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Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy
Thesis (MSc)--Stellenbosch University, 2025.
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Stellenbosch : Stellenbosch University
2025
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| access_status_str | Open Access |
| author | Karani, Alvin Wekesa |
| author2 | Decloedt, Eric |
| author_browse | Decloedt, Eric Karani, Alvin Wekesa |
| author_facet | Decloedt, Eric Karani, Alvin Wekesa |
| author_sort | Karani, Alvin Wekesa |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134652 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:45:28.762Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
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| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134652 Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy Karani, Alvin Wekesa Decloedt, Eric Van Rensburg, Roland Kellermann, Tracy Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology. Metformin -- Therapeutic use -- Africa, Sub-Saharan HIV infections -- Treatment -- Africa, Sub-Saharan Side effects of drugs -- Africa, Sub-Saharan Metabolic syndrome -- Africa, Sub-Saharan Antiretroviral therapy, Highly active -- Africa, Sub-Saharan Thesis (MSc)--Stellenbosch University, 2025. Karani, A. W. 2025. Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy. Unpublished masters thesis. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/b95f8992-2918-4304-91e2-6a6baa030b36 ENGLISH ABSTRACT: Introduction: The prevalence of obesity among people living with HIV (PLWH) is increasing in sub-Saharan Africa, with associated increases in morbidity and mortality. Metformin, a widely available oral medicine used to manage type 2 diabetes mellitus, is also used off-label to prevent weight gain and promote moderate weight loss in the general population. Its affordability makes it a favourable treatment option for low- and middle-income countries. However, the mechanism underlying metformin's effects on weight, particularly in obese PLWH, remains unclear. We hypothesised that the effect of metformin on weight is mediated by its effect on increasing appetite-suppressing hormones, specifically glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and growth differentiation factor-15 (GDF-15), and decreasing the appetite-stimulating hormone, ghrelin. Methods: This observational study analysed previously collected plasma samples from 15 obese PLWH with metabolic syndrome. Blood samples were collected at baseline (-15 minutes preprandial) and at 1 hour, 3 hours, and 4 hours postprandially following administration of metformin (1000 mg) and a standardised meal. The concentrations of appetite hormones were measured using enzyme-linked immunosorbent assays. We compared preprandial with the postprandial concentrations. Results were subsequently compared with historical control data from obese individuals without metformin treatment. Results: GLP-1, PYY and GDF-15 concentrations were markedly elevated in obese PLWH receiving metformin compared to historical controls of obese individuals without metformin treatment. GLP-1 concentrations in the metformin-treated group were higher than those reported by Oliván et al. (2009), both preprandially (16.1 ± 2.00 vs 5.23 ± 3.6 pmol/L) and at postprandial peak (37.7 ± 3.04 vs 10.1 ± 5.2 pmol/L; absolute increase: 21.6 pmol/L; percentage change: 134%; P < 0.0001). PYY showed a similar trend, with concentrations in the metformin-treated group exceeding those reported by Batterham et al. (2003) both preprandially (21.7 ± 3.2 vs 10.2 ± 0.7 pmol/L) and at postprandial peak (41.3 ± 2.25 vs 14.4 ± 1.2 pmol/L; absolute increase: 19.6 pmol/L; percentage change: 90%; P < 0.0001). Preprandial GDF-15 concentrations in the metformin-treated group were also higher than those reported by Coll et al. (2020) (2,273 pg/mL vs 1,242 pg/mL). GDF-15 concentrations remained stable postprandially in the metformin-treated group, with no comparable postprandial data available from Coll et al. (2020). Unexpectedly, ghrelin concentrations were higher in the metformin-treated group compared to controls from Oliván et al. (2009), both preprandially (1520 ± 184 vs 409 ± 112 pg/mL) and at the postprandial nadir (1146 ± 126 pg/mL vs 315 ± 124 pg/mL; absolute decrease: 374 pg/mL; percentage change: 24.6%; P = 0.0022), contrary to the anticipated appetite-suppressing response. Conclusion: Metformin's weight loss effects appear to be mediated by increased concentrations of GLP-1, PYY, and GDF-15, rather than through ghrelin suppression. Increased GLP-1, PYY, and GDF-15 concentrations lead to reduced appetite and food intake, thereby promoting weight loss. These findings offer mechanistic insight into how metformin may promote weight loss in obese PLWH by modulating appetite regulating hormones. AFRIKAANSE OPSOMMING: Die voorkoms van vetsug onder mense wat met WV (PLWH) neem toe