgery and OutcomesPancreatic function and diabetesDiabetes Treatment and Management

Gastric Bypass Surgery Enhances Glucagon-Like Peptide 1–Stimulated Postprandial Insulin Secretion in Humans

Open access
Salehi, Marzieh, Prigeon, Ronald L., D’Alessio, David A.·2011·Diabetes
DOI 10.2337/db11-0203PMC PMC3161307
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Abstract

OBJECTIVE: Gastric bypass (GB) surgery is associated with postprandial hyperinsulinemia, and this effect is accentuated in postsurgical patients who develop recurrent hypoglycemia. Plasma levels of the incretin glucagon-like peptide 1 (GLP-1) are dramatically increased after GB, suggesting that its action contributes to alteration in postprandial glucose regulation. The aim of this study was to establish the role of GLP-1 on insulin secretion in patients with GB. RESEARCH DESIGN AND METHODS: Twelve asymptomatic individuals with previous GB (Asym-GB), 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB (Hypo-GB) had pre- and postprandial hormone levels and insulin secretion rates (ISR) measured during a hyperglycemic clamp with either GLP-1 receptor blockade with exendin-(9–39) or saline. RESULTS: Blocking the action of GLP-1 suppressed postprandial ISR to a larger extent in Asym-GB individuals versus control subjects (33 ± 4 vs.16 ± 5%; P = 0.04). In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20). Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups. CONCLUSIONS: Increased GLP-1–stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.

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Written from the paper’s full text.

TL;DR

In humans with prior gastric bypass, GLP-1 receptor blockade with exendin-(9–39) reduced postprandial insulin secretion more than in nonoperated control subjects, indicating enhanced GLP-1–stimulated insulin secretion after surgery. However, this GLP-1 effect did not differ significantly between asymptomatic gastric bypass and recurrent hypoglycemia gastric bypass patients, so post-gastric bypass hypoglycemia is not explained by disproportionate GLP-1 action alone.

Key findings

  • Blocking GLP-1 action suppressed postprandial insulin secretion rates by 33 ± 4% in asymptomatic gastric bypass subjects versus 16 ± 5% in control subjects (P = 0.04); in hypoglycemia gastric bypass patients it accounted for 43 ± 4%, not significantly higher than asymptomatic gastric bypass (P = 0.20) but higher than controls (P = 0.002).
  • Enteral factors accounted for 70 ± 2% of insulin secretion from 95–270 min in asymptomatic gastric bypass, 73 ± 4% in hypoglycemia gastric bypass, and 55 ± 5% in controls; in the first hour after eating, these were 80 ± 1%, 81 ± 3%, and 53 ± 7%, respectively (P < 0.001 for pairwise comparison).
  • Glucagon was suppressed by IV hyperglycemia in all groups, but rose significantly after meal ingestion in both surgical groups while remaining suppressed in nonsurgical controls; GLP-1 receptor blockade increased postprandial glucagon in both surgical groups.
  • Plasma GLP-1 responses to meal ingestion were larger in gastric bypass subjects than controls and higher in hypoglycemia gastric bypass than asymptomatic gastric bypass subjects, but the estimated GLP-1 effect on insulin secretion was not significantly different between the two surgical groups.

Methods

  • Twelve asymptomatic subjects with previous gastric bypass, 12 patients with recurrent hypoglycemia after gastric bypass, and 10 matched healthy nonoperated control subjects underwent paired mixed-meal tolerance tests with hyperglycemic clamps using either exendin-(9–39) or saline, separated by at least 1 week.
  • Insulin secretion rates were derived from plasma C-peptide by deconvolution; the endogenous GLP-1 contribution to postprandial insulin secretion was calculated as 100 × (ISR saline 95–270 − Ex-9 ISR 95–270)/ISR saline 95–270.
  • Hormones were measured by radioimmunoassay or ELISA, and comparisons used two-way repeated-measures ANOVA and ANOVA.

