Posts in Category: Diabetes & Obesity

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]

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]

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]

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

Adipose tissue depots occur throughout the body. Studies suggest that visceral adipose tissue accumulation is a major risk factor for cardiometabolic disease, whereas subcutaneous fat seems to be neutral or protective. Other adipose tissue depots of note include the epicardium, the perivascular space, and bone marrow, but the functional significance of these tissues is largely unknown. Brown adipose tissue occurs in the supraclavicular and paraspinal regions. In contrast to white adipose tissue, brown adipose tissue is metabolically active, and it functions to utilize fuel to produce heat. In addition, ectopic lipid can accumulate in tissues, such as liver, in metabolically dysfunctional organisms. [Powerpoint File]

Lipid Use and Misuse by the Heart

Lipid Use and Misuse by the Heart

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

Intracellular triglyceride storage and release. Triglycerides are stored within cardiomyocytes in lipid droplets (shown in yellow) that are surrounded by phospholipids and several proteins; the most abundant are the perilipins (PLINs such as PLIN 2, 3, and 5). These proteins modulate the actions of the major triglyceride hydrolytic enzyme adipose triglyceride lipase (ATGL), which removes the first fatty acid (FFA) from triglyceride. The second fatty acid is removed by hormone-sensitive lipase (HDL) and the final by monoglycerol lipase (MGL). The released fatty acid complex with CoA via long chain acyl coA synthetases (ACSL). [Powerpoint File]

Epigenetic Changes in Diabetes and Cardiovascular Risk

Epigenetic Changes in Diabetes and Cardiovascular Risk

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

Epigenomic profiling of human monocytes and endothelial cells. Distinguishing epigenomic profiles from distinct cell populations in the vasculature. In this example, histone modifications and genomic DNA methylation sequences are derived from human monocyte and endothelial cells using epigenomic profiling methodology combined with computational analyses and integration. Histone acetylation data from human CD14+ monocytes was accessed from the Encyclopedia of DNA Elements portal. Histone acetylation and DNA methylation data from human aortic endothelial cells were obtained from GEO (Gene Expression Omnibus; ID: GSE37378). This circos plot shows histone acetylation and DNA methylation patterns on chromosome 17. Peaks were uniformly generated using MACS (Model-based Analysis of ChIP-Seq) peak calling by comparing the samples to sequenced input for both cell types. The length of the peaks is proportional to the strength of the peak (calculated based on P value). Monocyte acetylation is shown in purple. Endothelial cell acetylation is shown in blue, whereas methylated regions are shown in red. The innermost track represents gene promoters from HAECs with differential histone acetylation (green) and deacetylation (orange) induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. All RefSeq (hg19) genes on chr17 are represented in the outer most track (blue with red outline). Names of genes associated with differential histone acetylation at the promoter are included. [Powerpoint File]

Insulin Signaling and Heart Failure

Insulin Signaling and Heart Failure

Christian Riehle, E. Dale Abel

Schematic representation of insulin signaling pathway. Simplified summary of key elements involved in insulin signal transduction that ultimately regulate multiple cellular processes. On binding to its ligand, insulin and insulin-like growth factor-1 (IGF-1) receptors undergo autophosphorylation, which increases their tyrosine kinase activities. Tyrosine phosphorylation and activation of the docking proteins insulin receptor substrates 1 and 2 (IRS1/2), engages regulatory subunits of the phosphatidylinositol-3-kinase (PI3K) that generates phosphatidylinositol (3,4,5)-triphosphate (PIP3) from phosphatidylinositol 3,4, bisphosphate (PIP2). The serine threonine kinases phosphoinositide-dependent protein kinase 1 (PDPK1) and Akt1 or Akt2 bind to PIP3 by their PH domains. PDPK1 phosphorylates Akt on Thr 308, and mechanistic target of Rapamycin complex 2 (mTORC2) phosphorylates Akt1/2 on Ser 473. Once activated, Akt in turn phosphorylates multiple targets of which a subset is shown. Phosphorylation of these targets induces pleiotropic cellular responses: B-cell leukemia/lymphoma 2 (BCL-2) phosphorylation inhibits apoptosis, forkhead box O (FOXO) protein phosphorylation promotes nuclear exclusion, thereby repressing the expression of FOXO-regulated transcripts that mediate autophagy and apoptosis. Tuberous sclerosis complex (TSC) 1/2 phosphorylation promotes mTOR activation, which increases mRNA translation, promotes protein synthesis, cell growth, mitochondrial fusion, and also inhibits autophagy. Phosphorylation of glycogen synthase kinase (GSK) removes the repression of glycogen synthase, which in concert with increased availability of glucose promotes glycogen synthesis. Phosphorylation of endothelial nitric oxide synthase (NOSIII) or eNOS by Akt increases the generation of nitric oxide to promote vasodilation. Akt phosphorylation mediates the translocation of vesicles containing the GLUT4 glucose transporter, in part, by phosphorylating downstream targets such as AS160 (not shown), leading to increased glucose transport after insertion into the plasma membrane. Akt also mediates, in part, translocation of the fatty acid translocase CD36. Insulin signaling also promotes activation of the mitogen-activated protein kinases (extracellular-regulated kinase [ERK]1/2) to increase the expression of various genes. [Powerpoint File]

Insulin Signaling and Heart Failure

Insulin Signaling and Heart Failure

Christian Riehle, E. Dale Abel

Summary of mechanisms that lead to insulin resistance in heart failure or in the metabolic syndrome. Signaling events in skeletal muscle, liver, adipose tissue, and brain (not shown) impair insulin signaling in each respective organ leading to metabolic perturbations as illustrated, which alter the systemic milieu in ways that may adversely affect cardiac structure and function. [Powerpoint File]