Chronic administration of apple polyphenols ameliorates hyperglycaemia in high-normal and borderline subjects: A randomised, placebo-controlled trial.

AIMS: We previously reported that apple polyphenols (AP) and their major active components, procyanidins, had beneficial effects on glucose homeostasis and diabetes in diabetic ob/ob mice. The present study was performed to evaluate the effects of chronic AP administration on glucose tolerance in high-normal and borderline human subjects. METHODS: Subjects (n=65) with a fasting plasma glucose (FPG) level of 100-125mg/dL determined during a recent health check-up were randomised to receive tablets containing AP (600mg/day) or placebo tablets for 12weeks in a double-blinded, placebo-controlled clinical trial. The primary outcome was insulin resistance, assessed using a 75g oral glucose tolerance test (OGTT). RESULTS: The 12-week chronic administration of AP significantly reduced the increase in glucose at 30-min post-75g OGTT (OGTT30-min glucose) value, compared to the placebo regimen. Furthermore, in a subgroup of the high-normal (FPG value, 100-109mg/dL; 2-h post-75g OGTT glucose (OGTT2-h glucose) value, <140mg/dL) and borderline (FPG value, 110-125mg/dL; OGTT2-h glucose value, <140mg/dL and FPG value, <126mg/dL; OGTT2-h glucose value, 140-199mg/dL) subjects, OGTT30-min glucose value in the AP group (164.0±7.4mg/dL) was significantly lower than that of the placebo group (194.7±10.4mg/dL, p<0.05). No significant changes in the other lipid parameters and cytokine levels were observed. CONCLUSIONS: Chronic AP administration significantly improved impaired glucose tolerance in high-normal and borderline subjects. Larger and/or longer-term scale human studies are required to confirm the potential glucose homeostasis of AP.

Oral Administration of Apple Procyanidins Ameliorates Insulin Resistance via Suppression of Pro-Inflammatory Cytokine Expression in Liver of Diabetic ob/ob Mice.

Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic ß-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity.

Individual members of the RGK family of Ras-related GTPases, which comprise Rad, Gem/Kir, Rem and Rem2, have been implicated in important functions such as the regulation of voltage-gated calcium channel activity and remodeling of cell shape. The GTPase Kir/Gem inhibits the activity of calcium channels by interacting with the beta-subunit and also regulates cytoskeleton dynamics by inhibiting the Rho-Rho kinase pathway. In addition, Kir/Gem interacts with 14-3-3 and calmodulin, but the significance of this interaction on Kir/Gem function is poorly understood. Here, we present a comprehensive analysis of the binding of 14-3-3 and calmodulin to Kir/Gem. We show that 14-3-3, in conjunction with calmodulin, regulates the subcellular distribution of Kir/Gem between the cytoplasm and the nucleus. In addition, 14-3-3 and calmodulin binding modulate Kir/Gem-mediated cell shape remodeling and downregulation of calcium channel activity. Competition experiments show that binding of 14-3-3, calmodulin and calcium channel beta-subunits to Kir/Gem is mutually exclusive, providing a rationale for the observed regulatory effects of 14-3-3 and calmodulin on Kir/Gem localization and function.