Limitations

  • The paper states that the small sample limits statistical power and that approximately 80 subjects in each of the asymptomatic and hypoglycemia gastric bypass groups would be required for the apparent difference in GLP-1–mediated insulin secretion to reach statistical significance.
  • The paper states that screening meal tests were stopped in patients who became symptomatically hypoglycemic, so the depth of the glucose nadir may have been underestimated in the hypoglycemia group; it also assumes that Roux-en-Y gastric bypass does not affect C-peptide kinetics for insulin secretion rate calculations.
  • Evident from the text: only 2 of 11 hypoglycemia gastric bypass subjects completed the screening meal test, and glucagon and GIP measurements were available for subsets of 29 and 33 subjects, respectively.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/db11-0203

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 25 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Ex-9 infusion significantly increased GLP-1 in response to food intake in all three groups.

    “Ex-9 infusion significantly increased GLP-1 in response to food intake in all three groups (Table 2, Fig. 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Postprandial plasma d-xylose levels were significantly higher in surgical groups compared with nonsurgical control subjects.

    “Postprandial plasma d-xylose levels were significantly higher in surgical groups compared with nonsurgical control subjects; but infusion of Ex-9 had minimal effects on the passage of d-xylose from stomach or gastric pouch to the intestine (AUCd-xylose (90–130 min), saline, GB: 17.3 ± 3.9 vs. control: 3.4 ± 0.4 mmol/L⋅min; Ex-9, GB: 18.0 ± 3.5 vs. control: 4.1 ± 0.9 mmol/L⋅min; P = 0.03 for pairwi”
    Quote in the paperNot a substantial claim
  • Findingown data

    Hypoglycemic gastric bypass subjects had an earlier glucose drop during the meal tolerance test compared with asymptomatic gastric bypass subjects (time to nadir 95 ± 30 vs 128 ± 43 min; P = 0.045).

    “The Hypo-GB subjects had an earlier glucose drop (time to reach nadir glucose level during MTT, Asym-GB 128 ± 43 min vs. Hypo-GB 95 ± 30 min; P = 0.045) and a greater β-cell response immediately after meal ingestion compared with the Asym-GB group (insulinogenic index, Asym-GB: 195 ± 28 [pmol insulin]/[mmol glucose] vs. Hypo-GB: 455 ± 100 [pmol insulin]/[mmol glucose]; P = 0.02) (Fig. 1).”
    Quote in the paperNot a substantial claim
  • Findingnone given

    The exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.

    “However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycemia.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.
  • Findingown data

    Blocking endogenous GLP-1 had no effect on GIP secretion.

    “Blocking endogenous GLP-1 had no effect on GIP secretion (Table 2, Fig. 3).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingown data

    After meal ingestion, plasma glucagon rose significantly in surgical individuals but remained suppressed in nonsurgical control subjects.

    “Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects.”
    • Also stated in: § MTT-clamp · plain
      “However, meal ingestion resulted in a substantial rise in plasma glucagon over preprandial values, and this response was greater when the action of endogenous GLP-1 was blocked particularly in the 1st h after meal ingestion (Table 2, Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fasting blood glucose and insulin levels were comparable in asymptomatic and hypoglycemic gastric bypass groups.

    “Fasting blood glucose and insulin levels were comparable in Asym-GB and Hypo-GB groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Meal consumption increased plasma GIP concentrations in all three groups, but with an earlier peak in gastric bypass surgical subjects.

    “Meal consumption also increased plasma GIP concentrations in all three groups, but with an earlier peak in the GB surgical subjects (Table 2, Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The GLP-1 effect was consistent throughout the 3-h period after meal ingestion even though the highest plasma GLP-1 levels were in the first hour after meal ingestion.

    “Second, the GLP-1 effect was consistent throughout the 3-h period after meal ingestion even though the highest plasma GLP-1 levels were in the 1st h after meal ingestion.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • May combine two claims.

    Findingown data

    Following the test meal, blood glucose fell to <2.8 mmol/L in 9 of 11 hypoglycemic subjects who became symptomatic and in 2 of 12 asymptomatic subjects without associated symptoms.

    “Following ingestion of the test meal, blood glucose fell to <2.8 mmol/L in 9 of 11 hypoglycemic subjects, who became symptomatic, within 60–150 min; 2 of 12 asymptomatic subjects had a glucose level <2.8 mmol/L within 100–120 min but without associated symptoms of hypoglycemia (Supplementary Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Fasting GLP-1 levels were comparable among the three groups and between the two studies.

