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PubMed1995

Packing interactions of Aib-containing helices: molecular modeling of parallel dimers of simple hydrophobic helices and of alamethicin.

alpha-Aminoisobutyric acid (Aib) is a helicogenic alpha, alpha-dimethyl amino acid found in channel-forming peptaibols such as alamethicin. Possible effects of Aib on helix-helix packing are analyzed. Simulated annealing via restrained molecular dynamics is used to generate ensembles of approximately parallel helix dimers. Analysis of variations in geometrical and energetic parameters within ensembles defines how tightly a pair of helices interact. Simple hydrophobic helix dimers are compared: Ala20, Leu20, Aib20, and P20, the latter a simple channel-forming peptide [G. Menestrina, K.P. Voges, G. Jung, and G. Boheim (1986) Journal of Membrane Biology, Vol. 93, pp. 111-132]. Ala20 and Leu20 dimers exhibit well-defined ridges-in-grooves packing with helix crossing angles (omega) of the order of +20 degrees. Aib20 alpha-helix dimers are much more loosely packed, as evidenced by a wide range of omega values and small helix-helix interaction energies. However, when in a 3(10) conformation Aib20 helices pack in three well-defined parallel modes, with omega ca. -15 degrees, +5 degrees, and 10 degrees. Comparison of helix-helix interaction energies suggests that dimerization may favor the 3(10) conformation. P20, with 8 Aib residues, also shows looser packing of alpha-helices. The results of these studies of hydrophobic helix dimers are analyzed in the context of the ridges-in-grooves packing model. Simulations are extended to dimers of alamethicin, and of an alamethicin derivative in which all Aib residues are replaced by Leu. This substitution has little effect on helix-helix packing. Rather, such interactions appear to be sensitive to interactions between polar side chains. Overall, the results suggest that Aib may modulate the packing of simple hydrophobic helices, in favor of looser interactions. For more complex amphipathic helices, interactions between polar side chains may be more critical.

Alamethicin↗
PubMed2004

D-dimer testing in patients with suspected acute thromboembolic occlusion of the superior mesenteric artery.

BACKGROUND: There is no accurate non-invasive method available for the diagnosis of acute thromboembolic occlusion of the superior mesenteric artery (SMA). The aim of this study was to assess the diagnostic properties of the fibrinolytic marker D-dimer. METHODS: From September 2000 to April 2003 consecutive patients aged over 50 years admitted to hospital with acute abdominal pain were studied. Patients with possible acute SMA occlusion at presentation had blood samples taken within 24 h of the onset of the pain for analysis of D-dimer, plasma fibrinogen, activated partial thromboplastin time, prothrombin time and antithrombin. The value of D-dimer testing to diagnose SMA occlusion was assessed by means of likelihood ratios. RESULTS: Nine of 101 patients included had acute SMA occlusion. The median D-dimer concentration was 1.6 (range 0.4-5.6) mg/l, which was higher than that in 25 patients with inflammatory disease (P = 0.007) or in 14 patients with intestinal obstruction (P = 0.005). The combination of a D-dimer level greater than 1.5 mg/l, atrial fibrillation and female sex resulted in a likelihood ratio for acute SMA occlusion of 17.5, whereas no patient with a D-dimer concentration of 0.3 mg/l or less had acute SMA occlusion. CONCLUSION: D-dimer testing may be useful for the exclusion of patients with suspected acute SMA occlusion.

Abdominal Pain↗
PubMed2006

Molecular recognition: preorganization of a bis(pyrrole) Schiff base derivative for tight dimerization by hydrogen bonding.

