Glycaemic regulation, appetite and ex vivo oxidative stress in young adults following consumption of high-carbohydrate cereal bars fortified with polyphenol-rich berries.

Consumption of certain berries appears to slow postprandial glucose absorption, attributable to polyphenols, which may benefit exercise and cognition, reduce appetite and/or oxidative stress. This randomised, crossover, placebo-controlled study determined whether polyphenol-rich fruits added to carbohydrate-based foods produce a dose-dependent moderation of postprandial glycaemic, glucoregulatory hormone, appetite and ex vivo oxidative stress responses. Twenty participants (eighteen males/two females; 24 (sd 5) years; BMI: 27 (sd 3) kg/m2) consumed one of five cereal bars (approximately 88 % carbohydrate) containing no fruit ingredients (reference), freeze-dried black raspberries (10 or 20 % total weight; LOW-Rasp and HIGH-Rasp, respectively) and cranberry extract (0·5 or 1 % total weight; LOW-Cran and HIGH-Cran), on trials separated by ≥5 d. Postprandial peak/nadir from baseline (Δmax) and incremental postprandial AUC over 60 and 180 min for glucose and other biochemistries were measured to examine the dose-dependent effects. Glucose AUC0-180 min trended towards being higher (43 %) after HIGH-Rasp v. LOW-Rasp (P=0·06), with no glucose differences between the raspberry and reference bars. Relative to reference, HIGH-Rasp resulted in a 17 % lower Δmax insulin, 3 % lower C-peptide (AUC0-60 min and 3 % lower glucose-dependent insulinotropic polypeptide (AUC0-180 min) P<0·05. No treatment effects were observed for the cranberry bars regarding glucose and glucoregulatory hormones, nor were there any treatment effects for either berry type regarding ex vivo oxidation, appetite-mediating hormones or appetite. Fortification with freeze-dried black raspberries (approximately 25 g, containing 1·2 g of polyphenols) seems to slightly improve the glucoregulatory hormone and glycaemic responses to a high-carbohydrate food item in young adults but did not affect appetite or oxidative stress responses at doses or with methods studied herein.

A carbohydrate-reduced high-protein diet acutely decreases postprandial and diurnal glucose excursions in type 2 diabetes patients.

The aim of the study was to assess whether a simple substitution of carbohydrate in the conventionally recommended diet with protein and fat would result in a clinically meaningful reduction in postprandial hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). In all, sixteen subjects with T2DM treated with metformin only, fourteen male, with a median age of 65 (43-70) years, HbA1c of 6·5 % (47 mmol/l) (5·5-8·3 % (37-67 mmol/l)) and a BMI of 30 (sd 4·4) kg/m2 participated in the randomised, cross-over study. A carbohydrate-reduced high-protein (CRHP) diet was compared with an iso-energetic conventional diabetes (CD) diet. Macronutrient contents of the CRHP/CD diets consisted of 31/54 % energy from carbohydrate, 29/16 % energy from protein and 40/30 % energy from fat, respectively. Each diet was consumed on 2 consecutive days in a randomised order. Postprandial glycaemia, pancreatic and gut hormones, as well as satiety, were evaluated at breakfast and lunch. Compared with the CD diet, the CRHP diet reduced postprandial AUC of glucose by 14 %, insulin by 22 % and glucose-dependent insulinotropic polypeptide by 17 % (all P<0·001), respectively. Correspondingly, glucagon AUC increased by 33 % (P<0·001), cholecystokinin by 24 % (P=0·004) and satiety scores by 7 % (P=0·035), respectively. A moderate reduction in carbohydrate with an increase in fat and protein in the diet, compared with an energy-matched CD diet, greatly reduced postprandial glucose excursions and resulted in increased satiety in patients with well-controlled T2DM.

Probiotic Lactobacillus gasseri SBT2055 improves glucose tolerance and reduces body weight gain in rats by stimulating energy expenditure.

