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Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass

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Abstract

Aims/hypothesis

Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones, including GLP-1, is altered.

Methods

Eleven severely obese glucose-tolerant individuals underwent three hyperglycaemic clamps with arginine bolus and co-infusion of either GLP-1, glucose-dependent insulinotropic polypeptide (GIP) or saline before, and at 1 week and 3 months after RYGB. In addition, an OGTT was performed before and 3 months after surgery.

Results

After RYGB, insulin sensitivity improved at 1 week and 3 months, while insulin stimulation and glucagon suppression in response to the clamp with saline co-infusion were largely unaltered. The influence of i.v. GLP-1 and GIP on insulin and glucagon secretion was also unchanged postoperatively. In response to the postoperative OGTT at 3 months, insulin and GLP-1, but not GIP, secretion increased. Furthermore, the glucose profile during the OGTT was altered, with a substantial reduction in 2 h plasma glucose and a paradoxical hypersecretion of glucagon.

Conclusions/interpretation

After RYGB, insulin hypersecretion is linked to the oral, but not the i.v., route of administration and is associated with exaggerated release and preserved insulinotropic action of GLP-1, while both the secretion and action of GIP are unchanged. The results highlight the importance of increased GLP-1 secretion for improving postoperative glucose metabolism.

Trial registration

ClinicalTrials.gov NCT01559779.

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Abbreviations

AGRarg :

Acute glucagon response to arginine

AIRarg :

Acute insulin response to arginine

AIRglu :

Acute insulin response to glucose

DI:

Disposition index

GIP:

Glucose-dependent insulinotropic polypeptide

GLP:

Glucagon-like peptide

iAUC:

Incremental AUC

IGI:

Insulinogenic index

ISR:

Insulin secretion rate

OGIS:

Oral glucose insulin sensitivity

RYGB:

Roux-en-Y gastric bypass

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Acknowledgements

The authors are grateful to K. B. Hansen (Hvidovre Hospital, Denmark) for valuable support in the initiation of the study, and A. Andersen and D. Baunbjerg (Hvidovre Hospital, Denmark) for technical assistance.

Funding

The study was funded by Hvidovre Hospital, the Danish Ministry of Science, Technology and Innovation through the UNIK project at the University of Copenhagen, the Danish Council for Independent Research Medical Sciences, the Danish Diabetes Association, the Novo Nordisk Foundation and the Strategic Counsel for the Capital Area of Copenhagen.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

CD and KNB wrote the study protocol, identified eligible participants, conducted the study, researched data, performed data analysis, contributed to the discussion and wrote the manuscript. NBJ, SHJ, VBK, LSN, DLH and DW contributed to data analysis and discussion and reviewed/edited the manuscript. JJH and SM contributed to the design of the study protocol, data generation and analysis, and discussion and reviewed/edited the manuscript. All authors have approved the final version of the manuscript.

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Correspondence to Carsten Dirksen.

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Dirksen, C., Bojsen-Møller, K.N., Jørgensen, N.B. et al. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass. Diabetologia 56, 2679–2687 (2013). https://doi.org/10.1007/s00125-013-3055-1

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