Multiple techniques have been used to delineate the self-assembly of a bis(pyrrole) Schiff base derivative (compound 4, C(16)H(14)N(4)), which forms an unusual dimer through complementary N-H...N=C hydrogen bonds between twisted, C2-symmetric monomer units. The asymmetric unit of the crystal structure comprises one and a half dimer units, with one dimer exhibiting approximate D2 point-group symmetry and the other exact D2 symmetry (space group C2/c). The dimers pack into columns whose axes are collinear with the a axis of the unit cell. The columns assemble into discrete layers with two distinct types of hydrogen-sized voids residing between the layers. Despite the promising architecture of the voids within the lattice of 4, the absence of genuine channels to interconnect the voids precludes the uptake of hydrogen gas, even at elevated pressures (10 bar). AM1 calculations of the structure of dimeric 4 indicate that self-recognition through hydrogen bonding depends primarily on favorable electrostatic interactions. The potential-energy surface for monomeric 4 mapped by counter-rotation of an adjacent pair of C=C-N=C torsion angles indicates that the X-ray structures of the four monomeric units are global minima with highly nonplanar conformations that are preorganized for self-recognition by hydrogen bonding. The in vacuo enthalpy of association for the dimer was calculated to be significantly exergonic (DeltaG(assoc)=-21.9 kJ mol(-1), 298 K) and in excellent agreement with that determined by 1H NMR spectroscopy in CDCl3 (DeltaG(assoc)=-16.6(4) kJ mol(-1), 298 K). Using population and bond order analyses, in conjunction with the conformation dependence of the frontier MO energies, we have been able to show that pi-electron delocalization is only marginally diminished in the nonplanar conformers of 4 and that the electronic structures of the constituent monomers of the dimer are well mixed.

Journal Article↗
PubMed1988

Orientation of epitopes influences the immunogenicity of synthetic peptide dimers.

The immunogenicity of synthetic peptide dimers based on epitope sequences derived from the mycobacterial 65-kDa antigen and the foot and mouth disease virus (FMDV) VP1 protein was examined in inbred mice. The analysis was directed towards the potential helper role of a T cell stimulatory mycobacterial epitope (65-85) with respect to poorly immunogenic sites either from the same molecule (422-436) or from VP1 (141-160). The 65-85 repeat homodimer induced an antibody response in CBA/ca but not in C57BL/6 mice, both nonresponders to the 65-85 monomer, and amplified the antibody response in BALB/c, monomer-responder mice. Analysis of the immunogenicity of hybrid dimers in BALB/c mice showed that the orientation of peptides within the dimer is critical for the extent of the produced antibody response. Only the 422-436/65-85 but not the 65-85/422-436 induced antibodies binding to the 422-436 sequence which was nonimmunogenic when injected either as a monomer or dimer. Despite the striking difference in immunogenicity, both tested hybrid dimers reacted equally in the solid-phase immunoassay with antisera raised to 65-85-dimer or 422-436/65-85 peptides or with a monoclonal antibody to the 422-436 epitope. The described differences in antibody responsiveness also cannot be attributed merely to the extent of T cell stimulation since the proliferative responses were uniformly expressed for all relevant combinations of peptides. Antisera to 65-85 dimer and 422-436/65-85 hybrid also reacted with the native 65-kDa protein. Furthermore, the production of FMDV-neutralizing antibodies in response to the 141-160 (VP1-derived)/65-85 hybrid peptide in 141-160 nonresponder B10.D2 mice also confirmed the helper activity of the 65-85 epitope. Thus, combining heterologous peptides with the N-terminal of the mycobacterial 65-85 sequence may be generally applicable for the potentiation of peptide vaccines.

Animals↗
PubMed1992

Transmembrane helical interactions: zeta chain dimerization and functional association with the T cell antigen receptor.

