Number 25, 2004
Heart failure in diabetes
Glossary
Gary D. Lopaschuk
AMP-activated protein kinase (AMPK)
AMPK is a widely distributed cellular kinase that is activated during times of metabolic stress. It has been termed a cellular “fuel gauge”, and primarily functions to turn off energy consuming pathways and turn on energy producing pathways during metabolic stress.
Acetyl-CoA carboxylase (ACC)
ACC is a key enzyme involved in both synthesis and metabolism of fatty acids. ACC produces malonyl CoA, which is both a substrate for fatty acid biosyntheis, and is a potent inhibitor of mitochondrial fatty acid uptake. In lipogenic tissues like the liver, ACC is the rate-limiting enzyme for fatty acid biosynthesis. In muscle, ACC is a key regulator of fatty acid oxidation, secondary to the production of malonyl CoA.
Adipokines
Adipokines is a term that is used to collectively describe a variety of signalling molecules that are released from adipose tissue. Examples of adipokines include adiponectin, and cytokines such as TNF-1α.
Adiponectin
Adiponectin is an adipokine that is released from adipose tissue. It is an important signalling molecule that acts centrally at the level of the hypothalamus to decrease food intake, and peripherally to modify fatty acid and glucose metabolism. Low levels of adiponectin are associated with obesity and insulin resistance.
Ceramides
Ceramides are specialized lipids that are derived from sphingomyelin and glycosphingolipids present in plasma membrane of cells. Various cytokines can release ceramide, which then act as important intracellular signalling molecules. Considerable interest has focused on ceramide as a signalling molecule in apoptosis (programmed cell death).
Dichloroacetate
Dichloroacetate is a molecule that activates pyruvate dehydrogenase (PDH). PDH is the rate-limiting enzyme involved in glucose oxidation. In muscle cells, dichloroacetate activation of PDH results in an increase in glucose oxidation. In the heart, this activation of glucose oxidation has cardioprotective effects during and following ischemia.
18F-labeled 6-thia-hepta-decanoic acid
18F-labeled 6-thia-hepta-decanoic acid is an 18F-labeled fatty acid. It can be used to measure fatty acid metabolism in tissue, by following the myocardial fate of 18F with positron emission tomography (PET) imaging. This tracer has been used for measuring fatty acid metabolism in vivo, including the identification of defects in fatty acid metabolism in subjects with medium- and short-chain fatty acid oxidation defects.
Glycogen synthase kinase 3 (GSK3)
GSK3 is an unusual protein serine/threonine kinase that, as the name implies phosphorylates glycogen synthase. The two mammalian isoforms, GSK-3α and β, play largely overlapping roles and have been implicated in a variety of human pathologies, including type 2 diabetes, Alzheimer's disease, bipolar disorder and cancer. Inhibition of glycogen synthase kinase-3 has been shown to prevent caspase-dependent apoptosis.
Lipid kinase termed PI3-kinase (phosphatidylinositol 3-kinase, PI3-K)
PI3-K is an intracellular kinase involved in a number of important cellular pathways, including glucose metabolism. PI3-K produces PtdIns(3,4,5)-P3, which is part a signalling cascade initiated by a number of different hormones, including insulin.
Leptin
Leptin is a peptide hormone synthesized by adipocytes that plays a key role in the regulation of appetite and energy expenditure. This can occur through direct actions of leptin on the hypothalamus or via direct actions of leptin on peripheral lipid and glucose metabolism.
Mitogen-activated protein kinase (MAPK) cascade
The MAPK cascade involves a number of kinases that have diverse functions in cells. The inflammatory effects of tumor necrosis factor (TNF)-α in cells is mediated by signaling pathways involving MAPK's. pathways. MAP-KAPK-1 (also known as p90 ribosomal S6 kinase, p90rsk).
The mitogen-activated protein kinase (MAPK)-activated kinase, p90 ribosomal S6 kinase is a kinase in the MAPK cascade. p90 ribosomal S6 kinase is activated by phosphorylation, whereby it then participates in many cellular processes, including the regulation of protein synthesis.
Malonyl-CoA
Malonyl CoA is a small molecule synthesized in cells by acetyl CoA carboxylase. Malonyl CoA has an important role in regulating muscle fatty acid oxidation, secondary to inhibiting mitochondrial fatty acid uptake. It also is an important substrate for fatty acid biosynthesis.
Nuclear transcription factor kappa-B (NFk-B)
NFk-B is a ubiquitous transcription factor that plays an important integrating role in the intracellular regulation of immune response, inflammation and cell cycle regulation. NFk-B is activated by various stimuli, such as those that are implicated in the progression of chronic heart failure. Signaling by NFk-B involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus, where it affects gene transcription.
Peroxisome proliferator-activated receptorγ (PPARγ)
Peroxisomal proliferators-activated receptors are nuclear receptors involved in the transcriptional regulation of proteins. One of these nuclear receptors is PPARγ, which modifies the expression of a number of proteins, including those involved in insulin sensitivity and lipid metabolism. Activation of PPARγ is a therapeutic approach to treating diabetes, which may in part be due lowering blood fatty acid levels, secondary to decreasing fatty acid release from adipose tissue.
