ABSTRACT
Despite being largely preventable, cardiovascular disease (CVD) is still the leading cause of death globally. Recent studies suggest that the immune system, particularly a form of systemic chronic inflammation (SCI), is involved in the mechanisms leading to CVD; thus, targeting SCI may help prevent or delay the onset of CVD. In a recent placebo-controlled randomized clinical trial, an oat product providing 3 g of ß-Glucan improved cholesterol low-density lipoprotein (LDL) levels and lowered cardiovascular risk in adults with borderline high cholesterol. Here, we conducted a secondary measurement of the serum samples to test whether the oat product has the potential to reduce SCI and improve other clinical outcomes related to healthy aging. We investigated the effects of the oat product on a novel metric for SCI called Inflammatory Age® (iAge®), derived from the Stanford 1000 Immunomes Project. The iAge® predicts multimorbidity, frailty, immune decline, premature cardiovascular aging, and all-cause mortality on a personalized level. A beneficial effect of the oat product was observed in subjects with elevated levels of iAge® at baseline (>49.6 iAge® years) as early as two weeks post-treatment. The rice control group did not show any significant change in iAge®. Interestingly, the effects of the oat product on iAge® were largely driven by a decrease in the Eotaxin-1 protein, an aging-related chemokine, independent of a person's gender, body mass index, or chronological age. Thus, we describe a novel anti-SCI role for oats that could have a major impact on functional, preventative, and personalized medicine.
Subject(s)
Avena , Cardiovascular Diseases , Adult , Humans , Cholesterol, LDL , Cardiovascular Diseases/etiology , Dietary Fiber/analysis , Cholesterol , Edible Grain/chemistry , Inflammation/drug therapyABSTRACT
The gastrointestinal (GI) side-effects of dietary fibers are recognized, but less is known about their effects on non-GI symptoms. We assessed non-GI symptoms in a trial of the LDL-cholesterol lowering effect of oat ß-glucan (OBG). Participants (n = 207) with borderline high LDL-cholesterol were randomized to an OBG (1 g OBG, n = 104, n = 96 analyzed) or Control (n = 103, n = 95 analyzed) beverage 3-times daily for 4 weeks. At screening, baseline, 2 weeks and 4 weeks participants rated the severity of 16 non-GI symptoms as none, mild, moderate or severe. The occurrence and severity (more or less severe than pre-treatment) were compared using chi-squared and Fisher's exact test, respectively. During OBG treatment, the occurrence of exhaustion and fatigue decreased versus baseline (p < 0.05). The severity of headache (2 weeks, p = 0.032), anxiety (2 weeks p = 0.059) and feeling cold (4 weeks, p = 0.040) were less on OBG than Control. The severity of fatigue and hot flashes at 4 weeks, limb/joint pain at 2 weeks and difficulty concentrating at both times decreased on OBG versus baseline. High serum c-reactive-protein and changes in c-reactive-protein, oxidized-LDL, and GI-symptom severity were associated with the occurrence and severity of several non-GI symptoms. These data provide preliminary, hypothesis-generating evidence that OBG may reduce several non-GI symptoms in healthy adults.
