Blockade of Glucagon-like Peptide 1 Receptor Corrects Postprandial Hypoglycemia After Gastric Bypass

doi:10.1053/j.gastro.2013.11.044

Gastroenterology

Volume 146, Issue 3, March 2014, Pages 669-680.e2

https://doi.org/10.1053/j.gastro.2013.11.044 Get rights and content

Background & Aims

Postprandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among patients with recurrent hypoglycemia. These patients also have increased postprandial levels of insulin and glucagon-like peptide 1 (GLP-1). We performed a clinical trial to determine the role of GLP-1 in postprandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass.

Methods

Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 patients who were asymptomatic after gastric bypass (A-GB), and 8 healthy control subjects underwent a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 separate days. On 1 day they received continuous infusion of the GLP-1 receptor antagonist exendin (9-39) (Ex-9), and on the other day they received a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal.

Results

Infusion of Ex-9 corrected hypoglycemia in all patients with H-GB. The reduction in postprandial insulin secretion by Ex-9 was greater in the H-GB group than in the other groups (H-GB, 50% ± 8%; A-GB, 13% ± 10%; controls, 14% ± 10%) (P < .05). The meal-derived glucose appearance was significantly greater in subjects who had undergone gastric bypass compared to the controls and in the H-GB group compared to the A-GB group. Ex-9 shortened the time to reach peak meal-derived glucose appearance in all groups without a significant effect on overall glucose flux. Postprandial glucagon levels were higher among patients who had undergone gastric bypass than controls and increased with administration of Ex-9.

Conclusions

Hypoglycemia after gastric bypass can be corrected by administration of a GLP-1 receptor antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP-1 activity contributes to hypoglycemia after gastric bypass. ClinicalTrials.gov, Number: NCT01803451.

Section snippets

Subjects

Nine patients with recurrent hypoglycemia after GB (H-GB), 7 subjects who were asymptomatic after GB (A-GB), and 8 healthy control subjects (CON) with normal glucose tolerance and no prior history of gastrointestinal (GI) surgery were recruited. The subjects in the H-GB group had recurrent episodes of neuroglycopenic symptoms (cognitive dysfunction, loss of consciousness, and/or seizure) within 5 hours of meal ingestion that were associated with blood glucose levels <50 mg/dL and resolved

Characteristics of Subjects

The subjects in the 3 groups had similar body mass index, waist circumference, fat and lean mass, and glycated hemoglobin A_1c values (Table 1). The H-GB and CON groups were almost all women, and the A-GB group included 4 men. The control subjects were slightly younger than surgical subjects, and the surgical subjects had comparable age and rates of diabetes before GB (Table 1). Total weight loss and time since GB were similar in the surgical groups, although subjects in the H-GB group had a

Discussion

The findings reported here show that postprandial hypoglycemia in subjects with H-GB can be corrected with GLP-1R blockade. Moreover, the disproportionate improvement in the glycemic response when Ex-9 is given to these subjects supports a pathogenic role for exaggerated GLP-1 action in the hyperinsulinemic hypoglycemic syndrome associated with GB. GLP-1 contributes to the significant increase in postprandial insulin secretion in subjects with H-GB, and administration of Ex-9 reduces the

Acknowledgments

The authors thank Leslie Baum, Brianne Reedy, and Radhakrishna Krishna from the Department of Medicine at the University of Cincinnati for technical support; the nursing staff at the Clinical Research Center of Cincinnati Children's Hospital for expert technical assistance; Godfrey C. Ford and other staff from the Mayo Clinic CTSA Metabolomics Translational Technology Core facility for technical assistance with measuring isotope enrichment; and the research participants.

