A Review on Metformin: Clinical Significance and Side Effects

Metformin is a biguanide that has been used extensively worldwide for the treatment of type II diabetes mellitus. It improves glycaemic control by enhancing insulin sensitivity in liver and muscle. An advantage of metformin treatment is the tendency of weight reduction and the absence of significant hypoglycaemia; blood glucose levels are reduced only to normal as it does not stimulate insulin secretion. Metformin also has a beneficial effect on several cardiovascular risk factors including dyslipidemia, elevated plasminogen activator inhibitor 1 levels, other fibrinolytic abnormalities, hyperinsulinemia, and insulin resistance. Metformin enhances muscle and adipocyte insulin receptor number and/or affinity, increases insulin receptor tyrosine kinase activity, stimulates glucose transport and glycogen synthesis, and reduces both hepatic gluconeogenesis and glycogenolysis. The disadvantages are confined to the gastro-intestinal side effects and the potential risk of vitamin B 12 and folic acid deficiency during long-term use. These side effects can be minimized by slow titration and consumption with meals. The under lying mechanism for gastrointestinal intolerance are proposed to be stimulation of intestinal secretion of serotonin, alteration in incretin and metabolism of glucose, and malabsorption of bile salts. Lactic acidosis is rare contraindication associated with metformin. Most reported cases of lactic acidosis occur in patients with contraindications, particularly impaired renal function. Metformin has a good safety profile, efficacy and comparatively reduced cost. Its ability to improve insulin sensitivity and the cardiovascular risk profile of type II diabetic patients has enhanced its clinical use as first-line therapy.

Upregulated insulin receptor tyrosine kinase substrate promotes the proliferation of colorectal cancer cells via the bFGF/AKT signaling pathway

Background Some recent studies on insulin receptor tyrosine kinase substrate (IRTKS) have focused more on its functions in diseases. However, there is a lack of research on the role of IRTKS in carcinomas and its mechanism remains ambiguous. In this study, we aimed to clarify the role and mechanism of IRTKS in the carcinogenesis of colorectal cancer (CRC). Methods We analysed the expression of IRTKS in CRC tissues and normal tissues by researching public databases. Cancer tissues and adjacent tissues of 67 CRC patients who had undergone radical resection were collected from our center. Quantitative real-time polymerase chain reaction and immunohistochemistry were performed in 52 and 15 pairs of samples, respectively. In vitro and in vivo experiments were conducted to observe the effect of IRTKS on CRC cells. Gene Set Enrichment Analysis and Metascape platforms were used for functional annotation and enrichment analysis. We detected the protein kinase B (AKT) phosphorylation and cell viability of SW480 transfected with small interfering RNAs (siRNAs) with or without basic fibroblast growth factor (bFGF) through immunoblotting and proliferation assays. Results The expression of IRTKS in CRC tissues was higher than that in adjacent tissues and normal tissues (all P < 0.05). Disease-free survival of patients with high expression was shorter. Overexpression of IRTKS significantly increased the proliferation rate of CRC cells in vitro and the number of tumor xenografts in vivo. The phosphorylation level of AKT in CRC cells transfected with pLVX-IRTKS was higher than that in the control group. Furthermore, siRNA-IRTKS significantly decreased the proliferation rate of tumor cells and the phosphorylation level of AKT induced by bFGF. Conclusion IRTKS mediated the bFGF-induced cell proliferation through the phosphorylation of AKT in CRC cells, which may contribute to tumorigenicity in vivo.

Arthropod IGF, relaxin and gonadulin, putative orthologs of Drosophila insulin-like peptides 6, 7 and 8, likely originated from an ancient gene triplication

