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Insulin Has Which Metal

Metal Ions Affect Insulin-degrading Enzyme Activity

Metal Ions Affect Insulin-degrading Enzyme Activity

Abstract Insulin degradation is a finely tuned process that plays a major role in controlling insulin action and most evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, the biomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure, rendering the specific enzyme activity quite difficult to target. On the other hand, biometals, such as copper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer's disease or diabetes mellitus. The metabolic disorders connected with the latter lead to some metallostasis alterations in the human body and many studies point at a high level of interdependence between diabetes and several cations. We have previously reported (Grasso et al., Chem. Eur. J. 17 (2011) 2752-2762) that IDE activity toward Aβ peptides can be modulated by metal ions. Here, we have investigated the effects of different metal ions on the IDE proteolytic activity toward insulin as well as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very low affinity for metal ions. The results obtained by different experimental techniques clearly show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II). Continue reading >>

A Metal Present In Insulin Is?

A Metal Present In Insulin Is?

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Metals In The Pathogenesis Of Type 2 Diabetes

Metals In The Pathogenesis Of Type 2 Diabetes

Go to: Abstract Minerals are one of the components of food, though they are not synthesized in the body but they are essential for optimal health. Several essential metals are required for the proper functioning of many enzymes, transcriptional factors and proteins important in various biochemical pathways. For example Zn, Mg and Mn are cofactors of hundreds of enzymes, and Zn is involved in the synthesis and secretion of insulin from the pancreatic beta-cells. Similarly, Cr enhances the insulin receptor activity on target tissues, especially in muscle cells. Insulin is the key hormone required to maintain the blood glucose level in normal range. In case of insulin deficiency or resistance, blood glucose concentration exceeds the upper limit of the normal range of 126 mg/dl. Persistent increase of blood serum glucose level leads to overt chronic hyperglycemia, which is a major clinical symptom of diabetes mellitus. Poor glycemic control and diabetes alters the levels of essential trace elements such as Zn, Mg, Mn, Cr, Fe etc. by increasing urinary excretion and their concomitant decrease in the blood. Hence, the main purpose of this review is to discuss the important roles of essential trace elements in normal homeostasis and physiological functioning. Moreover, perturbation of essential trace elements is also discussed in perspective of type 2 diabetes pathobiology. Keywords: Diabetes, Essential metals, Toxic metals, Insulin, Zinc Go to: Introduction Metals and type 2 diabetes (T2D) Metals are naturally occurring inorganic elements which are present in very small amounts in the living tissues but are important for the vital processes of life [1]. Some metals (e.g. magnesium) are known as macro-metals and are found in high amount in the body tissues, therefore they are Continue reading >>

Thermodynamics Of Formation Of The Insulin Hexamer: Metal-stabilized Proton-coupled Assembly Of Quaternary Structure

Thermodynamics Of Formation Of The Insulin Hexamer: Metal-stabilized Proton-coupled Assembly Of Quaternary Structure

Abstract The thermodynamics of formation of the insulin hexamer, which is stabilized by two Zn2+ ions, were quantified by isothermal titration calorimetry (ITC). Because the insulin monomer is unstable to aggregation (fibrillation) during ITC measurements, an original method involving EDTA chelation of Zn2+ from the hexamer was employed. The two metal ions are chelated sequentially, reflecting stepwise Zn2+ binding and stabilization of the quaternary structure. Analysis of the ITC data reveals that two to three H+ bind to the hexamer upon its formation at pH 7.4, which is both enthalpically and entropically favored. The former is due to Zn2+ coordination to His residues from three subunits, and the latter is associated with desolvation that accompanies the protonation and the packing of the subunits in the hexamer. Continue reading >>

