Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is not associated with weight gain and is taken by mouth. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics.
Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.
Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.
Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.
Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.
Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.
Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.
Enzyme activators are molecules that bind to enzymes and increase their activity. They are the opposite of enzyme inhibitors. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism. An example of an enzyme activator working in this way is fructose 2,6-bisphosphate, which activates phosphofructokinase 1 and increases the rate of glycolysis in response to the hormone glucagon. In some cases, when a substrate binds to one catalytic subunit of an enzyme, this can trigger an increase in the substrate affinity as well as catalytic activity in the enzyme's other subunits, and thus the substrate acts as an activator.
Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.
PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.
Tribbles homolog 3 is a protein that in humans is encoded by the TRIB3 gene.
Melior Discovery, Inc. is a private biopharmaceutical company based in Exton, Pennsylvania, USA. The company specializes in drug repositioning and has established a proprietary phenotypic screening platform that it uses for this purpose. Melior also offers certain contract research organization (CRO) services comprising animal models representing different disease conditions. The Company has issued press releases disclosing partnerships with Pfizer, Merck & Co., Johnson & Johnson, and AstraZeneca, all citing the use of the company’s drug repositioning technology. Melior Discovery has also used its technology to discover its own drug candidates.
Darglitazone is a member of the thiazolidinedione class of drugs and an agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), an orphan member of the nuclear receptor superfamily of transcription factors. It has a variety of insulin-sensitizing effects, such as improving glycemic and lipidemic control, and was researched by Pfizer as a treatment of metabolic disorders such as type 2 diabetes mellitus.
Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner. Phenotypic screening must be followed up with identification and validation, often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.
Celastrol (tripterine) is a chemical compound isolated from the root extracts of Tripterygium wilfordii and Tripterygium regelii. Celastrol is a pentacyclic nortriterpen quinone and belongs to the family of quinone methides. In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy. Also in mice, celastrol increase expression of IL1R1, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.
Chinmoy Sankar Dey is an Indian molecular biologist and a professor at Kusuma School of Biological Sciences of the Indian Institute of Technology, Delhi. Known for his research on insulin resistance, Dey's is a J. C. Bose National Fellow of the Department of Science and Technology and an elected fellow of the National Academy of Sciences, India and the Indian National Science Academy. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards for his contributions to Medical Sciences in 2003. He is also a recipient of the National Bioscience Award for Career Development of the Department of Biotechnology.
ADX71743 is a drug which acts as a potent and selective negative allosteric modulator of the metabotropic glutamate receptor 7. Few selective ligands are available for this receptor, and so ADX71743 has played an important role into scientific research into the role of this receptor in various processes such as memory formation, nociception, absence seizures and psychosis.