Probiotic Lactobacillus gasseri SBT2055 (LG2055) reduces postprandial TAG absorption and exerts anti-obesity effects in rats and humans; however, the underlying mechanisms are not fully understood. In the present study, we addressed the mechanistic insights of the anti-obesity activity of LG2055 by feeding Sprague-Dawley rats diets containing skimmed milk fermented or not by LG2055 for 4 weeks and by analysing energy expenditure, glucose tolerance, the levels of SCFA in the caecum and serum inflammatory markers. Rats fed the LG2055-containing diet demonstrated significantly higher carbohydrate oxidation in the dark cycle (active phase for rats) compared with the control group, which resulted in a significant increase in energy expenditure. LG2055 significantly reduced cumulative blood glucose levels (AUC) compared with the control diet after 3 weeks and increased the molar ratio of butyrate:total SCFA in the caecum after 4 weeks. Furthermore, the LG2055-supplemented diet significantly reduced the levels of serum amyloid P component - an indicator of the inflammatory process. In conclusion, our results demonstrate that, in addition to the inhibition of dietary TAG absorption reported previously, the intake of probiotic LG2055 enhanced energy expenditure via carbohydrate oxidation, improved glucose tolerance and attenuated inflammation, suggesting multiple additive and/or synergistic actions underlying the anti-obesity effects exerted by LG2055.

Soya milk exerts different effects on plasma amino acid responses and incretin hormone secretion compared with cows' milk in healthy, young men.

Apart from the well-known action of insulin, the mechanism by which soya and cows' milk improve postprandial glycaemia control was examined. In total, twelve healthy, young, Chinese men were studied on three separate occasions, in random order with isovolumetric (322 ml) control water, soya milk and cows' milk. Plasma total amino acid concentrations increased 30 min after test meals consumption and were higher after soya milk (230 %) and cow milk (240 %) consumption compared with water. Cows' milk ingestion induced higher branched-chain amino acids (BCAA) (40 %) than soya milk. Postprandial incretin concentrations increased after meal consumption. Cows' milk meal was accompanied by higher incremental AUC (iAUC) (170 %) for glucagon-like peptide-1 (GLP-1) compared with soya milk and control (P=0·06). However, glucose-dependent insulinotropic polypeptide (GIP) concentrations increased to significantly greater levels after soya milk consumption (iAUC 60 % higher) compared with cows' milk and control. Consumption of both soya and cows' milk with carbohydrates induced a similar reduction in glycaemic response through a different mechanism, beyond insulin action. Plasma amino acids (alanine and arginine), and incretins in particular (GIP was stimulated), may be involved in the hyperinsulinaemia after soya milk meals. However, BCAA and GLP-1 release may be responsible for the reduced glycaemia after cows' milk consumption by delaying gastric emptying. This could be the result of different milk protein/amino acid composition, but also differences in milk carbohydrate composition (i.e. lactose v. sucrose). It can be concluded that soya milk is a good alternative to cows' milk with regard to glycaemic regulation, with different mechanisms involved.

Bioavailability of milk protein-derived bioactive peptides: a glycaemic management perspective.

Milk protein-derived peptides have been reported to have potential benefits for reducing the risk of type 2 diabetes. However, what the active components are and whether intact peptides exert this bioactivity has received little investigation in human subjects. Furthermore, potentially useful bioactive peptides can be limited by low bioavailability. Various peptides have been identified in the gastrointestinal tract and bloodstream after milk-protein ingestion, providing valuable insights into their potential bioavailability. However, these studies are currently limited and the structure and sequence of milk peptides exerting bioactivity for glycaemic management has received little investigation in human subjects. The present article reviews the bioavailability of milk protein-derived peptides in human studies to date, and examines the evidence on milk proteins and glycaemic management, including potential mechanisms of action. Areas in need of advancement are identified. Only by establishing the bioavailability of milk protein-derived peptides, the active components and the mechanistic pathways involved can the benefits of milk proteins for the prevention or management of type 2 diabetes be fully realised in future.

Variation in responses to incretin therapy: Modifiable and non-modifiable factors.

Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation and weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-stimulated insulinotropic polypeptide (GIP) are the incretin hormones that provide the foundations for these drugs. While these therapies have been highly effective for some, the results are variable. Incretin therapies target the class B G protein-coupled receptors GLP-1R and GIPR, expressed mainly in the pancreas and the hypothalamus, while some therapeutical approaches include additional targeting of the related glucagon receptor (GCGR) in the liver. The proper functioning of these receptors is crucial for incretin therapy success and here we review several mechanisms at the cellular and molecular level that influence an individual's response to incretin therapy.

Exendin-4 inhibits small intestinal glucose sensing and absorption through repression of T1R2/T1R3 sweet taste receptor signalling in streptozotocin diabetic mice.