Background Insects have several genes coding for insulin-like peptides and they have been particularly well studied in Drosophila. Some of these hormones function as growth hormones and are produced by the fat body and the brain. These act through a typical insulin receptor tyrosine kinase. Two other Drosophila insulin-like hormones are either known or suspected to act through a G-protein coupled receptor. Although insulin-related peptides are known from other insect species, Drosophila insulin-like peptide 8, one that uses a G-protein coupled receptor, has so far only been identified from Drosophila and other flies. However, its receptor is widespread within arthropods and hence it should have orthologs. Such putative orthologs were recently identified in decapods and have been called gonadulins. Methodology In an effort to identify gonadulins in other arthropods public genome assemblies and short-read archives from insects and other arthropods were explored for the presence of genes and transcripts coding insulin-like peptides and their putative receptors. Results Gonadulins were detected in a number of arthropods. In those species for which transcriptome data from the gonads is available insect gonadulin genes are expressed in the ovaries and at least in some species also in the testes. In some insects differences in gonadulin expression in the ovary between actively reproducing and non-reproducing females differs more than 100-fold. Putative orthologs of Drosophila ilp 6 were also identified. In several non-Dipteran insects these peptides have C-terminally extensions that are alternatively spliced. The predicted peptides have been called arthropod insulin-like growth factors. In cockroaches, termites and stick insects genes coding for the arthropod insulin-like growth factors, gonadulin and relaxin, a third insulin-like peptide, are encoded by genes that are next to one another suggesting that they are the result of a local gene triplication. Such a close chromosomal association was also found for the arthropod insulin-like growth factor and gonadulin genes in spiders. Phylogenetic tree analysis of the typical insulin receptor tyrosine kinases from insects, decapods and chelicerates shows that the insulin signaling pathway evolved differently in these three groups. The G-protein coupled receptors that are related to the Drosophila ilp 8 receptor similarly show significant differences between those groups. Conclusion A local gene triplication in an early ancestor likely yielded three genes coding gonadulin, arthropod insulin-like growth factor and relaxin. Orthologs of these genes are now commonly present in arthropods and almost certainly include the Drosophila insulin-like peptides 6, 7 and 8.

Arthropod IGF, Relaxin and Gonadulin, putative orthologs of Drosophila insulin-like peptides 6, 7 and 8, likely originated from an ancient gene triplication

BackgroundInsects have several genes coding for insulin-like peptides and they have been particularly well studied in Drosophila. Some of these hormones function as growth hormones and are produced by the fat body and the brain. These act through a typical insulin receptor tyrosine kinase. Two other Drosophila insulin-like hormones are either known or suspected to act through a G-protein coupled receptor. Although insulin-related peptides are known from other insect species, Drosophila insulin-like peptide 8, one that uses a G-protein coupled receptor, has so far only been identified from Drosophila and other flies. However, its receptor is widespread within arthropods and hence it should have orthologs. Such putative orthologs were recently identified in decapods and have been called gonadulins.MethodologyIn an effort to identify gonadulins in other arthropods public genome assemblies and short-read archives from insects and other arthropods were explored for the presence of genes and transcripts coding insulin-like peptides and their putative receptors.ResultsGonadulins were detected in a number of arthropods. In those species for which transcriptome data from the gonads is available insect gonadulin genes are expressed in the ovaries and at least in some species also in the testes. In some insects differences in gonadulin expression in the ovary between actively reproducing and non-reproducing females differs more than 100-fold. Putative orthologs of Drosophila ilp 6 were also identified. In several non-Dipteran insects these peptides have C-terminally extensions that are alternatively spliced. The predicted peptides have been called arthropod insulin-like growth factors. In cockroaches, termites and stick insects genes coding for the arthropod insulin-like growth factors, gonadulin and relaxin, a third insulin-like peptide, are encoded by genes that are next to one another suggesting that they are the result of a local gene triplication. Such a close chromosomal association was also found for the arthropod insulin-like growth factor and gonadulin genes in spiders. Phylogenetic tree analysis of the typical insulin receptor tyrosine kinases from insects, decapods and chelicerates shows that the insulin signaling pathway evolved differently in these three groups. The G-protein coupled receptors that are related to the Drosophila ilp 8 receptor similarly show significant differences between those groups.ConclusionA local gene triplication in an early ancestor likely yielded three genes coding gonadulin, arthropod insulin-like growth factor and relaxin. Orthologs of these genes are now commonly present in arthropods and almost certainly include the Drosophila insulin-like peptides 6, 7 and 8.

Molecular Docking Studies and Pharmacophore Modeling of Some Insulin Mimetic Agents from Herbal Sources: A Rational Approach towards Designing of Orally Active Insulin Mimetic Agents

Background:: Many herbal drugs have been found to possess oral insulin mimetic property as evidenced from the literature. Although, to date there is no efficient, synthetic orally active insulin-mimetic drug available clinically. Computer-Aided Drug Design (CADD) may help in the development of such agents through Pharmacophore modeling. Objective:: The present work is aimed at the In-silico designing of Pharmacophore that defines the structural requirements of a molecule to possess oral insulin-mimetic properties. Methods:: A set of 16 orally active insulin-mimetic natural compounds available through literature was used to develop a structure-based pharmacophore in a “three-step filtration process” comprised of Lipinski’s rule of 5, Minimum binding energy with the receptor and Ghose filter to the Lipinski’s rule for oral bioavailability of the drugs. The selected ligands were docked with phosphorylated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog (PDB ID: 1IR3) using Autodock 4.2 and their interaction with the receptor was analyzed followed by the generation of shared and merged feature pharmacophore by Ligandscout 4.2.1. Results:: There are three important structural features that contribute to interaction with the active site of the insulin receptor: these are hydrogen bond donor groups, hydrogen bond acceptor groups and hydrophobic interactions. It is important to note that positive or negative ionizable groups or the presence of aromatic rings are not important for the activity. Conclusion:: Taking a clue from the developed pharmacophore, one may design new lead having necessary groups required for the insulin-mimetic activity that can be elaborated synthetically to get a series of compounds with possible oral insulin-mimetic activity.

