Metabolic Diseases Arrays and Assays

Metabolic Diseases

Metabolism comprises of catabolism and anabolism. Catabolism breaks down organic compounds to generate energy (ATP) through many series of chemical reactions. Anabolism uses energy to construct components of cells such as proteins and nucleic acids. Any factor affecting metabolic process, including the digestive or urinary tracts, enzymes, coenzymes, vitamins, hormones, cytokines, growth factors, minerals, and cofactors, can cause metabolic diseases. To learn how to use QIAGEN’s Glucose Metabolism, Fatty Acid Metabolism, or Energy Metabolism PCR array to study diabetes, obesity and other disorders, see details here.

Glucose homeostasis is regulated by insulin and its counter-regulatory hormone, glucagon. The normal control of glucose metabolism requires not only secretion of insulin but also its action in key target tissues including muscle, liver, and fat. Deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes. Type 1 diabetes results from an autoimmune destruction of the insulin-producing pancreatic beta-cells. Insulin resistance, the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle, etc., is the main cause of type 2 diabetes. Insulin resistance is also a major feature of many common metabolic diseases and has high heritability. Beta-cell dysfunction, which is strongly associated with mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation, is also a critical step in the pathogenesis of type 2 diabetes. The most common forms of diabetes - type 1 and type 2, are polygenic. There is another form of diabetes - monogenic form, in which mutations of a single gene cause diabetes. Monogenic forms of diabetes account for about 1 to 2 percent of all cases of diabetes in young people. Most mutations in monogenic diabetes reduce the body's ability to produce insulin. So far, other than mutations in the insulin receptor, only a single human family (with a mutation in AKT2) has been reported in which a primary defect in the insulin signal transduction pathway leads to a monogenic form of diabetes. QIAGEN's Glucose PCR Array, Insulin Signaling Pathway PCR Array, Diabetes PCR Array, Mitochondria PCR Array, Mitochondrial Energy Metabolism PCR Array, Unfolded Protein Response PCR Array, Inflammatory Cytokines and Receptors PCR Array, and Th17 for Autoimmunity and Inflammation PCR Array can be used to study diabetes.

Lipids include fatty acids, triglycerides (fats), cholesterols, steroid, eicosanoids, phospholipids, sphingolipids, ketone bodies, and glycolipids, etc. Fatty acids, stored as triglycerides, are an important source of energy. Fats or lipids are broken down in the body by enzymes called lipases produced in the pancreas. Lipolysis, the hydrolysis of lipids, breaks down triglycerides into free fatty acids within cells. Growth hormone, cortisol, glucagon, adrenaline, and noradrenaline can induce lipolysis. Fatty acid degradation includes three major steps, all carried out in mitochondria: transport into mitochondria, beta-oxidation, and processing by electron transport chain. The liver acts as a major organ for fatty acid processing, generating various water soluble lipoprotein forms, in particular very-low-density lipoprotein (VLDL) and low-density-lipoprotein (LDL). Fatty acids synthesized by the liver are converted to triglyceride and transported to the blood as VLDL. High-density lipoprotein (HDL) collects cholesterol, glycerol and fatty acids from the blood and transports them to the liver. QIAGEN's Mitochondria PCR Array, Mitochondrial Energy Metabolism PCR Array, Fatty Acids Metabolism PCR Array, and Lipoprotein Signaling and Cholesterol Metabolism PCR Array can be used to study lipid and energy metabolism.

High plasma concentrations of glucose and lipid contribute to pancreatic beta-cell dysfunction. People with type 2 diabetes are very often obese or overweight. Obesity, even in non-diabetic individuals, tends to lead to a state of insulin resistance. Even in the absence of hyperglycemia (high blood sugar), insulin resistance is strongly associated with, and may even have a causative role in, atherosclerosis, dyslipidaemia (abnormal amounts of lipids or lipoproteins in the blood), hypertension, non-alcoholic steatohepatitis ("steato", meaning fat), and polycystic ovarian syndrome.

Many hormones and peptides have been found to cause obesity. Leptin is one of the most important adipose-derived hormones. It acts on receptors in the hypothalamus of the brain where it inhibits appetite. Since leptin's discovery, ghrelin, orexin, PYY 3-36, cholecystokinin, adiponectin, as well as many other mediators have been studied. Obesity is now considered as a chronic low-grade inflammation. TNF-alpha, a pivotal pro-inflammatory cytokine in the inflammatory cascade, is expressed and secreted by adipose tissue with its level correlating to the degree of adiposity and the associated insulin resistance. The chronic inflammatory response caused by obesity, and the enhanced production of IL-6 and TNF can even increase the risk of developing cancers, especially liver cancer. Please use QIAGEN's Inflammatory Cytokines and Receptors PCR Array, TNF Ligands and Receptors PCR Array, Obesity PCR Array, and Liver Cancer Methylation PCR Array to study obesity and liver cancer.

A few kinases, including IKK-beta, JNK, ERK, mTOR, and S6K, can be activated by the inducers of insulin resistance. These kinases integrate signals from metabolic and inflammatory stresses in adipose tissue, liver, and hypothalamus, leading to insulin resistance. mTOR (mammalian Target of Rapamycin) is a conserved serine-threonine protein kinase that integrates growth factor, amino acid, nutrient, and energy sensing signals. mTOR controls lipid biosynthesis. It contributes to the development of obesity, insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease. Inhibition of mTOR can extend lifespan in both invertebrates and vertebrates. Moreover, IKK-beta/NF-kappaB and JNK1 pathways represent a core mechanism involved in inflammation linked to obesity.

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions (response elements) on the DNA. PPARs are key regulators of metabolism. Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPAR gamma coactivator-1 alpha (PGC-1 alpha) is a transcriptional regulator for genes involved in mitochondrial biogenesis, fatty acid oxidation, and gluconeogenesis.

5' adenosine monophosphate-activated protein kinase (AMPK) has energy-sensing capability attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio during rest and exercise. AMPK therefore acts as a metabolic master switch regulating the uptake of glucose, the beta-oxidation of fatty acids, and the biogenesis of metabolic molecules.

Histone deacetylases such as sirtuins (SIRTs), the NAD(+)-dependent deacetylases that regulate the binding of transcription factors, mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. SIRTs are located in nucleus, cytoplasm, and mitochondria. SIRT1 has been proposed as a promising new therapeutic target for the treatment of type 2 diabetes. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the PGC-1 alpha, the forkhead box O1 (FOXO1), and O3 (FOXO3) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism. SIRT3 is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes. During fasting, livers from mice lacking both SIRT3 alleles have higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Acetylation is therefore a novel mechanism for regulating mitochondrial fatty-acid oxidation. All together, QIAGEN's mTOR Signaling PCR Array, NFkB Signaling PCR Array, MAPK Signaling PCR Array, Nuclear Receptors and Coregulators PCR Array, and ChIP-qPCR Arrays can be used to explore the mechanisms of different metabolic disorders.