References (36)

A. Gastaldelli et al.
Eight weeks of treatment with long-acting GLP-1 analog taspoglutide improves postprandial insulin secretion and sensitivity in metformin-treated patients with type 2 diabetes
Metabolism
(2013)
M.C. Moore et al.
Regulation of hepatic glucose uptake and storage in vivo
Adv Nutr
(2012)
F. Rodieux et al.
Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release
Obesity (Silver Spring)
(2008)
S.H. Jacobsen et al.
Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose-tolerant individuals
Diabetologia
(2013)
N.B. Jorgensen et al.
Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance
Am J Physiol Endocrinol Metab
(2012)
J. Schirra et al.
Gastric emptying and release of incretin hormones after glucose ingestion in humans
J Clin Invest
(1996)
R. Chaikomin et al.
Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects
Am J Physiol Endocrinol Metab
(2005)
M. Salehi et al.
Gastric bypass surgery enhances glucagon-like Peptide 1-stimulated postprandial insulin secretion in humans
Diabetes
(2011)
M.E. Patti et al.
Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia
Diabetologia
(2005)
G.J. Service et al.
Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery
N Engl J Med
(2005)

A.B. Goldfine et al.

Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal

J Clin Endocrinol Metab

(2007)

J.J. Meier et al.

Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover

Diabetes Care

(2006)

P.E. Cryer et al.

Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline

J Clin Endocrinol Metab

(2009)

H. Sigstad

A clinical diagnostic index in the diagnosis of the dumping syndrome. Changes in plasma volume and blood sugar after a test meal

Acta Med Scand

(1970)

S. Camastra et al.

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

Diabetologia

(2011)

M. Salehi et al.

Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes

Diabetes

(2010)

M. Salehi et al.

Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion

J Clin Endocrinol Metab

(2008)

E. Van Cauter et al.

Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance

Diabetes

(1992)

Cited by (210)

