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Proanthocyanidins and Glucose Homeostasis: An Analysis of Bioavailability and Mechanisms in Rats
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- Author / Creator
- Yang, Kaiyuan
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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.
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- Graduation date
- Fall 2015
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.