The small intestine, which is the area where sugars are absorbed, should be considered in the approaches developed for the treatment of diabetes. However, studies on small intestine damage in diabetic individuals, and the effects of current treatments on the small intestine are very limited. This is the first study to investigate the effects of exendin-4, a GLP-1 receptor agonist, on small intestine injury in diabetic mice. BALB/c male mice were divided into 4 groups for this study. The first group was given citrate buffer, the second group was given exendin-4, the third group was given streptozotocin (STZ), and the fourth group was given both exendin-4, and STZ. As the results, we determined a decrease in the edema and deterioration in the integrity of the villi, disruption in continuity of the brush border, fibrosis and enterocyte apoptosis, while the TNFα level and crypt cell proliferation were increased in the small intestinal tissue of exendin-4 treated STZ diabetic mice. Furthermore, the levels of duodenal tissue glucose, SGLT1, and GLUT2 were decreased, whereas there was an increase in GIP level in diabetic mice administered with exendin-4. Moreover, we determined that the sweet taste receptors T1R2/T1R3, downstream molecules PLCß2, α-gustducin and associated secondary messengers IP3, cAMP, which were increased in the duodenal tissue of STZ-diabetic mice, decreased with exendin-4 administration. These findings were evaluated as that exendin-4 reduces glucose absorption by suppressing the T1R2/T1R3 sweet taste signal perception pathway in duodenum of STZ diabetic mice.

A comprehensive review on the glucoregulatory properties of food-derived bioactive peptides.

Diabetes mellitus, a group of metabolic disorders characterized by persistent hyperglycemia, affects millions of people worldwide and is on the rise. Dietary proteins, from a wide range of food sources, are rich in bioactive peptides with antidiabetic properties. Notable examples include AGFAGDDAPR, a black tea-derived peptide, VRIRLLQRFNKRS, a ß-conglycinin-derived peptide, and milk-derived peptide VPP, which have shown antidiabetic effects in diabetic rodent models through variety of pathways including improving beta-cells function, suppression of alpha-cells proliferation, inhibiting food intake, increasing portal cholecystokinin concentration, enhancing insulin signaling and glucose uptake, and ameliorating adipose tissue inflammation. Despite the immense research on glucoregulatory properties of bioactive peptides, incorporation of these bioactive peptides in functional foods or nutraceuticals is widely limited due to the existence of several challenges in the field of peptide research and commercialization. Ongoing research in this field, however, is fundamental to pave the road for this purpose.

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease.

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

The role of Gαq/Gα11 signaling in intestinal epithelial cells.

Intestinal homeostasis and the coordinated actions of digestion, absorption and excretion are tightly regulated by a number of gastrointestinal hormones. Most of them exert their actions through G-protein-coupled receptors. Recently, we showed that the absence of Gαq/Gα11 signaling impaired the maturation of Paneth cells, induced their differentiation toward goblet cells, and affected the regeneration of the colonic mucosa in an experimental model of colitis. Although an immunohistochemical study showed that Gαq/Gα11 were highly expressed in enterocytes, it seemed that enterocytes were not affected in Int-Gq/G11 double knock-out intestine. Thus, we used an intestinal epithelial cell line to examine the role of signaling through Gαq/Gα11 in enterocytes and manipulated the expression level of Gαq and/or Gα11. The proliferation was inhibited in IEC-6 cells that overexpressed Gαq/Gα11 and enhanced in IEC-6 cells in which Gαq/Gα11 was downregulated. The expression of T-cell factor 1 was increased according to the overexpression of Gαq/Gα11. The expression of Notch1 intracellular cytoplasmic domain was decreased by the overexpression of Gαq/Gα11 and increased by the downregulation of Gαq/Gα11. The relative mRNA expression of Muc2, a goblet cell marker, was elevated in a Gαq/Gα11 knock-down experiment. Our findings suggest that Gαq/Gα11-mediated signaling inhibits proliferation and may support a physiological function, such as absorption or secretion, in terminally differentiated enterocytes.

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic ß cells.

BACKGROUND: Pancreatic ß cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying ß cell failure is important to develop ß cell protective approaches. SCOPE OF REVIEW: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in ß cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in ß cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human ß cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into ß cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in ß cells. MAJOR CONCLUSIONS: Pancreatic ß cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.

Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects: A randomized placebo controlled trial.