New Lessons from the gut: Studies of the role of gut peptides in weight loss and diabetes resolution after gastric bypass and sleeve gastrectomy
2024, Peptides
It has been known since 2005 that the secretion of several gut hormones changes radically after gastric bypass operations and, although more moderately, after sleeve gastrectomy but not after gastric banding. It has therefore been speculated that increased secretion of particularly GLP-1 and Peptide YY (PYY), which both inhibit appetite and food intake, may be involved in the weight loss effects of surgery and for improvements in glucose tolerance. Experiments involving inhibition of hormone secretion with somatostatin, blockade of their actions with antagonists, or blockade of hormone formation/activation support this notion. However, differences between results of bypass and sleeve operations indicate that distinct mechanisms may also be involved. Although the reductions in ghrelin secretion after sleeve gastrectomy would seem to provide an obvious explanation, experiments with restoration of ghrelin levels pointed towards effects on insulin secretion and glucose tolerance rather than on food intake. It seems clear that changes in GLP-1 secretion are important for insulin secretion after bypass and appear to be responsible for postbariatric hypoglycemia in glucose-tolerant individuals; however, with time the improvements in insulin sensitivity, which in turn are secondary to the weight loss, may be more important. Changes in bile acid metabolism do not seem to be of particular importance in humans.
An update on pancreatic regeneration mechanisms: Searching for paths to a cure for type 2 diabetes
2023, Molecular Metabolism
Over the last decades, various approaches have been explored to restore sufficient β-cell mass in diabetic patients. Stem cells are certainly an attractive source of new β-cells, but an alternative option is to induce the endogenous regeneration of these cells.
Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth.
Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.
Practical guideline on obesity care in patients with gastrointestinal and liver diseases – Joint ESPEN/UEG guideline
2023, Clinical Nutrition
Patients with chronic gastrointestinal disease such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, gastroesophageal reflux disease (GERD), pancreatitis, and chronic liver disease (CLD) often suffer from obesity because of coincidence (IBD, IBS, celiac disease) or related pathophysiology (GERD, pancreatitis and CLD). It is unclear if such patients need a particular diagnostic and treatment that differs from the needs of lean gastrointestinal patients. The present guideline addresses this question according to current knowledge and evidence.
The present practical guideline is intended for clinicians and practitioners in general medicine, gastroenterology, surgery and other obesity management, including dietitians and focuses on obesity care in patients with chronic gastrointestinal diseases.
The present practical guideline is the shortened version of a previously published scientific guideline developed according to the standard operating procedure for ESPEN guidelines. The content has been re-structured and transformed into flow-charts that allow a quick navigation through the text.
In 100 recommendations (3× A, 33× B, 24 × 0, 40× GPP, all with a consensus grade of 90% or more) care of gastrointestinal patients with obesity – including sarcopenic obesity – is addressed in a multidisciplinary way. A particular emphasis is on CLD, especially metabolic associated liver disease, since such diseases are closely related to obesity, whereas liver cirrhosis is rather associated with sarcopenic obesity. A special chapter is dedicated to obesity care in patients undergoing bariatric surgery. The guideline focuses on adults, not on children, for whom data are scarce. Whether some of the recommendations apply to children must be left to the judgment of the experienced pediatrician.
The present practical guideline offers in a condensed way evidence-based advice how to care for patients with chronic gastrointestinal diseases and concomitant obesity, an increasingly frequent constellation in clinical practice.
Unraveling, contributing factors to the severity of postprandial hypoglycemia after gastric bypass surgery
2023, Surgery for Obesity and Related Diseases
Citation Excerpt :
Although the explanation for these findings remains speculative, GLP-1 receptor desensitization in an attempt to prevent hypoglycemia appears to be a possible mechanism and has been previously reported, although in slightly different settings [16]. Of note, 2 previous studies explored the effect of GLP-1 on postprandial insulin secretion using GLP-1 receptor blockade with exendin-9-39 (Ex-9) and found conflicting results [5,17]. Following the ingestion of a mixed-meal with clamped hyperglycemic plasma glucose levels, reduction in insulin secretion with Ex-9 versus saline infusion was comparable between PBH and asymptomatic patients following RYGB.
Despite the increasing prevalence of postbariatric hypoglycemia (PBH), a late metabolic complication of bariatric surgery, our understanding of its diverse manifestations remains incomplete.
To contrast parameters of glucose-insulin homeostasis in 2 distinct phenotypes of PBH (mild versus moderate hypoglycemia) based on nadir plasma glucose.
University Hospital (Bern, Switzerland).
Twenty-five subjects with PBH following gastric bypass surgery (age, 41 ± 12 years; body mass index, 28.1 ± 6.1kg/m²) received 75g of glucose with frequent blood sampling for glucose, insulin, C-peptide, and glucagon-like peptide 1 (GLP)-1. Based on nadir plasma glucose (</≥50mg/dL), subjects were grouped into level 1 (L1) and level 2 (L2) PBH groups. Beta-cell function (BCF), GLP-1 exposure (λ), beta-cell sensitivity to GLP-1 (π), potentiation of insulin secretion by GLP-1 (PI), first-pass hepatic insulin extraction (HE), insulin sensitivity (SI), and rate of glucose appearance (Ra) were calculated using an oral model of GLP-1 action coupled with the oral minimal model.
Nadir glucose was 43.3 ± 6.0mg/dL (mean ± standard deviation) and 60.1 ± 9.1mg/dL in L2- and L1-PBH, respectively. Insulin exposure was significantly higher in L2 versus L1 (P = .004). Mathematical modeling revealed higher BCF in L2 versus L1 (34.3 versus 18.8 10^-9∗min^-1; P = .003). Despite an increased GLP-1 exposure in L2 compared to L1 PBH (50.7 versus 31.9pmol∗L^-1∗min∗10²; P = .021), no significant difference in PI was observed (P = .204). No significant differences were observed for HE, Ra, and SI.
Our results suggest that higher insulin exposure in PBH patients with lower postprandial nadir glucose values mainly relate to a higher responsiveness to glucose, rather than GLP-1.
Clinical Presentation and Diagnostic Approach to Hypoglycemia in Adults Without Diabetes Mellitus
2023, Endocrine Practice
To review the clinical presentation, causes, and diagnostic approach to spontaneous hypoglycemia in adults without diabetes mellitus.
A literature review was performed using the PubMed and Google Scholar databases.
Hypoglycemia is uncommon in people who are not on glucose-lowering medications. Under normal physiologic conditions, multiple neural and hormonal counterregulatory mechanisms prevent the development of abnormally low levels of plasma glucose. If spontaneous hypoglycemia is suspected, the Whipple triad should be used to confirm hypoglycemia before pursuing further diagnostic workup. The Whipple criteria include the following: (1) low levels of plasma glucose, (2) signs or symptoms that would be expected with low levels of plasma glucose, and (3) improvement in those signs or symptoms when the level of plasma glucose increases. Spontaneous hypoglycemia can be caused by conditions that cause endogenous hyperinsulinism, including insulinoma, postbariatric hypoglycemia, and noninsulinoma pancreatogenous hypoglycemia. Spontaneous hypoglycemia can also be seen with critical illness, hepatic or renal dysfunction, hormonal deficiency, non–diabetes-related medications, and non–islet cell tumors. The initial diagnostic approach should begin by obtaining a detailed history of the nature and timing of the patient’s symptoms, medications, underlying comorbid conditions, and any acute illness. A laboratory evaluation should be conducted at the time of the spontaneous symptomatic episode. Supervised tests such as a 72-hour fast or mixed-meal test may be needed to recreate the situation under which the patient is likely to experience symptoms.
We provide an overview of the physiology of counterregulatory response to hypoglycemia, its causes, and diagnostic approaches to spontaneous hypoglycemia in adults.
The entero-insular axis and metabolic syndrome
2023, Metabolic Syndrome: From Mechanisms to Interventions
This chapter introduces the concept of entero-insular axis defined by gut-derived factors that control endocrine pancreas incorporating both historical as well as modern perspectives. It is focused mostly on the clinically relevant mediators namely incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1), and their negative regulator dipeptidyl peptidase-4 (DPP4). Detailed discussions on the impact of these mediators on various pathophysiological facets of metabolic syndrome are elaborated. A note on the future prospects in research and clinical practice has been incorporated at the end.