Phosphorylation
Phosphorylation refers to the process of adding a phosphate group to proteins, usually a tyrosine, serine or threonine residue. This occurs via the action of numerous kinases. Phosphorylation is a very important mechanism that regulates enzyme activity, and is a component of most cellular signaling pathways.
Phosphatidylinositol (4,5) biphosphate (PtdIns(4,5)-P2)
Phosphoinositol-4,5-bisphosphate (PIP2) is an intracellular signalling molecule produced by phosphoinositol-4-phosphate-5-kinase. PIP2 is produced by various stimuli, including activation of the insulin receptor. PIP2 then acts as a substrate for phosphoinositol 3-kinase (PI 3-K) to produce PtdIns(3,4,5)-P3 (see below).
PtdIns(3,4,5)-P3
PtdIns(3,4,5)-P3 is released from membrane phosphatidylinositol as part of a signaling cascade initiated by a number of different hormones, including insulin. PtdIns(3,4,5)-P3 activates downstream targets, such as 3-phosphinositide-dependent kinase-1 (PDK-1). This kinase then acts on downstream kinases such as PKB and protein kinase C to mediate numerous cellular events.
Pleckstrin homology domain
Pleckstrin homology (PH) domains are the 11th most common domain in the human genome, and are best known as domains in an enzyme that have the ability to target cellular membranes by binding specifically to phosphoinositides. Most PH domains are not capable of independent membrane targeting and usually require both phosphoinositide and non-phosphoinositide determinants for their subcellular localization.
Phosphoinositide-dependent protein kinase-1 (PDK-1) and PKB (protein kinase B also known as Akt)
3-phosphinositide-dependent kinase-1 (PDK-1) is a signaling kinase activated by PtdIns(3,4,5)-P3. This kinase then acts on downstream kinases such as PKB and protein kinase C to mediate numerous cellular events. Protein kinase B is an intracellular kinase that is important in regulating glucose metabolism. It is a kinase downstream of PDK-1, and insulin activation of PKB will result in GLUT-4 translocation to the cell membrane, thereby stimulating glucose uptake.
Proto-oncogene Cbl
Cb1 is a protooncogene product that was initially identified as part of a murine retrovirus transforming protein. Cb1 is ubiquitously expressed protein containing a set of sequences providing interactions with a wide range of receptor and nonreceptor tyrosine kinases and signaling proteins. These properties permit Cb1 to take part in many protein-protein interactions as an adaptor, which forms multimolecular signaling complexes, and coordinates the activity of its components.
Peroxisome proliferator-activated receptor α (PPARα)
PPARα is a nuclear receptor involved in the transcriptional regulation of proteins. PPARα has many functions, including regulating the expression of many enzymes involved in the control of fatty acid oxidation in muscle.
Pyruvate dehydrogenase (PDH)
PDH is an intramitochondrial complex that converts pyruvate (which primarily originates from glucose or lactate) into acetyl CoA. PDH is the rat-limiting enzyme for the mitochondrial metabolism of carbohydrates. Maintaining mitochondrial glucose metabolism is an important therapeutic strategy to protect the ischemic heart. Therefore, activating PDH is a potential therapeutic approach to treating heart disease.
6-phosphofructo-2-kinase (PFK-2)
PFK-2 is an enzyme that converts fructose 6-phosphate to fructose 2,6-bisphosphate. Fructose 2,6-bisphosphate is a potent stimulator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. As a result, increasing fructose 2,6-biphosphate is an important mechanism by which glycolysis is regulated.
Thiazolidinediones (TZDs)
TZDs are a class of drugs that act as ligands for PPARγ. An example of a TZD is rosiglitazone. Activation of PPARγ by TZDs can improve muscle insulin sensitivity. They also can have beneficial effects on blood lipids and vascular smooth muscle lipid accumulation.
Tyrosine kinase
Tyrosine kinase is a kinase that phosphorylates tyrosine residues on proteins. Many different tyrosine kinases exist, with an important one being the insulin receptor. Insulin binding to the receptor stimulates a tyrosine kinase to initiate the downstream insulin-signalling pathway.
TC10 family of Rho GTP-binding proteins
The Rho GTPases are related to the Ras proto-oncogenes and consist of 22 family members. These proteins have important roles in regulating the organization of the actin filament system, and thereby the morphogenesis of vertebrate cells as well as their ability to migrate. Signal initiation from the insulin receptor and a series of adapter proteins result in the activation of the G protein TC10. TC10 can influence a number of cellular processes, including changes in the actin cytoskeleton, recruitment of adapter proteins CIP4, and assembly of the exocyst complex. These events play crucial roles in the trafficking, docking and fusion of vesicles containing the insulin-responsive glucose transporter Glut4 at the plasma membrane.
VCAM, ICAM, E-selectin
Vascular cell adhesion molecule (VCAM)-1, intracellular adhesion molecule-1 (ICAM-1) and E-Selectin play a central role in the recruitment of inflammatory cells, and its expression is rapidly induced by proinflammatory cytokines such as TNFalpha. VCAM-1, ICAM-1 and E-Selection also play critical roles in many other processes, such as early atherogenesis.
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