    “Fasting GLP-1 levels were comparable among the three groups and between the two studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In patients with recurrent hypoglycemia after gastric bypass, GLP-1 accounted for 43 ± 4% of postprandial insulin secretion rate, which was not significantly higher than in asymptomatic gastric bypass subjects (P = 0.20).

    “In Hypo-GB patients, GLP-1 accounted for 43 ± 4% of postprandial ISR, which was not significantly higher than that in Asym-GB subjects (P = 0.20).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The order of the infusions was balanced so that half the subjects received saline first and half Ex-9 first.

    “The order of the infusions was balanced so that half the subjects received saline first and half Ex-9 first.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Asymptomatic and hypoglycemic gastric bypass subjects had similar total weight loss and time since surgery, even though hypoglycemic subjects had a larger weight loss in the first year after surgery and consequently larger weight gain prior to recruitment.

    “Asym-GB and Hypo-GB subjects had similar total weight loss and time since surgery, even though Hypo-GB subjects had a larger weight loss in the 1st year after surgery (P = 0.01) and consequently larger weight gain prior to their recruitment compared with Asym-GB subjects (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Fasting glucose and insulin levels were not different among the asymptomatic gastric bypass, hypoglycemic gastric bypass, and control groups or between the paired studies with saline or Ex-9.

    “Fasting glucose and insulin levels were not different among the Asym-GB, Hypo-GB, and control groups or between the paired studies with saline or Ex-9 in each individual (Table 2, Fig. 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Synthetic exendin-(9-39) was greater than 95% pure, sterile, and free of pyrogens.

    “Synthetic exendin-(9–39) (Ex-9) (C S Bio, Menlo Park, CA) was greater than 95% pure, sterile and free of pyrogens.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Gastric bypass surgery enhances GLP-1 action after meal ingestion, contributing to the exaggerated postprandial insulin secretion typically described after this surgery.

    “Our results indicate that gastric bypass surgery enhances GLP-1 action after meal ingestion, contributing to the exaggerated postprandial insulin secretion typically described after this surgery.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Glucagon secretion after gastric bypass is not altered among subjects with recurrent hypoglycemia.

    “and is not altered among subjects with recurrent hypoglycemia (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Goldfine, 2007, Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Gastric bypass surgery causes increased GLP-1 secretion and action, effects that are likely to contribute to the changes in glucose metabolism seen in patients after this procedure.

    “Based on these findings, it appears that GB surgery causes increased GLP-1 secretion and action, effects that are likely to contribute to the changes in glucose metabolism seen in patients after this procedure.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The average coefficient of variation of glucose concentrations from 60-270 min during saline clamps was 4.4 ± 0.3%, 5.2 ± 0.4%, and 4.7 ± 0.8% for asymptomatic gastric bypass, hypoglycemic gastric bypass, and control groups, respectively.

    “The average coefficient of variation of the glucose concentrations from 60–270 min during the saline clamps was 4.4 ± 0.3, 5.2 ± 0.4, and 4.7 ± 0.8% for Asym-GB, Hypo-GB, and control groups, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The asymptomatic and hypoglycemic gastric bypass groups segregated regarding their symptomatic response to hypoglycemia and their average nadir glucose levels during the meal tolerance test, indicating that each group represents a distinct metabolic phenotype after gastric bypass.

    “While there was some overlap in glycemia after the MTT, the Asym-GB and Hypo-GB groups segregated regarding their symptomatic response to hypoglycemia as well as the average of their nadir glucose levels during MTT, indicating that each group represents a distinct metabolic phenotype after GB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The early rise in insulin secretion rate is consistent with increased GLP-1 and GIP stimulation, and the profile of insulin secretion in gastric bypass groups mimics that of the incretins.

    “The early rise in ISR is consistent with increased GLP-1 and GIP stimulation, and in fact the profile of insulin secretion in the GB groups mimics that of the incretins (Figs. 2 and 3).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Addition of oxyntomodulin to the glucagon radioimmunoassay demonstrated cross-reactivity of less than 0.1%.

    “Addition of oxyntomodulin to the glucagon radioimmunoassay demonstrated cross-reactivity of <0.1%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The three groups had similar BMI, age, and sex distribution, and had stable body weight for at least a month before study.