BACKGROUND: Caloric restriction and n-3 polyunsaturated fatty acid (PUFA) supplementation protect from some of the metabolic complications. The aim of this study was to assess the influence of a low calorie diet with or without n-3 PUFA supplementation on glucose dependent insulinotropic polypeptide (GIP) output and insulin sensitivity markers in obese subjects. METHODS: Obese, non-diabetic subjects (BMI 30-40 kg/m(2)) and aged 25-65 yr. were put on low calorie diet (1200-1500 kcal/day) supplemented with either 1.8 g/day n-3 PUFA (DHA/EPA, 5:1) (n = 24) or placebo capsules (n = 24) for three months in a randomized placebo controlled trial. Insulin resistance markers and GIP levels were analysed from samples obtained at fasting and during an oral glucose tolerance test (OGTT). RESULTS: Caloric restriction with n-3 PUFA led to a decrease of insulin resistance index (HOMA-IR) and a significant reduction of insulin output as well as decreased GIP secretion during the OGTT. These effects were not seen with caloric restriction alone. Changes in GIP output were inversely associated with changes in red blood cell EPA content whereas fasting GIP level positively correlated with HOMA-IR index. Blood triglyceride level was lowered by caloric restriction with a greater effect when n-3 PUFA were included and correlated positively with fasting GIP level. CONCLUSIONS: Three months of caloric restriction with DHA + EPA supplementation exerts beneficial effects on insulin resistance, GIP and triglycerides. GENERAL SIGNIFICANCE: Combining caloric restriction and n-3 PUFA improves insulin sensitivity, which may be related to a decrease of GIP levels.

Lipid-rich diet enhances L-cell density in obese subjects and in mice through improved L-cell differentiation.

The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation. Alteration in GLP-1 secretion during obesity has been reported but is still controversial. Due to the high adaptability of intestinal cells to environmental changes, we hypothesised that the density of GLP-1-producing cells could be modified by nutritional factors to prevent the deterioration of metabolic condition in obesity. We quantified L-cell density in jejunum samples collected during Roux-en-Y gastric bypass in forty-nine severely obese subjects analysed according to their fat consumption. In mice, we deciphered the mechanisms by which a high-fat diet (HFD) makes an impact on enteroendocrine cell density and function. L-cell density in the jejunum was higher in obese subjects consuming >30 % fat compared with low fat eaters. Mice fed a HFD for 8 weeks displayed an increase in GLP-1-positive cells in the jejunum and colon accordingly to GLP-1 secretion. The regulation by the HFD appears specific to GLP-1-producing cells, as the number of PYY (peptide YY)-positive cells remained unchanged. Moreover, genetically obese ob/ob mice did not show alteration of GLP-1-positive cell density in the jejunum or colon, suggesting that obesity per se is not sufficient to trigger the mechanism. The higher L-cell density in HFD-fed mice involved a rise in L-cell terminal differentiation as witnessed by the increased expression of transcription factors downstream of neurogenin3 (Ngn3). We suggest that the observed increase in GLP-1-positive cell density triggered by high fat consumption in humans and mice might favour insulin secretion and therefore constitute an adaptive response of the intestine to balance diet-induced insulin resistance.

Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice.

The widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from ß cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose-dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7-36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption.

Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells.

The molecular mechanisms regulating secretion of the orexigenic-glucoregulatory hormone ghrelin remain unclear. Based on qPCR analysis of FACS-purified gastric ghrelin cells, highly expressed and enriched 7TM receptors were comprehensively identified and functionally characterized using in vitro, ex vivo and in vivo methods. Five Gαs-coupled receptors efficiently stimulated ghrelin secretion: as expected the ß1-adrenergic, the GIP and the secretin receptors but surprisingly also the composite receptor for the sensory neuropeptide CGRP and the melanocortin 4 receptor. A number of Gαi/o-coupled receptors inhibited ghrelin secretion including somatostatin receptors SSTR1, SSTR2 and SSTR3 and unexpectedly the highly enriched lactate receptor, GPR81. Three other metabolite receptors known to be both Gαi/o- and Gαq/11-coupled all inhibited ghrelin secretion through a pertussis toxin-sensitive Gαi/o pathway: FFAR2 (short chain fatty acid receptor; GPR43), FFAR4 (long chain fatty acid receptor; GPR120) and CasR (calcium sensing receptor). In addition to the common Gα subunits three non-common Gαi/o subunits were highly enriched in ghrelin cells: GαoA, GαoB and Gαz. Inhibition of Gαi/o signaling via ghrelin cell-selective pertussis toxin expression markedly enhanced circulating ghrelin. These 7TM receptors and associated Gα subunits constitute a major part of the molecular machinery directly mediating neuronal and endocrine stimulation versus metabolite and somatostatin inhibition of ghrelin secretion including a series of novel receptor targets not previously identified on the ghrelin cell.