Posts in Category: Diabetes & Obesity

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Dariush Mozaffarian, Jason H.Y. Wu

Selected cardiometabolic benefits of flavonoids and potential underlying molecular mechanisms. In vitro and animal studies support bioactivity of purified flavonoids or flavonoid-rich plant extracts across multiple tissues. Relevant molecular pathways seem to include (1) modulation of gene expression and signaling pathways. Enhancement of AMPK (5′-monophosphate-activated protein kinase) phosphorylation and activation appears to be a common mechanism affected by several types of flavonoids. Modulation of other signaling pathways has also been observed including increased expression of PPAR-γ (peroxisome proliferator-activated receptor-γ) and inhibition of NF-κB (nuclear factor-κB) activation; (2) interaction with gut microbiota. Dietary flavonoids may alter gut-microbial composition because of probiotic-like properties and stimulate growth of specific bacteria (eg, Akkermansia muciniphila) that may confer metabolic benefits. Conversely, metabolism of dietary flavonoids by gut bacteria generates downstream metabolites (eg, phenolic acids) that may possess unique properties and reach higher circulating and tissue concentrations compared with parent flavonoids, thus enhancing biological activity of flavonoids; (3) Direct flavonoid–protein interactions. Growing evidence suggests that flavonoids both stimulate and inhibit protein function, including of ion channels in the vasculature and liver and carbohydrate digestive enzymes (α-amylase and α-glucosidase) in the gastrointestinal tract. Such effects may partly contribute to regulation of vascular tone and glucose metabolism. ERK1/2 indicates extracellular signal-regulated kinases 1 and 2; GLUT4, glucose transporter type 4; IRS2, insulin receptor substrate-2; MAPK, mitogen-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PKA; protein kinase-A; SREBP-1c, sterol regulatory element–binding protein-1c; TG, triglycerides; and TLR4, toll-like receptor 4. (Illustration Credit: Ben Smith.) [Powerpoint File]

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Flavonoids, Dairy Foods, and Cardiovascular and Metabolic Health: A Review of Emerging Biologic Pathways

Dariush Mozaffarian, Jason H.Y. Wu

Relevant characteristics of dairy foods and selected molecular pathways potentially linked to cardiometabolic disease risk. Dairy foods are characterized by a complex mixture of nutrients and processing methods that may influence cardiovascular and metabolic pathways. Examples of relevant constituents include specific fatty acids, calcium, and probiotics. Relevant processing methods may include animal breeding and feeding, fermentation, selection and cultivation of bacterial and yeast strains (eg, as fermentation starters), and homogenization. Such modifications can alter the food’s composition (eg, fermentation leads to production of vitamin K2 from vitamin K1) and its lipid structures (eg, homogenization damages MFGM), each of which can affect downstream molecular and signaling pathways. BCSFA indicates branched-chain saturated fats; GLP-1, glucagon-like peptide 1; MCSFA, medium-chain saturated fats; MFGM, milk-fat globule membranes; MGP, matrix glutamate protein; mTOR, mammalian target of rapamycin; and OCSFA, odd-chain saturated fats. (Illustration Credit: Ben Smith.) [Powerpoint File]

Extracellular Vesicles in Metabolic Syndrome

Extracellular Vesicles in Metabolic Syndrome

M. Carmen Martínez, Ramaroson Andriantsitohaina

Extracellular vesicles (EVs) participate in the development of atherosclerotic plaque. EVMP from smooth muscle cells (pink) induce endothelial dysfunction and macrophage infiltration in the vessel wall through the reactive oxygen species (ROS) production and p38 activation in endothelial cells. EVEXO derived from dendritic cells (blue) increase endothelial inflammation by activation of nuclear factor-κB (NF-κB) pathway and increasing expression of proinflammatory molecules, including vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM1), and E-selectin. [Powerpoint File]

