aspalathin and Diabetes-Mellitus--Type-2

In the pursuit of bioactive phytochemicals as a therapeutic strategy to manage metabolic risk factors for type 2 diabetes (T2D), aspalathin,

Topics: Animals; Biological Availability; Biotransformation; Chalcones; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Humans; Phytochemicals; Treatment Outcome

Natural compounds may bear promising therapeutic benefits against metabolic diseases such as type 2 diabetes mellitus (T2DM), which are characterized by a state of insulin resistance and mitochondrial dysfunction. Here, we examined the cellular mechanisms by which aspalathin, a dihydrochalcone C-glucoside unique to rooibos, may ameliorate palmitate-induced insulin resistance and mitochondrial dysfunction in cultured C2C12 myotubules. This current study demonstrated that aspalathin remains effective in improving glucose uptake in insulin-resistant skeletal muscle cells, supported by the upregulation of insulin-dependent signaling that involves the activation of insulin receptor (IR) and direct phosphorylation of protein kinase B (AKT). Interestingly, aspalathin also improved mitochondrial respiration and function, which was evident by an increased expression of carnitine palmitoyltransferase 1 (Cpt1), fatty acid transport protein 1 (Fatp1), sirtuin 1 (Sirt1), nuclear respiratory factor 1 (Nrf1), and transcription factor A, mitochondrial (Tfam). Importantly, our results showed that aspalathin treatment was effective in ameliorating the devastating outcomes of insulin resistance and mitochondrial dysfunction that are linked with an undesired pro-inflammatory response, by reducing the levels of well-known pro-inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and protein kinase C-theta (PKC-theta). Thus, beyond improving glucose uptake and insulin signaling, the current study brings a new perspective in the therapeutic benefits of aspalathin in improving mitochondrial respiration and blocking inflammation to attenuate the detrimental effect of palmitate in skeletal muscle cells.

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Mitochondria; Muscle Fibers, Skeletal; Muscle, Skeletal; Palmitates

Oral therapeutics used to treat type 2 diabetes and cardiovascular disease often fail to prevent the progression of disease and their comorbidities. Rooibos (Aspalathus linearis), an endemic South African plant used as an herbal tea, has demonstrated positive effects on glycemia and hypercholesterolemia. However, the treatment efficacy of rooibos extract in combination with conventional hypoglycemic and hypolipidemic medications on blood glucose and lipid profiles has not been established. This study aimed to investigate the effects of combining an aspalathin-rich green rooibos extract (Afriplex GRT™) with pioglitazone and atorvastatin, on blood glucose and lipid levels in obese diabetic (db/db) mice. Six-week-old male db/db mice and their nondiabetic lean littermate controls (db+) were divided into 8 experimental groups (n = 6/group). Db/db mice were treated daily either with pioglitazone (25 mg/kg), atorvastatin (80 mg/kg) and GRT (100 mg/kg), a combination of either drug with GRT or a combination of GRT-pioglitazone and atorvastatin for 5 weeks. Untreated vehicle controls were given dimethyl sulfoxide (0.1%) and phosphate buffered saline solution. At termination, serum and liver tissue were collected for lipid and gene expression analysis. Treatment with GRT, pioglitazone and atorvastatin combination effectively lowered fasting plasma glucose (FPG) levels in db/db mice (p = 0.02), whilst increasing body weight, liver weight, and reducing retroperitoneal fat weight. Atorvastatin monotherapy was effective at reducing cholesterol (from 4.00 ± 0.12 to 2.93 ± 0.13, p = 0.0003), LDL-C (from 0.58 ± 0.04 to 0.50 ± 0.00, p = 0.04), HDL-C (from 2.86 ± 0.05 to 2.50 ± 0.04, p = 0.0003) and TG (from 2.77 ± 0.50 to 1.48 ± 0.23, p = 0.04), compared to the untreated diabetic control. The hypotriglyceridemic effect of atorvastatin was enhanced when used in combination with both GRT and pioglitazone. The addition of pioglitazone to GRT significantly lowered FPG and TG. In db/db mice, Apoa1 was significantly downregulated in the liver, whilst Pparγ was significantly upregulated compared to their db+ counterparts. GRT monotherapy downregulated Apoa1 expression (p = 0.02). Atorvastatin combined with GRT significantly downregulated mRNA expression of Apoa1 (p = 0.03), whilst upregulating the expression of Pparγ (p = 0.03), Pparα (p = 0.002), Srebp1 (p = 0.002), and Fasn (p = 0.04). The GRT-pioglitazone-atorvastatin combination therapy downregulated Apoa1 (p = 0.006), whilst

Topics: Animals; Aspalathus; Atorvastatin; Blood Glucose; Chalcones; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucose; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Liver; Male; Mice; Mice, Inbred Strains; Phytotherapy; Pioglitazone; Plant Extracts

Metformin is the first line therapy of type 2 diabetics, but continued reduction of their life expectancy warrants further investigation into alternative treatment strategies. This study reports on the combinational use of metformin with aspalathin, a C-glucosyl dihydrochalcone with known glucose lowering and antioxidant properties, as an effective hypoglycemic therapy in a type 2 diabetic (db/db) mouse model. When tested as a monotherapy, a low dose of aspalathin (13 mg/kg) showed no effect, while a high dose (130 mg/kg) has already displayed a better potential than metformin in protecting against diabetes associated symptoms in db/db mice. Thus, it remains of interest to determine whether this dihydrochalcone can improve the efficacy of metformin. The results showed that this combination therapy was more effective than the use of metformin as a monotherapy in ameliorating diabetes associated symptoms, including abnormal raised fasting plasma glucose levels, impaired glucose tolerance, as well as excessively increased body weights and fat content. The treated mice also had reduced food and water consumption when compared to untreated controls, with a pronounced effect evident in the last week of treatment. Therefore, this study supports further investigations into the ameliorative effect of combination therapy of metformin and aspalathin against diabetes associated symptoms.

Topics: Animals; Aspalathus; Chalcones; Diabetes Mellitus, Type 2; Drug Synergism; Flavonoids; Hypoglycemic Agents; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Transgenic

Saturated-free fatty acids, such as palmitate, are associated with insulin resistance. This study aimed to establish if an aspalathin-enriched green rooibos extract (GRE) and, its major flavanoid, aspalathin (ASP) could contribute significantly to the amelioration of experimentally induced insulin resistance in 3T3-L1 adipocytes.. 3T3-L1 adipocytes were cultured in DMEM containing 0.75 mM palmitate for 16 h to induce insulin resistance before treatment for 3 h with GRE (10 μg/mL) or ASP (10 μM). GRE and ASP reversed the palmitate-induced insulin resistance. At a protein level GRE and ASP suppressed nuclear factor kappa beta (NF-κB), insulin receptor substrate one (serine 307) (IRS1 (Ser (307) )) and AMP-activated protein kinase phosphorylation and increased serine/threonine kinase AKT (AKT) activation, while only GRE increased glucose transporter four (Glut4) protein expression. Peroxisome proliferator-activated receptor alpha and gamma (PPARα and γ), and carnitine palmitoyltransferase one (CPT1) expression were increased by ASP alone.. Together these effects offer a plausible explanation for the ameliorative effect of GRE and ASP on insulin-resistance, an underlying cause for obesity and type 2 diabetes.

Topics: 3T3-L1 Cells; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Aspalathus; Chalcones; Diabetes Mellitus, Type 2; Glucose; Glucose Transporter Type 4; Insulin; Insulin Resistance; Lipid Metabolism; Mice; NF-kappa B; Palmitates; Plant Extracts