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Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0002-7083-8912
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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: urn:nbn:se:uu:diva-517684ISBN: 978-91-513-1996-4 (print)OAI: oai:DiVA.org:uu-517684DiVA, id: diva2:1819667
Public defence
2024-02-15, H:son Holmdahlsalen, ing 100/101, Akademiska Sjukhuset, Dag Hammarskjölds väg 8, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2024-01-19 Created: 2023-12-14 Last updated: 2024-01-19
List of papers
1. Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
Open this publication in new window or tab >>Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
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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
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-390513 (URN)10.1530/EJE-19-0171 (DOI)000472835100013 ()31176298 (PubMedID)
Funder
Swedish Diabetes AssociationErnfors FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2023-12-14Bibliographically approved
2. Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
Open this publication in new window or tab >>Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
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2021 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 70, no 6, p. 1265-1277Article in journal (Refereed) Published
Abstract [en]

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.

Place, publisher, year, edition, pages
American Diabetes Association, 2021
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-452976 (URN)10.2337/db20-1172 (DOI)000671940300008 ()33674408 (PubMedID)
Note

K.E.A. and M.H.L. contributed equally.

Available from: 2021-09-15 Created: 2021-09-15 Last updated: 2023-12-14Bibliographically approved
3. Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes
Open this publication in new window or tab >>Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes
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2021 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 10Article in journal (Refereed) Published
Abstract [en]

Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

Objective: Integrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB.

Design and Setting: Follow-up of single-center randomized study.

Patients: Thirteen patients with obesity and T2D compared to 22 healthy subjects. Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P<0.001). At 4 weeks, morning cortisol (P<0.05) and adrenocorticotropin (P=0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P<0.05) and peaked at 24 weeks (P<0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P<0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P<0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P<0.01).

Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

Place, publisher, year, edition, pages
Endocrine SocietyThe Endocrine Society, 2021
Keywords
T2D, RYGB, neuroendocrine changes, adipose effects
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-457938 (URN)10.1210/clinem/dgab398 (DOI)000705200500042 ()34086911 (PubMedID)
Funder
Diabetesfonden, DIA2019-490Ernfors FoundationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk, NNF20OC0063864
Available from: 2021-11-08 Created: 2021-11-08 Last updated: 2024-01-15Bibliographically approved
4. Effects of acute GLP-1 receptor activation on the glycemic and neurohormonal responses to meal test after gastric bypass
Open this publication in new window or tab >>Effects of acute GLP-1 receptor activation on the glycemic and neurohormonal responses to meal test after gastric bypass
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(English)Manuscript (preprint) (Other academic)
Keywords
Roux-en Y gastric bypass, post-bariatric hypoglycaemia, GLP-1 analogue, hypoglycaemia counterregulation, cortisol
National Category
Endocrinology and Diabetes
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-517680 (URN)
Available from: 2023-12-13 Created: 2023-12-13 Last updated: 2023-12-14

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