View all citing articles on Scopus

: Conflicts of interest The authors disclose no conflicts.

: Funding Supported by grants from the National Institutes of Health (DK083554 to M.S. and DK57900 to D.A.D.) and in part by National Center for Advancing Translational Sciences, National Institutes of Health grant 8 UL1 TR000077 as well as the Medical Research Service of the Department of Veterans Affairs.

View full text

Original ResearchFull Report: Clinical—Alimentary TractBlockade of Glucagon-like Peptide 1 Receptor Corrects Postprandial Hypoglycemia After Gastric Bypass

Background & Aims

Methods

Results

Conclusions

Section snippets

Subjects

Characteristics of Subjects

Discussion

Acknowledgments

Metabolism

Adv Nutr

Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release

Obesity (Silver Spring)

Effects of gastric bypass surgery on glucose absorption and metabolism during a mixed meal in glucose-tolerant individuals

Diabetologia

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance

Am J Physiol Endocrinol Metab

Gastric emptying and release of incretin hormones after glucose ingestion in humans

J Clin Invest

Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects

Am J Physiol Endocrinol Metab

Gastric bypass surgery enhances glucagon-like Peptide 1-stimulated postprandial insulin secretion in humans

Diabetes

Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia

Diabetologia

Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery

N Engl J Med

Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal

J Clin Endocrinol Metab

Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover

Diabetes Care

Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline

J Clin Endocrinol Metab

A clinical diagnostic index in the diagnosis of the dumping syndrome. Changes in plasma volume and blood sugar after a test meal

Acta Med Scand

Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes

Diabetologia

Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes

Diabetes

Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion

J Clin Endocrinol Metab

Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance

Diabetes

Original Research
Full Report: Clinical—Alimentary Tract
Blockade of Glucagon-like Peptide 1 Receptor Corrects Postprandial Hypoglycemia After Gastric Bypass