Impact of nutritional-behavioral and supervised exercise intervention following bariatric surgery: The BARI-LIFESTYLE randomized controlled trial.

OBJECTIVE: The study's aim was to investigate the impact of a 12-month adjunctive lifestyle intervention on weight loss and health outcomes after bariatric surgery. METHODS: A total of 153 participants (78.4% females; mean [SD], age 44.2 [10.6] years; BMI 42.4 [5.7] kg/m2 ) were randomized to intervention (n = 79) and control (n = 74). The BARI-LIFESTYLE program combined 17 nutritional-behavioral tele-counseling sessions plus once-weekly supervised exercise for 12 weeks. The primary outcome was percentage weight loss at 6 months post surgery. Secondary outcomes included body composition, physical activity levels, physical function and strength, health-related quality of life, depressive symptomatology, and comorbidities. RESULTS: Longitudinal analysis of the entire cohort showed significant reductions in body weight, fat mass, fat-free mass, and bone mineral density at the total hip, femoral neck, and lumbar spine (all p < 0.001). The 6-minute walk test, sit-to-stand test, health-related quality of life, and depressive symptomatology improved significantly (all p < 0.001). The time spent in moderate-to-vigorous physical activity and sedentary behavior remained the same as before surgery (both p > 0.05). There was no significant difference in the primary outcome between the intervention versus control (20.4% vs. 21.2%; mean difference = -0.8%; 95% CI: -2.8 to 1.1; p > 0.05) and no between-group differences in secondary outcomes. CONCLUSIONS: An adjunctive lifestyle program implemented immediately after surgery had no favorable impact upon weight loss and health outcomes.

The BACE1 product sAPPß induces ER stress and inflammation and impairs insulin signaling.

OBJECTIVE: ß-secretase/ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPß (sAPPß), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. MATERIALS/METHODS: Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/-mice and mice treated with sAPPß and adipose tissue and plasma from obese and type 2 diabetic patients. RESULTS: We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator-Activated Receptor γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPß in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1α mRNA levels and by an increase in sAPPß plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPß administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. CONCLUSIONS: Collectively, these findings indicate that the BACE1 product sAPPß is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.

Bace1-dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice.

Obesity places an enormous medical and economic burden on society. The principal driver appears to be central leptin resistance with hyperleptinemia. Accordingly, a compound that reverses or prevents leptin resistance should promote weight normalisation and improve glucose homeostasis. The protease Bace1 drives beta amyloid (Aß) production with obesity elevating hypothalamic Bace1 activity and Aß1-42 production. Pharmacological inhibition of Bace1 reduces body weight, improves glucose homeostasis and lowers plasma leptin in diet-induced obese (DIO) mice. These actions are not apparent in ob/ob or db/db mice, indicating the requirement for functional leptin signalling. Decreasing Bace1 activity normalises hypothalamic inflammation, lowers PTP1B and SOCS3 and restores hypothalamic leptin sensitivity and pSTAT3 response in obese mice, but does not affect leptin sensitivity in lean mice. Raising central Aß1-42 levels in the early stage of DIO increases hypothalamic basal pSTAT3 and reduces the amplitude of the leptin pSTAT3 signal without increased inflammation. Thus, elevated Aß1-42 promotes hypothalamic leptin resistance, which is associated with diminished whole-body sensitivity to exogenous leptin and exacerbated body weight gain in high fat fed mice. These results indicate that Bace1 inhibitors, currently in clinical trials for Alzheimer's disease, may be useful agents for the treatment of obesity and associated diabetes.

Altered amyloid precursor protein processing regulates glucose uptake and oxidation in cultured rodent myotubes.