    “The three groups had similar BMI, age, and sex distribution, and had stable body weight for at least a month before study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The relatively higher postprandial insulin responses seen in patients after gastric bypass are not a response to insulin resistance or the result of general hypersensitivity of β-cells to glucose.

    “These findings suggest that the relatively higher postprandial insulin responses seen in patients after GB (8,9,12,23) are not a response to insulin resistance or the result of general hypersensitivity of β-cells to glucose.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Korner, 2007, Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding, Surg Obes Relat Dis source

      Not checked in the free run.

    • cites [9] Laferrère, 2008, Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [12] Rodieux, 2008, Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release, Obesity (Silver Spring) source

      Not checked in the free run.

    • cites [23] le Roux, 2006, Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters, Ann Surg source

      Not checked in the free run.

    • The authors state this as an assumption: Roux-en-Y gastric bypass does not affect C-peptide kinetics.

  • May combine two claims.

    Interpretationreasoning

    The alteration in α-cell regulation in subjects with gastric bypass occurred exclusively in the postprandial state, consistent with enhanced nutrient or neural stimulation of the islets.

    “Similar to changes in β-cell function, the alteration in α-cell regulation in subjects with GB also occurred exclusively in the postprandial state, consistent with enhanced nutrient or neural stimulation of the islets.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The insulin assay has a sensitivity of 2 pmol/L, intra- and interassay coefficients of variation of 5% and 7%, respectively, and recognizes proinsulin equally to insulin.

    “The sensitivity of this assay is 2 pmol/L, the intra- and interassay coefficients of variation are 5 and 7%, respectively, and proinsulin is recognized equally to insulin.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Blood glucose concentrations were raised to the target level of hyperglycemia in each group and were maintained comparably during the saline and Ex-9 studies from 60-270 min.

    “Blood glucose concentrations were raised to the target level of hyperglycemia in each group (Table 2, Fig. 2), and were maintained comparably during the duration of the saline and Ex-9 studies (60–270 min).”
    Quote in the paperSubstantial claim
23 of 23

  • The authors state this as an assumption.

    Roux-en-Y gastric bypass does not affect C-peptide kinetics.

    “an assumption underlying this analysis is that Roux-en-Y GB does not affect C-peptide kinetics.”
1 of 1

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References 31 · Cited by 323

Authors
Salehi, M., Prigeon, R. L., & D’Alessio, D. A.
Affiliations
  • University of Cincinnati (US)
  • University of Maryland, Baltimore (US)
  • Cincinnati VA Medical Center (US)
Corresponding author
Salehi, Marzieh
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-08-20
Volume
60
Issue
9
Pages
2308-2314
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-0203
PMC
PMC3161307
OpenAlex
W2119976901
Semantic Scholar
b4452988a5685d429be4c1bdfbc665d7083aec53
Cited by
323
References
31
Citations by year
2026: 9 · 2025: 3 · 2024: 6 · 2023: 19 · 2022: 19 · 2021: 22 · 2020: 16 · 2019: 20 · 2018: 21 · 2017: 25 · 2016: 39 · 2015: 36 · 2014: 25 · 2013: 35 · 2012: 22
FWCI
28.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • American Heart Association
  • Cincinnati Children's Hospital Medical Center
  • University of Cincinnati
  • American Society for Metabolic and Bariatric Surgery
  • MannKind Corporation
  • Novo Nordisk
  • National Institutes of Health (5ul1rr026314-03, UL1TR000077, UL1 RR-026314)
  • U.S. Public Health Service (#UL1 RR026314, RR026314)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK57900, DK083554, R01DK057900, K23DK083554)
  • National Center for Research Resources (UL1-RR026314)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
gastric bypass, glucagon-like peptide-1, postprandial insulin secretion, recurrent hypoglycemia, hyperinsulinism, exendin-9-39, glucagon, incretins, postprandial glucose regulation, bariatric surgery
MeSH terms
Insulin Secretion, Adult, Blood Glucose, Female, Glucagon, Humans, Insulin, Male, Middle Aged, Pancreas, Gastric Bypass, Postprandial Period, Glucagon-Like Peptide 1

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