Extracellular Vesicles in Metabolic Syndrome

Extracellular Vesicles in Metabolic Syndrome

M. Carmen Martínez, Ramaroson Andriantsitohaina

Effects of extracellular vesicles (EVs) on blood vessel. EVMP from endothelial cells (dark pink) transfer miR-503 to pericytes and subsequently inhibit vascular endothelial growth factor (VEGF) expression, resulting in decreased migration and proliferation. EVEXO from smooth muscle cells (pink) induce downregulation of LC3 II, ATG5, and Beclin-1 expression in endothelial cells. EVEXO from macrophages (green) evoke intercellular adhesion molecule 1 (ICAM1) overexpression in endothelial cells and reduce level of miR-17. Also, macrophage foam cell–derived EVs favor both migration and adhesion of vascular smooth muscle cells by activating ERK (extracellular signal-regulated kinase) and Akt (protein kinase B/AKT) pathways and by transfer integrins β1 and α5 into vascular smooth muscle cells. EVMP from metabolic syndrome (MetS) patients act on smooth muscle cells and induce overexpression of inducible nitric oxide synthase (iNOS) and monocyte chemoattractant molecule (MCP)-1, leading to vascular hyporeactivity. Also, these EVMP directly act on endothelial cells evoking reduced nitric oxide (NO) production, enhanced cytosolic and mitochondrial reactive oxygen species (ROS) production, and unfolding protein response (UPR). All effects of EVMP from MetS patients are mediated by the interaction Fas/FasL. [Powerpoint File]

Gut Microbiota in Cardiovascular Health and Disease

Gut Microbiota in Cardiovascular Health and Disease

W.H. Wilson Tang, Takeshi Kitai, Stanley L. Hazen

Gut microbiota and possible molecular pathways linked to cardiovascular and cardiometabolic diseases. BAT indicates brown adipose tissue; FXR, farnesoid X receptor; GLP, glucagon-like peptide; GPR, G-protein–coupled receptor; LPS, lipopolysaccharide; PYY, peptide YY; TLR, toll-like receptor; TMA, trimethylamine; and TMAO, trimethylamine N-oxide. [Powerpoint File]

Treatment of Obesity: Weight Loss and Bariatric Surgery

Treatment of Obesity: Weight Loss and Bariatric Surgery

Bruce M. Wolfe, Elizaveta Kvach, Robert H. Eckel

Diagram of surgical options. Image credit: Walter Pories, MD, FACS. [Powerpoint File]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Increased cardiac fatty acid oxidation, reactive oxygen species (ROS) formation, and cardiolipin remodeling. Insulin resistance–induced increased cardiac β oxidation of free fatty acids (FFAs) causes greater H2O2 production than does increased glucose oxidation because of increased electron leakage from the electron transfer flavoprotein (ETF) complex. These ROS activate Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) transcription. ALCAT1, located in the mitochondrial-associated membrane of the endoplasmic reticulum, causes pathological remodeling of cardiolipin from tetra 18:2 cardiolipin to cardiolipin with highly unsaturated fatty acid side chains and cardiolipin deficiency because of oxidative damage. This reduces ETC (electron transport chain) electron flux, ATP synthesis, and further increases ROS. [Powerpoint File]

Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes

Heart Failure Considerations of Antihyperglycemic Medications for Type 2 Diabetes

Eberhard Standl, Oliver Schnell, Darren K. McGuire

Heart failure in type 2 diabetes mellitus: the ominous octet. CAD indicates coronary artery disease; CV, cardiovascular; and SNS, sympathetic nervous system. [Powerpoint File]

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

José J. Fuster, Noriyuki Ouchi, Noyan Gokce, Kenneth Walsh

Functional adipose tissue (left), predominantly found in lean organisms, tends to express anti-inflammatory adipokines that protect against cardiovascular disease. In contrast, excess adipose tissue expansion promotes dysfunction (right), leading to the expression of proinflammatory adipokines that promote cardiovascular disease. Dysfunctional adipose tissue is characterized by enlarged adipocytes, vascular rarefaction, increased inflammatory cell infiltrate, and the appearance of crown-like structures. [Powerpoint File]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Increased mitochondrial oxidation of glucose or fatty acids activates nuclear factor of activated T cells (NFAT)–mediated transcription of genes promoting diabetic atherosclerosis and heart failure. Mitochondrial overproduction of reactive oxygen species (ROS) causes increased intracellular Ca++, which activates the calcium-activated neutral cysteine protease calpain. Calpain then activates the Ca2+/calmodulin-dependent (CaM; Ca2+)serine/threonine phosphatase calcineurin. Dephosphorylation facilitates nuclear translocation of the transcription factor NFAT. In the nucleus, NFAT interacts with polyADP-ribose polymerase (PARP), which increases NFAT transcriptional activity via NFAT polyADP-ribosylation. ICAM-1 indicates intercellular adhesion molecule-1; IL-6, interleukin-6; and MCP-1, monocyte chemoattractant protein-1. [Powerpoint File]