IRTKS Promotes Insulin Signaling Transduction through Inhibiting SHIP2 Phosphatase Activity

Insulin signaling is mediated by a highly integrated network that controls glucose metabolism, protein synthesis, cell growth, and differentiation. Our previous work indicates that the insulin receptor tyrosine kinase substrate (IRTKS), also known as BAI1-associated protein 2-like 1 (BAIAP2L1), is a novel regulator of insulin network, but the mechanism has not been fully studied. In this work we reveal that IRTKS co-localizes with Src homology (SH2) containing inositol polyphosphate 5-phosphatase-2 (SHIP2), and the SH3 domain of IRTKS directly binds to SHIP2’s catalytic domain INPP5c. IRTKS suppresses SHIP2 phosphatase to convert phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3, PIP3) to phosphatidylinositol (3,4) bisphosphate (PI(3,4)P2). IRTKS-knockout significantly increases PI(3,4)P2 level and decreases cellular PI(3,4,5)P3 content. Interestingly, the interaction between IRTKS and SHIP2 is dynamically regulated by insulin, which feeds back and affects the tyrosine phosphorylation of IRTKS. Furthermore, IRTKS overexpression elevates PIP3, activates the AKT–mTOR signaling pathway, and increases cell proliferation. Thereby, IRTKS not only associates with insulin receptors to activate PI3K but also interacts with SHIP2 to suppress its activity, leading to PIP3 accumulation and the activation of the AKT–mTOR signaling pathway to modulate cell proliferation.

Hepatic Insulin Clearance: Mechanism and Physiology

Upon its secretion from pancreatic β-cells, insulin reaches the liver through the portal circulation to exert its action and eventually undergo clearance in the hepatocytes. In addition to insulin secretion, hepatic insulin clearance regulates the homeostatic level of insulin that is required to reach peripheral insulin target tissues to elicit proper insulin action. Receptor-mediated insulin uptake followed by its degradation constitutes the basic mechanism of insulin clearance. Upon its phosphorylation by the insulin receptor tyrosine kinase, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) takes part in the insulin-insulin receptor complex to increase the rate of its endocytosis and targeting to the degradation pathways. This review summarizes how this process is regulated and how it is associated with insulin-degrading enzyme in the liver. It also discusses the physiological implications of impaired hepatic insulin clearance: Whereas reduced insulin clearance cooperates with increased insulin secretion to compensate for insulin resistance, it can also cause hepatic insulin resistance. Because chronic hyperinsulinemia stimulates hepatic de novo lipogenesis, impaired insulin clearance also causes hepatic steatosis. Thus impaired insulin clearance can underlie the link between hepatic insulin resistance and hepatic steatosis. Delineating these regulatory pathways should lead to building more effective therapeutic strategies against metabolic syndrome.

THE ASSOCIATION BETWEEN THE GLY972ARG POLYMORPHISM IN IRS1 GENE AND THE RISK OF PREDIABETES AMONG VIETNAMESE WOMEN

Insulin receptor substrate 1 (IRS1) is a ligand of the insulin receptor tyrosine kinase and participates in the insulin receptor signal transduction pathway. Dysregulations in IRS1 expression and function increase incidence of insulin-resistant states such as prediabetes and type 2 diabetes. The study aimed to investigate the association of the Gly972Arg (rs1801278) polymorphism in IRS1 gene with prediabetes in Northern Vietnamese women. The case-control study consisted of 1617 women (250 prediabetic cases and 1367 normoglycemic controls). The IRS1 Gly972Arg polymorphism was genotyped in these subjects using polymerase chain reaction–restriction fragment length polymorphism. The frequency of the ‘‘A’’ allele of the Gly972Arg (G>A) polymorphism was similar between the normal glucose and prediabetic subjects (2.7% and 2.6%, respectively). There was no significant difference in the genotypic frequency between the control and prediabetic cases (P = 0.673). The IRS1 Gly972Arg polymorphism was not associated with the risk of prediabetes in Vietnamese women before and after adjusted for socio-economic, lifestyles and clinical factors (P > 0.05).