Subject(s)
Affect/drug effects , Dietary Fiber/pharmacology , Eating/psychology , beta-Glucans/pharmacology , Adolescent , Adult , Aged , Anxiety/therapy , C-Reactive Protein/analysis , Chi-Square Distribution , Cholesterol, LDL/blood , Double-Blind Method , Fasting/blood , Fatigue/therapy , Female , Gastrointestinal Tract/drug effects , Headache/therapy , Healthy Volunteers , Humans , Male , Middle Aged , Musculoskeletal Pain/therapy , Nutritional Physiological Phenomena , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Quinic acid (QA) is an abundant natural compound from plant sources which may improve metabolic health. However, little attention has been paid to its effects on pancreatic beta-cell functions, which contribute to the control of metabolic health by lowering blood glucose. Strategies targeting beta-cell signal transduction are a new approach for diabetes treatment. This study investigated the efficacy of QA to stimulate beta-cell function by targeting the basic molecular machinery of metabolism-secretion coupling. EXPERIMENTAL APPROACH: We measured bioenergetic parameters and insulin exocytosis in a model of insulin-secreting beta-cells (INS-1E), together with Ca2+ homeostasis, using genetically encoded sensors, targeted to different subcellular compartments. Islets from mice chronically infused with QA were also assessed. KEY RESULTS: QA triggered transient cytosolic Ca2+ increases in insulin-secreting cells by mobilizing Ca2+ from intracellular stores, such as endoplasmic reticulum. Following glucose stimulation, QA increased glucose-induced mitochondrial Ca2+ transients. We also observed a QA-induced rise of the NAD(P)H/NAD(P)+ ratio, augmented ATP synthase-dependent respiration, and enhanced glucose-stimulated insulin secretion. QA promoted beta-cell function in vivo as islets from mice infused with QA displayed improved glucose-induced insulin secretion. A diet containing QA improved glucose tolerance in mice. CONCLUSIONS AND IMPLICATIONS: QA modulated intracellular Ca2+ homeostasis, enhancing glucose-stimulated insulin secretion in both INS-1E cells and mouse islets. By increasing mitochondrial Ca2+ , QA activated the coordinated stimulation of oxidative metabolism, mitochondrial ATP synthase-dependent respiration, and therefore insulin secretion. Bioactive agents raising mitochondrial Ca2+ in pancreatic beta-cells could be used to treat diabetes.
Subject(s)
Biological Products/pharmacology , Calcium/metabolism , Insulin Secretion/drug effects , Insulin-Secreting Cells/drug effects , Mitochondria/drug effects , Quinic Acid/pharmacology , Actinidia/chemistry , Animals , Biological Products/chemistry , Biological Products/isolation & purification , Cells, Cultured , Coffee/chemistry , Dose-Response Relationship, Drug , Hippophae/chemistry , Insulin-Secreting Cells/metabolism , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Prunus/chemistry , Quinic Acid/chemistry , Quinic Acid/isolation & purification , Rats , Structure-Activity Relationship , Vaccinium macrocarpon/chemistry , Vaccinium myrtillus/chemistryABSTRACT
Pancreatic ß-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of ß-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for ß-cell function and improves glycemia in a model of ß cell regeneration. We further investigated the role of Isx9 in ß-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in ß cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected ß cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to ß cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.
Subject(s)
Calbindins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Insulin-Secreting Cells/drug effects , Isoxazoles/pharmacology , Thiophenes/pharmacology , Animals , Calbindins/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Diabetes Mellitus, Experimental/metabolism , Humans , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Islets of Langerhans Transplantation , Mice, Inbred NOD , Mice, SCID , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , RatsABSTRACT
Diabetes prevalence increases with age, and ß-cell dysfunction contributes to the incidence of the disease. Dietary lipids have been recognized as contributory factors in the development and progression of the disease. Unlike long chain triglycerides, medium chain triglycerides (MCT) increase fat burning in animal and human subjects as well as serum C-peptide in type 2 diabetes patients. We evaluated the beneficial effects of MCT on ß-cells in vivo and in vitro. MCT improved glycemia in aged rats via ß-cell function assessed by measuring insulin secretion and content. In ß-cells, medium chain fatty acid (MCFA)-C10 activated fatty acid receptor 1 FFAR1/GPR40, while MCFA-C8 induced mitochondrial ketogenesis and the C8:C10 mixture improved ß cell function. We showed that GPR40 signaling positively impacts ketone body production in ß-cells, and chronic treatment with ß-hydroxybutyrate (BHB) improves ß-cell function. We also showed that BHB and MCFA help ß-cells recover from lipotoxic stress by improving mitochondrial function and increasing the expression of genes involved in ß-cell function and insulin biogenesis, such as Glut2, MafA, and NeuroD1 in primary human islets. MCFA offers a therapeutic advantage in the preservation of ß-cell function as part of a preventative strategy against diabetes in at risk populations.