Members of the zeta family of receptor subunits (zeta, eta and gamma) are structurally related proteins found as components of the T cell antigen receptor (TCR) and certain Fc receptors. These proteins share the ability to form disulfide-linked dimers with themselves and with other members of the family. Comparison of the amino acid sequences of zeta and gamma reveals a significant degree of homology, which is highest within their membrane-spanning domains. Analysis of their transmembrane sequences on a helical wheel projection suggests that all of the identical amino acids are clustered on one face of a potential alpha-helix. This face contains the only cysteine residue within zeta, suggesting that this conserved region may function to mediate dimerization. Indeed, replacing the transmembrane domain of the Tac antigen (alpha chain of the interleukin-2 receptor) by that of the zeta chain resulted in the formation of disulfide-linked dimers of Tac. The conserved aspartic acid residue found in the zeta and gamma transmembrane sequences was found to play a role in disulfide linkage. Replacing the aspartic acid with a lysine but not with an alanine or valine residue allowed formation of disulfide-linked dimers. The ability of the aspartic acid residue to support dimerization was dependent upon its position within the helix. Thus, these observations indicate that residues within the zeta transmembrane domain play a critical role in the formation of disulfide-linked dimers. Expression of zeta mutants in zeta-deficient T cells revealed that the zeta transmembrane domain is also responsible for reconstituting transport of functional TCR complexes to the cell surface and differentiated the requirements for disulfide-linked dimerization per se from assembly of the TCR complex.

Amino Acid Sequence↗
PubMed1992

Disulfide-linked and noncovalent dimers of p185HER-2 in human breast carcinoma cells.

Enhanced levels of disulfide-linked dimers of the neu oncogene product have been suggested to be associated with the transformed state [Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI: Nature 338:230-231, (1989)]. We, therefore, investigated the properties of the dimeric forms of p185HER-2/neu from the human breast carcinoma cell line, SK-BR-3. We found disulfide-linked dimers as well as noncovalently associated dimers that were detected by cross-linking with bis(sulfosuccinimidyl) suberate (BS3). However, the disulfide-linked dimers did not exist in intact cells, since they were eliminated when the cells were lysed in the presence of the alkylating agent, sodium iodoacetate. Moreover, the disulfide-linked dimeric molecules were not the activated form of p185HER-2 since they incorporated about the same level of phosphate in an in vitro kinase reaction as the monomeric molecules. In contrast, the noncovalent dimers appeared to be present on the surface of intact cells and were phosphorylated at levels at least tenfold higher than monomers in an in vitro kinase reaction.

Alkylating Agents↗
PubMed2006

Accurate-mass identification of chlorinated and brominated products of 4-nonylphenol, nonylphenol dimers, and other endocrine disrupters.

LC/ToF-MS was used to identify new chlorination and bromination products of 4-nonylphenol (4-NP), such as 4-NPBr2, 4-NPBrCl, 4-NP dimer (2 isomers), 4-NPCl dimer (2 isomers), 4-NPBr dimer, and a series of methoxy bromo and chloro 4-NPs from a laboratory study of nonylphenol chlorination. The identification procedure used the exact mass, exact mass of the isotope cluster, and their relative intensities, at an average mass accuracy of approximately 1 ppm. The products were produced by a simulated study of industrial cleaning procedures where 4-NP, nonylphenol ethoxylate (NPEO-1 and 2), and nonylphenol carboxylate (NPEC-1) were in contact with sodium hypochlorite solutions (with and without bromide) of various strengths (possible environmental scenarios) at neutral pH. The formation of the products was measured as a function of chlorine concentration, and it was found that 4-NP was the most reactive, producing 4-NPCl, 4-NPCl2, 4-NP (dimers), and the 4-NPCl (dimers). In the presence of bromide ions, a mixture results with products of 4-NPBr2, 4-NPCl, 4-NPCl2, 4-NPBrCl, 4-NPBr, and a 4-NPBr dimer. Less reactive to halogenation was NPEO, which formed only the monochloro and monobromo products, and the least reactive was NPEC. A simple stereochemical model is used to explain halogenation reactivity for the family of 4-NPs and NPEOs at neutral pH. The presence of halogenated 4-NP dimers (bromo and chloro diphenyl ethers) is discussed as a possible source of new endocrine disrupters.

Electrons↗
PubMed1996

Identification of the Serratia endonuclease dimer: structural basis and implications for catalysis.

