High-molecular-weight cocoa procyanidins possess enhanced insulin-enhancing and insulin mimetic activities in human primary skeletal muscle cells compared to smaller procyanidins

Dysregulation of glucose metabolism is a primary hallmark of metabolic disease (i.e., diabetes, obesity, etc.). Complementary nonpharmaceutical strategies are needed to prevent and/or ameliorate dysregulation of glucose metabolism and prevent progression from normoglycemia to prediabetes and type 2 diabetes across the lifespan. Cocoa compounds, particularly the procyanidins, have shown promise for improving insulin sensitivity and blood glucose homeostasis. However, the molecular mechanisms by which cocoa procyanidins exert these functions remain poorly understood. Furthermore, cocoa procyanidins exhibit size diversity, and evidence suggests that procyanidin bioactivity and size may be related. Here, we show that a procyanidin-rich cocoa extract elicits an antidiabetic effect by stimulating glycogen synthesis and glucose uptake, independent of insulin. Cocoa procyanidins did not appear to act via stimulation of AMPK or CaMKII activities. Additionally, in the presence of insulin, glycogen synthesis and AKT phosphorylation were affected. These mechanisms of action are most pronounced in response to oligomeric and polymeric procyanidins. These results demonstrate (1) specific mechanisms by which cocoa procyanidins improve glucose utilization in skeletal muscle and (2) that larger procyanidins appear to possess enhanced activities. These mechanistic insights suggest specific strategies and biological contexts that may be exploited to maximize the antidiabetic benefits of cocoa procyanidins.