Electron Paramagnetic Resonance In Single Crystals Of Cupric Insulin

Electron Paramagnetic Resonance In Single Crystals Of Cupric Insulin

THE binding of divalent metal ions to insulin has been the subject of several investigations, both chemical and physical in nature1–6. In describing here the application of electron paramagnetic resonance (EPR) spectroscopy to this problem, we wish to emphasize the richness of the data obtainable from orientation investigations of single crystals. This information is of the following kinds: (1) the number of distinct magnetic centres; (2) the orientation with respect to the crystal axes of the symmetry axes of the magnetic centres; (3) the symmetries of the protein environments of the magnetic centres, and the ground-states of the transition metal ions; (4) the delocalization of the electrons in metal ion–protein bonds; (5) identification of protein atoms bound to metal ions when the former have nuclear magnetic moments; (6) an estimate of the distance between metal ions. Continue reading >>

Effect Of Chromium And Zinc On Insulin Signaling In Skeletal Muscle Cells

Effect Of Chromium And Zinc On Insulin Signaling In Skeletal Muscle Cells

Abstract Patients on total parenteral nutrition without Cr supplementation develop symptoms similar to those of diabetes. Zn has been implicated in diabetes because of its antioxidant properties and interaction with insulin. To study the effect of these metal ions on insulin signaling proteins, cultured mouse skeletal muscle cells was used as an in vitro model, as the tissue accounts for more than 80% of insulin-stimulated glucose disposal in the body. In the present study, it has been observed that both Cr and Zn, upon prolonged exposure, could stimulate tyrosine phosphorylation of insulin receptor (IR) even in the absence of insulin. Insulin-mediated IR tyrosine phosphorylation was enhanced by the treatment with both of the metal ions. Both Cr and Zn could phosphorylate, insulin receptor substrate-1 (IRS-1). Phosphorylation of IRS-1 induced by metal ions was higher than that induced by insulin. Hence, both Cr and Zn were found to have insulin mimetic activity. Both of the metal ions were also found to potentiate insulin-mediated activation of IRS-1. The basal level of glucose uptake was also increased by prolonged treatment of the cells with the metal ions. The ions could also enhance the insulin-stimulated glucose uptake into the cells. Therefore, both Zn and Cr seem to have a positive effect on insulin signaling leading to glucose uptake. Preview Unable to display preview. Download preview PDF. Continue reading >>

The Relationship Between Zinc And Insulin Signaling: Implications For Type 2 Diabetes

The Relationship Between Zinc And Insulin Signaling: Implications For Type 2 Diabetes

Type 2 diabetes (T2D) is a debilitating metabolic disorder that is typically characterized by chronic hyperglycaemia and is concomitant with a range of other complications including cardiovascular disease, stroke, peripheral neuropathy, and renal disease [1]. The aetiology of T2D is highly complex and reflects multifaceted interactions with genetics and the environment, and thus requires a multipronged approach to develop better management and treatments options that are more patient tolerable. These are urgently needed to reduce the clinical symptoms and features of the disease. In this perspective, emerging research on insulin signaling processes associated with T2D has suggested that zinc is a novel metal ion that plays a critical role in the insulin signaling cascade and thus, could be utilized for therapeutic utility. Zinc is an essential ion that has a vital role in numerous enzymatic reactions and is critical for immunity, growth and development, and metabolism [2]. Recent studies have emphasized zinc as having a dynamic role in cell signaling transduction pathways in the control of insulin signaling transduction and glycaemic control [3]. Accordingly, aberrant zinc signaling is associated with a range of life-threatening diseases such as cancer, heart disease and stroke, Alzheimer’s disease, and T2D [4]. In cellular homeostasis, the activity of bioactive zinc requires that the delivery of this metal ion to tissues and cells, its intracellular bioavailability and distribution are tightly controlled. These processes are modulated by a family of transmembrane zinc transporter proteins that regulate the uptake, distribution and storage of zinc and are designated as the zinc importers (SLC39/ ZIPs; or ZIP1-14), and zinc exporters (SLC30/ZnTs; or ZnT1-10) [5]. Of th Continue reading >>

Towards Accurate Structural Characterization Of Metal Centres In Protein Crystals: The Structures Of Ni And Cu T6 Bovine Insulin Derivatives

Towards Accurate Structural Characterization Of Metal Centres In Protein Crystals: The Structures Of Ni And Cu T6 Bovine Insulin Derivatives