The Serratia endonuclease is an extracellularly secreted enzyme capable of cleaving both single- and double-stranded forms of DNA and RNA. It is the first member of a large class of related and usually dimeric endonucleases for which a structure is known. Using X-ray crystallography, the structure of monomer of this enzyme was reported by us previously (Miller MD et al., 1994, Nature Struct Biol 1:461-468). We now confirm the dimeric nature of this enzyme through light-scattering experiments and identify the physiologic dimer interface through crystal packing analysis. This dimerization occurs through an isologous twofold interaction localized to the carboxy-terminal subdomain of the enzyme. The dimer is a prolate ellipsoid with dimensions 30 A x 35 A x 90 A. The dimer interface is flat and contains four salt links, several hydrogen bonds, and nonpolar interactions. Buried water is prominent in this interface and it includes an unusual "cubic" water cluster. The position of the two active sites in the dimer suggests that they can act independently in their cleavage of DNA, but have a geometrical advantage in attacking substrate relative to the monomer.

Biopolymers↗
PubMed1994

Helix packing in proteins: prediction and energetic analysis of dimeric, trimeric, and tetrameric GCN4 coiled coil structures.

A simulated annealing method for atomic resolution structure prediction of alpha-helical coiled coil proteins is described which draws upon knowledge of the oligomerization state, the helix directionality, and the properties of heptad repeat sequences. Unknown structural parameters, such as the coiled coil twist angle and the side chain conformations, are heavily sampled while allowing for flexibility in the helix backbone geometry. Structures of the wild-type GCN4 dimer [O'Shea et al., Science 254:539-544, 1991] and a mutant tetramer [Harbury et al., Science 292:1401-1407, 1993] have been generated and compared with the X-ray crystal structures. The wild-type dimer model has a root mean square coordinate deviation from the crystal structure of 0.73 A for nonhydrogen atoms in the dimerization interface. Structures of a mutant dimer and a mutant trimer have been predicted. Packing energetics were analyzed for core leucine and isoleucine side chains in dimeric and tetrameric coiled coils. Strong packing preferences were found in the dimers but not in the tetramers. Thus, packing in the dimer may be responsible for the switch from a two-stranded to a four-stranded coiled coil caused by the GCN4 leucine zipper mutations.

Amino Acid Sequence↗
PubMed1993

Dimer- and oligomerization of the erythropoietin receptor by disulfide bond formation and significance of the region near the WSXWS motif in intracellular transport.

The receptor for erythropoietin (EpoR), a primary regulator of erythropoiesis, belongs to the cytokine receptor family. Although the mechanisms of signal transduction through the receptors of this family are largely unknown, increasing numbers of the receptors have been shown to form a hetero- or homodimer. To address the possibility that the EpoR dimerizes, we made a truncated mutant receptor that lacks most of the cytoplasmic domain and expressed it either alone or with the wild-type receptor in an IL-3-dependent cell line, DA-3. Dimerization of the receptor was demonstrated by a coimmunoprecipitation using an antiserum against the cytoplasmic domain of the receptor. Epo stimulation did not have a detectable effect on dimerization. Coimmunoprecipitation experiments in COS-7 cells further revealed that only the extracellular domain of the receptor is required for dimerization. The "WSXWS" motif, conserved in the cytokine receptor family, was shown to not be required for dimerization. Diagonal two-dimensional gel analysis of the EpoR expressed in DA-3 transfectants showed that a substantial portion of the receptor forms dimers or oligomers with disulfide bonds. Western blot analysis, using an antiphosphotyrosine antibody, revealed that a portion of these dimers or oligomers become tyrosine phosphorylated after Epo stimulation, thus suggesting that these forms are expressed on the cell surface and activated by Epo stimulation.

Amino Acid Sequence↗
PubMed1994

Aminoethylcysteine ketimine decarboxylated dimer inhibits mitochondrial respiration by impairing electron transport at complex I level.