AIMS/HYPOTHESIS: Impaired glucose uptake in skeletal muscle is an important contributor to glucose intolerance in type 2 diabetes. The aspartate protease, beta-site APP-cleaving enzyme 1 (BACE1), a critical regulator of amyloid precursor protein (APP) processing, modulates in vivo glucose disposal and insulin sensitivity in mice. Insulin-independent pathways to stimulate glucose uptake and GLUT4 translocation may offer alternative therapeutic avenues for the treatment of diabetes. We therefore addressed whether BACE1 activity, via APP processing, in skeletal muscle modifies glucose uptake and oxidation independently of insulin. METHODS: Skeletal muscle cell lines were used to investigate the effects of BACE1 and α-secretase inhibition and BACE1 and APP overexpression on glucose uptake, GLUT4 cell surface translocation, glucose oxidation and cellular respiration. RESULTS: In the absence of insulin, reduction of BACE1 activity increased glucose uptake and oxidation, GLUT4myc cell surface translocation, and basal rate of oxygen consumption. In contrast, overexpressing BACE1 in C2C12 myotubes decreased glucose uptake, glucose oxidation and oxygen consumption rate. APP overexpression increased and α-secretase inhibition decreased glucose uptake in C2C12 myotubes. The increase in glucose uptake elicited by BACE1 inhibition is dependent on phosphoinositide 3-kinase (PI3K) and mimicked by soluble APPα (sAPPα). CONCLUSIONS/INTERPRETATION: Inhibition of muscle BACE1 activity increases insulin-independent, PI3K-dependent glucose uptake and cell surface translocation of GLUT4. As APP overexpression raises basal glucose uptake, and direct application of sAPPα increases PI3K-protein kinase B signalling and glucose uptake in myotubes, we suggest that α-secretase-dependent shedding of sAPPα regulates insulin-independent glucose uptake in skeletal muscle.

Procyanidins improve some disrupted glucose homoeostatic situations: an analysis of doses and treatments according to different animal models.

This review analyses the potential beneficial effects of procyanidins, the main class of flavonoids, in situations in which glucose homeostasis is disrupted. Because the disruption of glucose homeostasis can occur as a result of various causes, we critically review the effects of procyanidins based on the specific origin of each type of disruption. Where little or no insulin is present (Type I diabetic animals), summarized studies of procyanidin treatment suggest that procyanidins have a short-lived insulin-mimetic effect on the internal targets of the organism, an effect not reproduced in normoglycemic, normoinsulinemic healthy animals. Insulin resistance (usually linked to hyperinsulinemia) poses a very different situation. Preventive studies using fructose-fed models indicate that procyanidins may be useful in preventing the induction of damage and thus in limiting hyperglycemia. But the results of other studies using models such as high-fat diet treated rats or genetically obese animals are controversial. Although the effects on glucose parameters are hazy, it is known that procyanidins target key tissues involved in its homeostasis. Interestingly, all available data suggest that procyanidins are more effective when administered in one acute load than when mixed with food.

Oligomers of grape-seed procyanidin extract activate the insulin receptor and key targets of the insulin signaling pathway differently from insulin.

Procyanidins are bioactive flavonoid compounds from fruits and vegetables that possess insulinomimetic properties, decreasing hyperglycaemia in streptozotocin-diabetic rats and stimulating glucose uptake in insulin-sensitive cell lines. Here we show that the oligomeric structures of a grape-seed procyanidin extract (GSPE) interact and induce the autophosphorylation of the insulin receptor in order to stimulate the uptake of glucose. However, their activation differs from insulin activation and results in differences in the downstream signaling. Oligomers of GSPE phosphorylate protein kinase B at Thr308 lower than insulin does, according to the lower insulin receptor activation by procyanidins. On the other hand, they phosphorylate Akt at Ser473 to the same extent as insulin. Moreover, we found that procyanidins phosphorylate p44/p42 and p38 MAPKs much more than insulin does. These results provide further insight into the molecular signaling mechanisms used by procyanidins, pointing to Akt and MAPK proteins as key points for GSPE-activated signaling pathways. Moreover, the differences between GSPE and insulin might help us to understand the wide range of biological effects that procyanidins have.

Effects of a grapeseed procyanidin extract (GSPE) on insulin resistance.

Flavonoids are beneficial compounds against risk factors for metabolic syndrome, but their effects and the mechanisms on glucose homeostasis modulation are not well defined. In the present study, we first checked the efficacy of grapeseed procyanidin extract (GSPE) for stimulating glucose uptake in insulin-resistant 3T3-L1 adipocytes. Results show that when resistance is induced with chronic insulin treatment, GSPE maintain a higher stimulating capacity than insulin. In contrast, when dexamethasone is used as the resistance-inducing agent, GSPE is less effective. Next we evaluated how effective different GSPE treatments are at improving glucose metabolism in hyperinsulinemic animals (fed a cafeteria diet). GSPE reduced plasma insulin levels. The lower dose (25 mg GSPE/kg body weight per day) administered for 30 days improved the HOmeostasis Model Assessment-insulin resistance index. This was accompanied by down-regulation of Pparg2, Glut4 and Irs1 in mesenteric white adipose tissue. Similarly, a chronic GSPE treatment of insulin-resistant 3T3-L1 adipocytes down-regulated the mRNA levels of those adipocyte markers, although cells were still able to respond to the acute stimulation of glucose uptake. In summary, 25 mg/kg body weight per day of GSPE has a positive long-term effect on glucose homeostasis, and GSPE could be targeted at adipose tissue, where it might directly stimulate glucose uptake. This work also highlights the need to carefully consider the bioactive dose, since a higher dose does not necessarily correlate to a greater positive effect.

Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet.

OBJECTIVE: The main objective of this study was to evaluate the effect of procyanidin intake on the level of inflammatory mediators in rats fed a hyperlipidic diet, which are a model of low-grade inflammation as they show an altered cytokine production. DESIGN: Male Zucker Fa/fa rats were randomly grouped to receive a low-fat (LF) diet, a high-fat (HF) diet or a high-fat diet supplemented with procyanidins from grape seed (HFPE) (3.45 mg/kg feed) for 19 weeks and were then euthanized. We determined biochemical parameters, C-reactive protein (CRP) and IL-6 levels in plasma. Adipose tissue depots and body weight were also determined. We assessed CRP, IL-6, TNF-alpha and adiponectin gene expression in liver and white adipose tissue (WAT). RESULTS: As expected, rats fed the HF diet show an enhanced production of CRP. Our results demonstrate that the HFPE diet decreases rat plasma CRP levels but not IL-6 levels. The decrease in plasma CRP in HFPE rats is related to a down-regulation of CRP mRNA expression in the liver and mesenteric WAT. We have also shown a decrease in the expression of the proinflammatory cytokines TNF-alpha and IL-6 in the mesenteric WAT. In contrast, adiponectin mRNA is increased in this tissue due to the procyanidin treatment. As previously reported, CRP plasma levels correlate positively with its expression in the mesenteric WAT, suggesting that procyanidin extract (PE) modulates CRP at the synthesis level. CRP plasma levels also correlate positively with body weight. As expected, body weight is associated with the adiposity index. Also, TNF-alpha expression and IL-6 expression have a strong positive correlation. In contrast, the expression of the anti-inflammatory cytokine adiponectin correlates negatively with the expression of TNF-alpha and IL-6 in the mesenteric WAT. CONCLUSION: These results suggest a beneficial effect of PE on low-grade inflammatory diseases, which may be associated with the inhibition of the proinflammatory molecules CRP, IL-6 and TNF-alpha and the enhanced production of the anti-inflammatory cytokine adiponectin. These findings provide a strong impetus to explore the effects of dietary polyphenols in reducing obesity-related adipokine dysregulation to manage cardiovascular and metabolic risk factors.

Bioactivity of Flavonoids on Insulin-Secreting Cells.

Flavonoids are usually found in fruits and other plant organs and therefore widely consumed. They are antioxidants, anti-inflammatory, anticarcinogenic, and protective against coronary disease and metabolic disorders. These beneficial effects make them good candidates for the development of new functional foods with potential protective/preventive properties against several diseases. We must consider that this fact could lead to a higher intake of some of these flavonoids. Most of the studies concerning their beneficial effects showed peripheral activity of these molecules, but there is no clear information about their central effects on a key organ on metabolic control: the endocrine pancreas. The pancreas has an endocrine function of major importance to regulate nutrient metabolism, such as control of glucose homeostasis via insulin and glucagon secretion. Its importance in whole body nutrient equilibrium is highlighted by the fact that several pathologies, such as type 1 and/or 2 diabetes, are related at some point to a pancreatic cell deregulation. In this review, we compile the most relevant results concerning the effects of flavonoids on several aspects of pancreatic functionality. Studies using animals with drug-induced diabetes support the hypothesis that flavonoids can ameliorate this pathogenesis. The great diversity of flavonoid structures makes it difficult to establish common effects in the pancreas. Published data suggest that there might be direct effects of flavonoids on insulin secretion, as well as on prevention of beta-cell apoptosis, and they could even act via modulation of proliferation. The mechanisms of action involve mainly their antioxidant properties, but other pathways might also take place.