1. Introduction Within the field of protein crystallography, an increased understanding of radiation damage from X-rays has developed throughout the last decade (Sliz et al., 2003; Ravelli & Garman, 2006; Garman & Nave, 2009). In particular, metal centres in metalloproteins are sensitive to radiation damage, and for redox-active proteins in which transition metals are actively involved it is crucial that the metal centres are accurately characterized for correct interpretation of the function of the protein. In X-ray structures, photoreduction of metal centres and the subsequent radiation damage is a well known problem when high-intensity synchrotron radiation (SR) is used. The detailed structure around a metal atom is often distorted owing to radiation damage, which means that looking for loosely bound water molecules in an active site, or determining the detailed coordination geometry of the metal, is not always possible from diffraction experiments, even at high resolution. Complementary techniques to X-ray diffraction (XRD) are thus required to extract information about the metal identity, ligation and redox states. The development of multifunctional beamlines which combine macromolecular crystallography with spectroscopy has facilitated single-crystal spectroscopy experiments on protein crystals with concurrent collection of crystallographic data (Antonyuk & Hough, 2011; Pearson & Owen, 2009; De la Mora-Rey & Wilmot, 2007). Among the spectroscopies used in combination with XRD are X-ray absorption spectroscopy (XAS; Arcovito & della Longa, 2012; Cotelesage et al., 2012; Yano & Yachandra, 2008; Strange et al., 2005; Hasnain & Strange, 2003), UV–visible absorption spectroscopy (Hersleth & Andersson, 2011; Ellis et al., 2008; Pearson et al., 2004) and Raman spectros Continue reading >>

Evaluation Of Insulin-mimetic Trace Metals As Insulin Replacements In Mammalian Cell Cultures

Evaluation Of Insulin-mimetic Trace Metals As Insulin Replacements In Mammalian Cell Cultures

Insulin is involved in a number of cellular functions, including the stimulation of cell growth, cell cycle progression and glucose uptake and is a common protein supplement in serum-free mammalian cell culture media. However, several trace metals have previously been reported to exhibit insulin-like effects on specific cell types. As a step towards developing chemically-defined, protein-free media for mammalian cells, we tested the effectiveness of five trace metals (cadmium, nickel, lithium, vanadium and zinc) as a replacement for insulin. Four cell lines of biotechnological relevance were used, including the hybridoma CRL1606, the myeloma NS0, and the Chinese hamster ovary cell lines CHO-IFN and CHO-K1. Zinc was found to be an effective insulin replacement for the hybridoma, myeloma and CHO-K1 cells. Cell growth, cell cycle progression and antibody production was not affected by the substitution. Furthermore, no adaptation procedure was required. Keywords: Insulin, Mammalian cell culture, Protein-free medium, Trace metals, Zinc Full Text Selected References These references are in PubMed. This may not be the complete list of references from this article. Continue reading >>

Affinity Of Zinc And Copper Ions For Insulin Monomers

Affinity Of Zinc And Copper Ions For Insulin Monomers

Zinc is an essential trace element involved in the correct packing and storage of insulin. Total zinc content in the pancreatic β-cells is among the highest in the body and changes in the Zn2+ levels have been found to be associated with diabetes. The most common form of the Zn–insulin complex is a hexamer containing two zinc ions. However, zinc can also form other complexes with insulin, whereas dissociation constants of these complexes are not known. We have determined that the dissociation constant value of the monomeric 1 : 1 Zn–insulin complex is equal to 0.40 μM. The apparent binding affinity decreases drastically at higher insulin concentrations where the peptide forms dimers. Cu2+ ions also bind to monomeric insulin, whereas the apparent Cu2+-binding affinity depends on HEPES concentration. The conditional dissociation constant of the Cu2+–insulin complex is equal to 0.025 μM. The analysis demonstrates that insulin cannot form complexes with zinc ions in circulation due to the low concentration of free Zn2+ in this environment. Continue reading >>