The product of the spontaneous dimerization and decarboxylation of aminoethylcysteine ketimine (simply named the dimer in this note) has been investigated for a possible biochemical activity. It has been found that the dimer inhibits the ADP-dependent oxidation of NAD(+)-linked substrates in rat liver mitochondria and electron transport from NADH to O2 in bovine heart submitochondrial particles (SMP). Oxidation of succinate by SMP is not impaired by concentrations of the dimer inhibiting almost totally NADH oxidation. Furthermore, the dimer did not affect the rotenone-insensitive electron transfer from NADH to menadione. These results give a preliminary indication suggesting that the dimer inhibits electron flow from NADH dehydrogenase to ubiquinone at or near the rotenone binding site(s). The dimer inhibition falls in the same range exhibited by some neurotoxins which are known to interact with the rotenone binding site.

Animals↗
PubMed1996

HIV-1 RT enhances the activity of a tethered dimer of HIV-1 proteinase.

HIV-1 reverse transcriptase (RT) can specifically enhance HIV-1 proteinase activity in vitro and in eukaryotic cells (1). To determine if the effect of RT on proteinase activity was due to changes in the equilibrium dimerization constant of the proteinase or the stability of the proteinase dimer, we studied the effect of RT on a genetically engineered covalent dimer (tethered dimer) of the proteinase. RT was found to increase the activity of the tethered dimer independent of pH and ionic strength. The effect of RT on the kinetic constants (Km and kcat) of the wild type HIV-1 proteinase and its tethered dimer were also determined. These results show that RT can increase the enzymatic catalytic efficiency and substrate affinity of the proteinase, by a mechanism independent of promoting dimer formation.

Amino Acid Sequence↗
PubMed2001

Mixed Micellization of Dimeric (Gemini) Surfactants and Conventional Surfactants.

The aqueous solutions of mixtures of various conventional surfactants and dimeric anionic and cationic surfactants have been investigated by electrical conductivity, spectrofluorometry, and time-resolved fluorescence quenching to determine the critical micelle concentrations and the micelle aggregation numbers in these mixtures. The following systems have been investigated: 12-2-12/DTAB, 12-2-12/C(12)E(6), 12-2-12/C(12)E(8), 12-3-12/C(12)E(8), Dim3/C(12)E(8), and Dim4/C(12)E(8) (12-2-12 and 12-3-12=dimethylene-1,2- and trimethylene-1,3-bis(dodecyldimethylammonium bromide), respectively; C(12)E(6) and C(12)E(8)=hexa- and octaethyleneglycol monododecylethers, respectively; Dim3 and Dim4=anionic dimeric surfactants of the disodium sulfonate type, Scheme 1; DTAB=dodecyltrimethylammonium bromide). For the sake of comparison the conventional surfactant mixtures DTAB/C(12)E(8) and SDS/C(12)E(8) (SDS=sodium dodecylsulfate) have also been investigated (reference systems). Synergism in micelle formation (presence of a minimum in the cmc vs composition plot) has been observed for the Dim4/C(12)E(8) mixture but not for other dimeric surfactant/nonionic surfactant mixtures investigated. The aggregation numbers of the mixed reference systems DTAB/C(12)E(8) and SDS/C(12)E(8) vary monotonously with composition from the value of the aggregation number of the pure C(12)E(8) to that of the pure ionic component. In contrast, the aggregation number of the dimeric surfactant/C(12)E(8) mixtures goes through a minimum at a low value of the dimeric surfactant mole fraction. This minimum does not appear to be correlated to the existence of synergism in micelle formation. The initial decrease of the aggregation number of the nonionic surfactant upon addition of ionic surfactant, up to a mole fraction of ionic surfactant of about 0.2 (in equivalent per total equivalent), depends little on the nature the surfactant, whether conventional or dimeric. The results also show that the microviscosity of the systems containing dimeric surfactants is larger than that of the reference systems. Copyright 2001 Academic Press.

Journal Article↗
PubMed1996

Affinity selective isolation of ligands from peptide libraries through display on a lac repressor "headpiece dimer".