in sub-Sahara-Afrika, met gepaardgaande toenames in morbiditeit en mortaliteit. Met'formien, 'n beskikbare orale medisyne wat gebruik word om tipe 2-diabetes tnellitus te behandel, word 00k buite-etiket gebruik om gewigstoenarne te voorkom en matige gewigsverlies in die algetnene bevoking te bevorder. Die bekostigbaarheid daarvan maak dit 'n gunstige behandelingsopsie vir lae- en middelinkomste-lande. Die meganisme onderliggend aan tnetformien se effekte op gewig, veral in vetsugtige PLWH, bly egter onduidelik. Ons het gehipotetiseer dat die effek van tnetformien op gewig bemiddel word deur sy invloed op die verhoging van eetlus-onderdrukkende horrnone, spesifiek glukagon-ge peptied-l (GLP-I), peptied YY (PW) en groeidifferensiasiefaktor-IS (GDF-IS), en die verlaging van die eetlus-stirnulerende hormoon, grelien. Hierdie waarnemingsstudie het voorheen versamelde plasmatnonsters van 15 vetsugtige PLWH met tnetabdiese sindroom geanaliseer. gloedmonsters is versamel by die aanvangstyd GIS minute voor ete) en I uur, 3 ure en 4 ure na ete na die toediening van metformien Ing) en 'n gestandaardiseerde maaltyd. konsentrasies van eetlushormone is gemeet met behulp van ensiemgekoppelde immunosorbent-toetse. Ons het voor ete met die na ete konsentrasies vergelyk. Resultate is vervolgens vergelyk met historiese kontroledata van vetsugtige individue sander tnetformienbehandeling. GLP-I, PYX en GDF-IS konsentrasies was aansienlik verhoog in vetsugtige PLWH wat tnetformien ontvang het in vergelvking met historiese kontroles van vetsugtige individue sander tnetformienbehandeling. GLP-I konsentrasies in die metformienbehandelde groep was hoer as dié wat deur Olivån et al. (2W9) gerapporteer is, beide voor ete (16.1 ± 2.00 vs 5.23 ± 3.6 pmoI/L) en by die na ete piek (37.7 ± 3.04 vs 10.1 ± 5.2 pmoI/L; absolute toename: 21.6 pmoI/L; persentasie verandering: 134%; PCO.OOOI). P" het -n soortgelyke tendens getoon, met konsentrasies in die tnetformienbehandelde groep wat dié oorskry het wat deur Batterham et al. (2CN)3) gerapporteer is, beide voor ete (21.7 3.2 vs 10.2 0.7 pmoI/L) en by die na ete piek (41.3 ± 2.25 vs 14.4 ± 1.2 pmoI/L; absolute toenarme: 19.6 pmoI/L; persentasie verandering: 90%; PcomOI). Voor ete GDF-IS konsentrasies in die metformienbehandelde groep was 00k hoer as dié wat deur Coll et al (2020) gerapporteer is (2,273 pg/mL vs 1,242 pg/mL). GDF-IS konsentrasies het stabiel gebly na ete in die tnetformienbehandelde groep, met geen vergelykbare na ete data beskikbaar van Coll et al. (2020) nie- Onverwagte hoe grelienkonsentrasies is waargeneem in die tnetformienbehandelde groep in vergelyking met die kontroles van Olivån et al. (2(E, beide voor ete (1520 ± 184 vs 409 ± 112 pg/mL) en by die na ete laagtepunt (1146 ± 126 pg/mL vs 315 ± 124 pg/mL; absolute afnatne: 374 pg/mL; persentasie verandering: 24.6%; PEO.0022), in teenstelling die verwagte eetlus-onderdrukkende reaksie. Gevolgtrekking: Metformien se gewigsverlieseffekte blyk bemiddel te word deur verhoogde konsentrasies van GLP-I, PW, en GDF-IS, eerder as deur grelien-onderdrukking. Verhoogde GLP-I, P", en GDP-IS konsentrasies lei tot verminderde eetlus en voedselinname, en bevorder dus gewigsverlies. Hierdie bevindinge bied tneganistiese insig in hoe metformien gewigsverlies in vetsugtige PLWH kan bevorder deur eetlus-regulerende hormone te tnoduleer. Masters 2025-12-22T07:49:25Z 2025-12-22T07:49:25Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134652 en Stellenbosch University xx, 136 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Metformin -- Therapeutic use -- Africa, Sub-Saharan HIV infections -- Treatment -- Africa, Sub-Saharan Side effects of drugs -- Africa, Sub-Saharan Metabolic syndrome -- Africa, Sub-Saharan Antiretroviral therapy, Highly active -- Africa, Sub-Saharan Karani, Alvin Wekesa Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title | Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title_full | Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title_fullStr | Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title_full_unstemmed | Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title_short | Investigating metformin’s mechanism of action for weight loss in obese people living with HIV treated with dolutegravir-based antiretroviral therapy |
| title_sort | investigating metformin s mechanism of action for weight loss in obese people living with hiv treated with dolutegravir based antiretroviral therapy |
| topic | Metformin -- Therapeutic use -- Africa, Sub-Saharan HIV infections -- Treatment -- Africa, Sub-Saharan Side effects of drugs -- Africa, Sub-Saharan Metabolic syndrome -- Africa, Sub-Saharan Antiretroviral therapy, Highly active -- Africa, Sub-Saharan |
| url | https://scholar.sun.ac.za/handle/10019.1/134652 |
| work_keys_str_mv | AT karanialvinwekesa investigatingmetforminsmechanismofactionforweightlossinobesepeoplelivingwithhivtreatedwithdolutegravirbasedantiretroviraltherapy |