Insulin-like Growth Factor-independent Effects Mediated By A C-terminal Metal-binding Domain Of Insulin-like Growth Factor Binding Protein-3*

Insulin-like Growth Factor-independent Effects Mediated By A C-terminal Metal-binding Domain Of Insulin-like Growth Factor Binding Protein-3*

Abstract Insulin-like growth factors (IGFs) play a central role in the integration of proliferative and survival responses of most mammalian cell types. IGF-binding protein-3 (IGFBP-3) influences IGF action directly as a carrier of IGFs but also modulates these actions indirectly via independent mechanisms involving interactions with plasma, extracellular matrix and cell surface molecules, conditional proteolysis, cellular uptake, and nuclear transport. Here we demonstrate that a short C-terminal metal-binding domain (MBD) of IGFBP-3 mediates binding to metals. MBD epitopes, sequestered in the intact molecule, are unmasked by incubation in the presence of ferrous (but not ferric or zinc) ions. An isolated 14-mer MBD peptide triggered apoptotic effects in stressed HEK293 cells as effectively as IGFBP-3. The MBD, which encompasses a nuclear localization sequence and an adjacent putative caveolin-binding sequence, mobilizes rapid cellular uptake and nuclear localization of unrelated proteins such as green fluorescent protein and streptavidin-horseradish peroxidase conjugate. Metal ions stimulate MBD-mediated cellular/nuclear uptake in vivo. Cross-linking studies showed a direct physical interaction of MBD with integrins αv and β1, caveolin-1, and transferrin receptor. MBD-mediated protein mobilization and pro-apoptotic effects are inhibited by nystatin but not chlorpromazine, suggesting an involvement of caveolar-mediated endocytosis. However, MBD effects are inhibited by antibodies to transferrin receptor or integrins. These results are discussed with particular reference to the cell target specificity of IGFBP-3 in disease processes such as cancer and atherosclerosis. Continue reading >>

Synthesis And Insulin-mimetic Activities Of Metal Complexes With 3-hydroxypyridine-2-carboxylic Acid

Synthesis And Insulin-mimetic Activities Of Metal Complexes With 3-hydroxypyridine-2-carboxylic Acid

Abstract Metal complexes of 3-hydroxypyridine-2-carboxylic acid (H2hpic), [Co(Hhpic)2(H2O)2] (1), [Fe(Hhpic)2(H2O)2] (2), [Zn(Hhpic)2(H2O)2] (3), [Mn(Hhpic)2(H2O)2] (4), and [Cu(Hhpic)2] (5) have been synthesized and characterized by mass spectrometry, elemental analysis, magnetic susceptibility, infrared, electronic absorption and electron paramagnetic resonance (EPR) spectroscopies. The solid-state structure of 1 has been established by X-ray crystallography. The EPR spectra of 4 and 5 displayed six and four-line hyperfine splitting patterns, respectively, due to coupling of the unpaired electron with the 55Mn (I = 5/2) nucleus and the 63Cu (I = 3/2) nucleus. In the EPR spectrum of 5, an additional five-line super-hyperfine splitting pattern was observed at 77 K, caused by additional interaction of the unpaired electron with ligand nitrogen atoms (I = 1), indicating that the structure of 5 was retained in dimethyl sulfoxide solution. The insulin-mimetic activity of these complexes was evaluated by means of in vitro measurements of the inhibition of free fatty acid (FFA) release from epinephrine-treated, isolated rat adipocytes. Complex 5 was found to exhibit the most potent insulin-mimetic activity among the complexes examined in this study. Continue reading >>

