Linda M. Pacioretty

Antidiabetic Screening of Commercial Botanical Products in 3T3-L1 Adipocytes and db/db Mice

Numerous botanicals are purported to improve glucose metabolism and diabetic risk factors with varying degrees of supportive evidence. We investigated 203 commercially available botanical products representing 90 unique botanical species for effects on lipogenic activity in differentiating 3T3-L1 adipocytes. Anti-inflammatory activity of 21 of these products was further assessed in tumor necrosis factor alpha (TNFalpha)-stimulated, mature 3T3-L1 adipocytes. From these results, rho-isoalpha acids, Acacia nilotica bark, fennel, and wasabi were tested in the db/db mouse model. Fifty-nine percent of the 90 unique botanicals increased adipogenesis as did the standard troglitazone relative to the solvent controls. Botanical species with the greatest percentage of positive products were Centella asiatica, Panax quinquefolius, and Phyllanthus amarus at 100%, Vitis vinifera at 80%, Humulus lupulus at 71%, Aloe barbadensis at 66%, and Momordica charantia, Phaseolus vulgaris, and Punica granatum at 60%. All 21 subset samples inhibited TNFalpha-stimulated free fatty acid release and attenuated TNFalpha inhibition of adiponectin secretion. Both rho-isoalpha acids and A. nilotica reduced nonfasting glucose in the db/db mouse model, whereas A. nilotica also decreased nonfasting insulin levels. A post hoc analysis of the screening results indicated that the positive predictive value of the lipogenesis assay alone was 72%, while adding the criterion of a positive response in the anti-inflammatory assays increased this figure to 82%. Moreover, this large-scale evaluation demonstrates that antidiabetic, in vitro efficacy of botanicals is more a function of manufacturing or quality control differences than the presence of marker compounds and further underscores the need to develop functional as well as analytical bases for standardization of dietary supplements.

Hop and acacia phytochemicals decreased lipotoxicity in 3T3-L1 adipocytes, db/db mice, and individuals with metabolic syndrome.

The plant-based compounds rho-iso-alpha acids (RIAA) from Humulus lupulus (hops) and proanthocyanidins (PAC) from Acacia nilotica have been shown to modulate insulin signaling in vitro. We investigated their effects on triglyceride (TG) deposition in 3T3-L1 adipocytes, glucose and insulin in obese mouse models, and metabolic syndrome markers in adults with metabolic syndrome. The combination of RIAA and PAC synergistically increased TG content and adiponectin secretion in 3T3-L1 adipocytes under hyperinsulinemic conditions and reduced glucose or insulin in obese mice. In a clinical trial, tablets containing 100 mg RIAA and 500 mg PAC or placebo were administered to metabolic syndrome subjects (3 tablets/day, n = 35; 6 tablets/day, n = 34; or placebo, n = 35) for 12 weeks. Compared to placebo, subjects taking 3 tablets daily showed greater reductions in TG, TG : HDL, fasting insulin, and HOMA scores. The combination of RIAA : PAC at 1 : 5 (wt : wt) favorably modulates dysregulated lipids in insulin resistance and metabolic syndrome.

Optimized mixture of hops rho iso-alpha acids-rich extract and acacia proanthocyanidins-rich extract reduces insulin resistance in 3T3-L1 adipocytes and improves glucose and insulin control in db/db mice.

Rho iso-alpha acids-rich extract (RIAA) from Humulus lupulus (hops) and proanthocyanidins-rich extracts (PAC) from Acacia nilotica exert anti-inflammatory and anti-diabetic activity in vitro and in vivo. We hypothesized that a combination of these two extracts would exert enhanced effects in vitro on inflammatory markers and insulin signaling, and on nonfasting glucose and insulin in db/db mice. Over 49 tested combinations, RIAA:PAC at 5:1 (6.25 µg/mL) exhibited the greatest reductions in TNFα-stimulated lipolysis and IL-6 release in 3T3-L1 adipocytes, comparable to 5 µg/mL troglitazone. Pretreatment of 3T3-L1 adipocytes with this combination (5 µg/mL) also led to a 3-fold increase in insulin-stimulated glucose uptake that was comparable to 5 µg/mL pioglitazone or 901 µg/mL aspirin. Finally, db/db mice fed with RIAA:PAC at 5:1 (100 mg/kg) for 7 days resulted in 22% decrease in nonfasting glucose and 19% decrease in insulin that was comparable to 0.5 mg/kg rosiglitazone and better than 100 mg/kg metformin. RIAA:PAC mixture may have the potential to be an alternative when conventional therapy is undesirable or ineffective, and future research exploring its long-term clinical application is warranted.