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Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
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2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD , 2019. Vol. 181, no 2, p. 161-171
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-390513DOI: 10.1530/EJE-19-0171ISI: 000472835100013PubMedID: 31176298OAI: oai:DiVA.org:uu-390513DiVA, id: diva2:1341845
Funder
Swedish Diabetes AssociationErnfors FoundationEXODIAB - Excellence of Diabetes Research in SwedenAvailable from: 2019-08-12 Created: 2019-08-12 Last updated: 2023-12-14Bibliographically approved
In thesis
1. Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery
Open this publication in new window or tab >>Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gastric bypass surgery (GBP) leads not only to considerable and consistent weight loss but to a number of beneficial metabolic effects, often including a swift remission of type 2 diabetes (T2DM). Increases in the gut hormone GLP-1 are considered central to this effect, although several other mechanism are likely involved. One complication to GBP is post-bariatric hypoglycaemia (PBH), where the individual suffers from episodes of low blood sugar after meals. The mechanism behind this is incompletely understood. 

Previous research has reported an attenuation of the counterregulatory response to hypoglycaemia in patients after GBP. Many hypoglycaemic episodes also appear to be asymptomatic. Together, this has led to the hypothesis that GBP and PBH may involve an adaptation to lower blood glucose levels, a lowered glycaemic set point. As much of hypoglycaemia counterregulation involves the central nervous system (CNS), such an adaptation would presumably involve neuroendocrine mechanism. Experimental treatment with GLP-1 receptor agonists (GLP-1RA) has been reported as successful against PBH, which is paradoxical as GLP-1RA stimulate insulin release. 

The aim of this thesis is to further explore the metabolic changes after GBP that may influence glycaemic control. In Paper I, euglycaemic-hypoglycaemic clamps were used to assess whether infusion with GLP-1RA affects the counterregulatory response to hypoglycaemia after GBP. In Paper II, normoglycaemic-hypoglycaemic clamps were performed before and after GBP during simultaneous brain imaging with fMRI and FDG-PET techniques, cognitive testing and assessment of counterregulatory hormones. Paper III details the time course of metabolic changes after GBP in patients with previous T2DM with focus on adipose tissue, including gene expression, and possible anti-inflammatory effects. Paper IV approaches the same question as Paper I, this time in the setting of a standardized meal test. All papers include assessment of heart rate variability (HRV) as a potential reflection of autonomic nervous system (ANS) activity. 

In Paper I, we do not find indications that GLP-1RA affects counterregulatory hormones, but that it may affect ANS activation during hypoglycaemia. In contrast, Paper IV reports higher cortisol levels with GLP1-RA after a meal, and indications of ANS effects, but no effect on post-prandial glucose levels. Results from Paper II support the hypothesis that GBP attenuates hormonal counterregulatory responses and affects how the CNS responds to hypoglycaemia. In Paper III we report sustained improvements in glucose uptake in adipocytes, potentially indications of decreased low-grade inflammation and signs of transient increases in parasympathetic activity. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2005
National Category
Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology; Medical Science; Medical Science
Identifiers
urn:nbn:se:uu:diva-517684 (URN)978-91-513-1996-4 (ISBN)
Public defence
2024-02-15, H:son Holmdahlsalen, ing 100/101, Akademiska Sjukhuset, Dag Hammarskjölds väg 8, Uppsala, 13:00 (English)
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Available from: 2024-01-19 Created: 2023-12-14 Last updated: 2024-01-19

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Almby, Kristina E.Abrahamsson, NiclasLundqvist, Martin H.Hammar, UlfThombare, KetanKarlsson, AndersSundbom, MagnusEriksson, Jan

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Clinical diabetology and metabolismMolecular epidemiologyUpper Abdominal Surgery
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