Choosing And Using An Insulin Pump Infusion Set

Choosing And Using An Insulin Pump Infusion Set

When a person uses an insulin pump to control his diabetes, one of the decisions he has to make is what model of infusion set to use. Pumps are often an excellent choice for people who use insulin and seek tight control of their diabetes but need some flexibility in their diabetes regimen. Most insulin pumps require the use of an infusion set to deliver insulin from the pump to the user. An infusion set consists of a length of thin plastic tubing, a very thin stainless steel or Teflon cannula that is inserted just under the skin, and a plastic connector that joins tubing and cannula together. The connector is generally mounted on an adhesive patch that is stuck to the skin at the insertion site to help keep the cannula in place. The connector allows a person to disconnect from his pump temporarily (for swimming, intimate situations, etc.) without removing the infusion set. Insulin infusion sets come in a variety of styles to suit individuals’ unique needs and preferences. In addition to having either a Teflon or steel cannula, infusion sets may be designed to have the cannula inserted straight into the subcutaneous tissue or at an angle. Some cannulas can only be inserted manually, while others can be inserted either manually or with an insertion device. All infusion sets offer a variety of tubing lengths. Teflon versus steel cannula A “soft” cannula is a thin, flexible needle made of the synthetic substance Teflon that is inserted into the subcutaneous tissue via a steel introducer needle. The introducer needle is then removed and only the soft cannula is left in place. Soft cannula sets are popular because they are comfortable to wear and they can remain inserted for up to 72 hours. One disadvantage of the soft cannula, however, is that its flexibility can poten Continue reading >>

Evaluation Of Insulin-mimetic Trace Metals As Insulin Replacements In Mammalian Cell Cultures

Evaluation Of Insulin-mimetic Trace Metals As Insulin Replacements In Mammalian Cell Cultures

Abstract Insulin is involved in a number of cellular functions, including the stimulation of cell growth, cell cycle progression and glucose uptake and is a common protein supplement in serum-free mammalian cell culture media. However, several trace metals have previously been reported to exhibit insulin-like effects on specific cell types. As a step towards developing chemically-defined, protein-free media for mammalian cells, we tested the effectiveness of five trace metals (cadmium, nickel, lithium, vanadium and zinc) as a replacement for insulin. Four cell lines of biotechnological relevance were used, including the hybridoma CRL1606, the myeloma NS0, and the Chinese hamster ovary cell lines CHO-IFN and CHO-K1. Zinc was found to be an effective insulin replacement for the hybridoma, myeloma and CHO-K1 cells. Cell growth, cell cycle progression and antibody production was not affected by the substitution. Furthermore, no adaptation procedure was required. Continue reading >>

Insulin-metal Ion Interactions: The Binding Of Divalent Cations To Insulin Hexamers And Tetramers And The Assembly Of Insulin Hexamers.

Insulin-metal Ion Interactions: The Binding Of Divalent Cations To Insulin Hexamers And Tetramers And The Assembly Of Insulin Hexamers.

Abstract An insulin hexamer containing one B10-bound Co(III) ion and one unoccupied B10 site has been synthesized. The properties of the monosubstituted hexamer show that occupancy of only one B10 site by Co3+ is sufficient to stabilize the hexameric form under the conditions of pH and concentration used in these studies. The experimentally determined, second-order rate constants for the binding of Zn2+ and Co2+ to the unoccupied B10 site are consistent with literature rate constants for the rate of association of these divalent metal ions with similar small molecule ligands. These findings indicate that the rate-limiting steps for Zn2+ and Co2+ binding involve the removal of the first aqua ligand. The rate constant for the binding of Cd2+ is significantly lower than the literature values for small molecule chelators, which suggests that some other protein-related process is rate-limiting for Cd2+ binding to the unoccupied, preformed B10 site. The kinetics of the assembly of insulin in the presence of limiting metal ion provides strong evidence indicating that the B13 site of the tetramer species can bind Zn2+, Cd2+, or Ca2+ prior to hexamer formation and that such binding assists hexamer formation. Both the tetramer and the hexamer B13 sites were found to exhibit similar affinities for Zn2+ and Cd2+ (Kd congruent to 9 microM), whereas the tetramer B13 sites bind Ca2+ much more weakly (Kd congruent to 1 mM for tetramer vs 83 microM for hexamer). The second-order rate constants estimated for the association of Zn2+ and Cd2+ to the tetrameric site indicate that the loss of the first inner-sphere aqua ligand is the rate-limiting step for binding. Continue reading >>

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