- Title
- Effects of selected natural flavonoids on an optimized insulin resistance model in myotubes and hepatocytes in vitro
- Creator
- van de Venter, Ruben
- Subject
- Flavonoids
- Subject
- Pharmaceutical chemistry
- Subject
- Insulin resistance
- Date Issued
- 2023-12
- Date
- 2023-12
- Type
- Master's theses
- Type
- text
- Identifier
- http://hdl.handle.net/10948/69648
- Identifier
- vital:78003
- Description
- As the third largest life-threatening non-communicable disease, further research to improve T2DM treatment remains pivotal. The approved insulin sensitizing agents, metformin and thiazolidinediones, although effective, have an array of adverse effects. This leads to the growing need for safer insulin sensitizing agents.To induce insulin resistance, an insulin resistance induction (IRI) model consisting of palmitic acid (PA), fructose, and dexamethasone (DEX), was optimized. The model was utilized to compare the insulin sensitizing efficacy of chrysin, apigenin, luteolin, and quercetin. The most effective flavonoid was extrapolated based on the hydroxylation hypothesis and relevant SAR. The flavonoid was combined with metformin to evaluate potential insulin sensitizing synergism. C3A hepatocytes and L6 myotubes were exposed to the IRI models: IR1, IR2, and OIR, for 24 and 48h. Morphological features indicative of insulin resistance were monitored through high-content analysis (HCA). Thereafter, cells were exposed to OIR and concurrently treated with the selected flavonoids. Cytotoxicity, oxidative stress (OS), mitochondrial content, mitochondrial membrane potential (MMP), and lipid accumulation, were once again evaluated through HCA. Subsequently, quercetin was combined with metformin (QM); insulin resistant conditions established through OIR exposure, and QM administered as prophylaxis. The efficacy of QM was determined through changes in phosphorylated-Akt, glucose uptake, and gluconeogenesis. Results: IR1 and IR2 demonstrated excessive potency, whereas OIR consistently generated insulin resistant C3A/L6 cells by increasing OS (↑14%/20%), lipid accumulation (0.7-fold/1.5-fold), and decreasing MMP (↓4%/6%). Of the selected flavonoids, quercetin was most effective at ameliorating each of these parameters. Furthermore, QM demonstrated potential insulin sensitizing synergism, as it improved Akt phosphorylation (Thr308: ↑31%/↑17%; Ser473: ↑29%), glucose uptake (↑10%/ 5%), and suppressed hepatic gluconeogenesis (15↓%) more effectively compared to monotherapy. Conclusions: OIR is an effective model for the induction of complete early-stage insulin resistance in myotubes and hepatocytes. Quercetin demonstrates exceptional antidiabetic activity due its unique expression of hydroxyl groups. Lastly, QM, comparative to monotherapy, improves insulin sensitivity with enhanced efficacy.
- Description
- Thesis (MPharm) -- Faculty of Health Sciences, School of Clinical Care & Medicinal Sciences, 2023
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (234 pages)
- Format
- Publisher
- Nelson Mandela University
- Publisher
- Faculty of Health Sciences
- Language
- English
- Rights
- Nelson Mandela University
- Rights
- All Rights Reserved
- Rights
- Open Access
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Collections
NMU School of Medicinal Sciences
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | van de Venter, R.pdf | 6 MB | Adobe Acrobat PDF | View Details Download |