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Manasi S. Shah, Michael Brownlee

Hyperglycemia-induced myocardial protein modification by O-GlcNAc causes increased intracellular Ca++ and delayed after polarizations. Increased intracellular glucose flux provides more substrate for the enzyme O-GlcNAc-transferase (OGT). This increases O-GlcNAc modification of calcium/calmodulin-dependent protein kinase IIδ (CaMKII), causing autonomous CaMKII activation. CaMKII increases intracellular Ca++ by phosphorylating ryanodine receptor 2 (RyR). OGT also modifies transcription complex factors regulating expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA2), reducing SERCA2A expression and contributing to increased intracellular Ca++. Increased O-GlcNAc modification of these proteins causes delayed afterdepolarizations in cardiomyocytes. PLB indicates phospholamban. [Powerpoint File]

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease

José J. Fuster, Noriyuki Ouchi, Noyan Gokce, Kenneth Walsh

Obesity leads to adipose tissue dysfunction, triggering the release of proinflammatory adipokines that can directly act on cardiovascular tissues to promote disease. The adipokine imbalance can also affect the function of metabolically important tissues and the microvasculature, promoting insulin resistance and indirectly contributing to cardiovascular disease. [Powerpoint File]

Lipid Use and Misuse by the Heart

Lipid Use and Misuse by the Heart

P. Christian Schulze, Konstantinos Drosatos, Ira J. Goldberg

Metabolism of circulating triglyceride-rich lipoproteins. Triglycerides (TG) within the circulation are predominantly carried by chylomicrons and very low–density lipoprotein (VLDL). Chylomicrons carry dietary lipids. Along with the lipids, it contains apolipoproteins including apoB-48 and C-II, the activator of lipoprotein lipase (LPL). VLDL contains apoB-100 and carry triglycerides secreted from the liver. Lipolysis converts triglycerides to fatty acids (FA) and also leads to the shedding of surface components that contain cholesterol (Chol). Defective lipolysis leads to reduced acquisition of fatty acids, cholesterol, and vitamin A by the heart. CE indicates cholesteryl ester; LDL, low-density lipoprotein; and LDL-R, low-density lipoprotein receptor. [Powerpoint File]

Lipid Use and Misuse by the Heart

Lipid Use and Misuse by the Heart

P. Christian Schulze, Konstantinos Drosatos, Ira J. Goldberg

Cellular fatty acid uptake. Fatty acids generated by lipoprotein lipase (LpL) or as nonesterified fatty acids associated with albumin enter cells via a cell surface receptor such as cluster of differentiation 36 (CD36) or at high levels are acquired via nonspecific movement across the cell membrane. Once inside the cells, fatty acids are complexed to CoA and then either used for ATP generation or stored within lipid droplets. ATGL indicates adipose triglyceride lipase; DGAT, DAG acyl transference; FFA, first fatty acid; PPAR, peroxisomal proliferator–activated receptor; and VLDL, very low–density lipoprotein. [Powerpoint File]

Epigenetic Changes in Diabetes and Cardiovascular Risk

Epigenetic Changes in Diabetes and Cardiovascular Risk

Samuel T. Keating, Jorge Plutzky, Assam El-Osta

Interpreting chromatin and constituent residues subject to modification. Chromatin regulates gene structure and function. DNA is packaged into a 30-nm macromolecular structure consisting of the chromatin fiber. Together with post-translational modifications (PTM) of histone residues, chromatin regulates the functions involving transcription, repair, replication, and condensation. The nucleosome at 11 nm is comprised of ≈147 bp of DNA comprising an octamer of 2 copies of each of the 4 core histone proteins: H2A, H2B, H3, and H4. The histone tail is subject to immense interpretation by writing enzymes that add PTM shown such as histone methyltransferase, Set7. Histone tails are also subject to erasing enzymes that specifically remove these modifications and interpreted by reader proteins that identify histone tail modifications. Cytosine residues of the DNA duplex are subject to 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications interpreted by methyl-CpG binding domain (MBD) and ten-eleven translocation (TET) enzyme. Methylation-mediated gene suppression events involve targeted MBD recruitment whereas TET proteins are implicated in active DNA demethylation and regulation of gene expression. [Powerpoint File]