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Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes
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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0001-8457-3372
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0001-5498-3899
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
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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
The Endocrine Society Endocrine Society, 2021. Vol. 106, no 10
Keywords [en]
T2D, RYGB, neuroendocrine changes, adipose effects
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-457938DOI: 10.1210/clinem/dgab398ISI: 000705200500042PubMedID: 34086911OAI: oai:DiVA.org:uu-457938DiVA, id: diva2:1609415
Funder
Diabetesfonden, DIA2019-490Ernfors FoundationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk, NNF20OC0063864Available from: 2021-11-08 Created: 2021-11-08 Last updated: 2024-01-15Bibliographically 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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Supervisors
Available from: 2024-01-19 Created: 2023-12-14 Last updated: 2024-01-19

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Almby, Kristina E.Katsogiannos, PetrosPereira, Maria J.Karlsson, AndersSundbom, MagnusKamble, Prasad G.Eriksson, Jan

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