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Proanthocyanidins and Glucose Homeostasis: An Analysis of Bioavailability and Mechanisms in Rats Open Access


Other title
Hepatic glucose production
Glucose homeostasis
Pancreatic β-cells
Type of item
Degree grantor
University of Alberta
Author or creator
Yang, Kaiyuan
Supervisor and department
Catherine B. Chan (Agricultural, Food and Nutritional Science)
Examining committee member and department
Yves Sauve (Physiology)
Lindsay Robinson (Human Health and Nutritional Sciences, University of Guelph)
Anna Farmer (Agricultural, Food and Nutritional Science)
Wendy Wismer (Agricultural, Food and Nutritional Science)
Catherine Field (Agricultural, Food and Nutritional Science)
Department of Agricultural, Food, and Nutritional Science
Nutrition and Metabolism
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Proanthocyanidins (PAC) belong to a highly consumed class of flavonoids and their consumption has been linked to beneficial effects on glycemic control in type 2 diabetes. However, limited gastrointestinal absorption occurs due to the structure complexity of polymeric PAC and the mechanisms by which PAC exerts such benefits are largely unknown. We hypothesized that hydrolysis of the PAC polymer would increase bioavailability, thus leading to enhanced beneficial effects on glucose homeostasis. We further hypothesized that PAC effects in vivo would be associated with improved pancreatic β-cell function and hepatic insulin sensitivity by acting on specific signalling pathways that could be detected using in vitro techniques. PAC-rich pea seed coats (PSC) were supplemented in a high fat diet (HFD) either in native (PAC) or hydrolyzed (HPAC) form and fed to HFD-induced glucose intolerant rats for 4 weeks. HFD or low fat diet (LFD) groups were controls. PAC-derived compounds were characterized in both PSC and serum. The results showed that hydrolysis significantly decreased the degree of polymerization (DP). Meanwhile increased PAC-derived metabolites were detected in the serum of HPAC-fed rats compared to PAC-fed rats, suggesting hydrolysis of PSC enhanced PAC bioavailability. This was associated with ~18% less (P<0.05) weight gain compared to HFD without affecting food intake, as well as improvement in glucose tolerance in vivo. There was a 50% decrease of the α/β-cell area ratio and a 2.5-fold increase (P<0.05) in glucose-stimulated insulin secretion (GSIS) from isolated islets of HPAC-fed rats. These results demonstrate that hydrolysis of PSC-derived PAC increased the bioavailability of PAC-derived products, which is critical for enhancing beneficial effects on glucose homeostasis and pancreatic β-cell function. The results from the in vitro study of a PAC metabolite on INS-1 cell line showed that a low but physiologically relevant concentration of epicatechin (EC, 0.3 μM) rectified stearic acid (SFA)-impaired insulin secretion via activation of CaMKII pathway, although it failed to attenuate elevated reactive oxygen species (ROS) production induced by high glucose and H2O2; whereas 30 μM EC effectively suppressed ROS production but showed no effects on insulin secretion. These results indicate that EC effects are concentration-dependent, and that EC can act as a molecule in regulating cell signaling pathways at physiological concentrations. Hepatic insulin sensitivity was assessed using the insulin tolerance test (ITT). PAC and HPAC had decreased glucose recovery rates during ITT (P<0.05 for both), indicating suppressed hepatic glucose production compared with HFD. Correspondingly, we detected reduced phosphoenolpyruvate carboxykinase (PEPCK) content in the livers of PAC (P<0.05) and HPAC (P=0.1). Furthermore, hepatic glycogen content and total glutathione were increased in PAC but not in HPAC compared with HFD, suggesting PAC alleviated hepatocyte insulin resistance via relief of oxidative stress, whereas HPAC was not as effective. In summary, reducing the structural complexity of PAC can improve bioavailability, leading to enhanced glycemic control in the condition of glucose intolerance. This is related to improvements in pancreatic islet function, especially insulin secretion from pancreatic β-cells as well as better-controlled hepatic glucose production. The present study also supports the theory that bioavailable PAC-derived compounds can exert effects via modulating cellular signaling pathways.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Yang K, Hashemi Z, Han W, Jin A, Yang H, Ozga J, Li L, Chan CB. Hydrolysis enhances bioavailability of proanthocyanidin-derived metabolites and improves β-cell function in glucose intolerant rats. J Nutr Biochem. 2015 Aug;26(8):850-9. doi: 10.1016/j.jnutbio.2015.03.002.

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