DNA binding by the Escherichia coli lac repressor is mediated by the approximately 60 amino acid residue 'headpiece' domain. The dimer of headpiece domains that binds to the lac operator is normally formed by association of the much larger approximately 300 amino acid residue C-terminal domain. We have used in vitro selection to isolate 'headpiece dimer' molecules containing two headpiece domains connected via a short peptide linker. These proteins bind plasmid molecules with sufficient stability to allow association of a peptide epitope displayed at the C terminus of the headpiece dimer with the plasmid encoding that peptide. Libraries of peptides displayed on the C terminus of a headpiece dimer can be screened for specific receptor ligands by affinity enrichment of peptide-headpiece dimer-plasmid complexes using an immobilized receptor. After each round of enrichment, transformation of E. coli with recovered plasmids permits amplification of the selected population. After several rounds of enrichment, sequencing of individual clones reveals the structure of the selected peptides. Headpiece dimer libraries allow selection of peptide ligands of higher average affinity than similar libraries based on the intact lac repressor. Interestingly, the presence of the lac operator is not required for plasmid binding by the headpiece dimer protein.

Amino Acid Sequence↗
PubMed2001

Thermally Averaged Spectroscopic Parameters of the Weakly Bound Dimers.

Spectroscopic parameters in an ensemble of the weakly bound dimers are derived making use of the quantum and classical statistical average over thermally excited rovibrational states. Argon dimers and oxygen dimers are taken as examples. It is shown that thermally averaged characteristics of dimers rapidly change as temperature of a gas rises. In an ensemble of quasi-diatomic tightly bound dimers, the high-temperature limit of the effective dissociation energy amounts to roughly D(0)/3, where D(0) is the dissociation energy from the ground state. It is demonstrated that the effective rotational B(eff)(T) constant for the oxygen dimers statistically averaged at near room temperature is merely one half of the ground state B(0) value. This conclusion is in agreement with recent spectroscopic observations. Rotationally resolved spectroscopic probe of (O(2))(2) in the slit-nozzle expansion resulted in B(0) = 0.095 cm(-1), while bandshape analysis of the room-temperature collision-induced absorption in the oxygen fundamental allowed an estimate of B(eff) approximately 0.038 cm(-1). The role of anisotropy of intermolecular interaction and the formation of various types of metastable dimeric states are discussed. Copyright 2001 Academic Press.

Journal Article↗
PubMed1997

Identification of sites that act together to direct dimerization of human foamy virus RNA in vitro.

Retroviral particles contain two molecules of genomic RNA, which are noncovalently linked near their 5' ends in a region called the dimer linkage structure (DLS). By using complementary DNA oligonucleotides and deletion mutants to impair RNA dimerization of the human foamy virus (HFV), three sites, designated SI, SII, and SIII, were found within a 159-nucleotide RNA fragment of HFV that are involved in dimerization in vitro. SI overlaps the primer-binding site; and SII contains the palindromic sequence, UCCCUAGGGA, the disruption of which impairs dimer formation; and SIII extends into the gag gene. The first two sites are highly conserved in the other primate foamy viruses, SFV-1, SFV-3, and SFVcpz, whereas the third appears to be shared only by HFV and SFVcpz. RNA of HFV and SFV-3 could form heterodimers, indicating that both viruses dimerize by similar mechanisms. On testing thermal stability, dimers of the 159-nucleotide fragment dissociated between 40 and 70 degrees, with half of the dimers dissociating at 55 degrees. Since the splice donor site of HFV is located at position 51 of viral RNA, the DLS is part of the genomic RNA exclusively.

Binding Sites↗
PubMed1984

Covalently-linked insulin dimers: their metabolism and biological effects in vivo as partial competitive antagonists of insulin clearance.

The biological properties of three covalently-linked insulin dimers were studied in greyhounds. Constant infusions showed that the plasma distribution kinetics were slower for the dimers than for insulin. The metabolic clearance rates of the three dimers (10.3 +/- 0.4, 8.8 +/- 0.5, 8.2 +/- 0.5 ml X min-1 X kg-1; mean +/- SEM) were significantly lower than that of insulin (19 +/- 0.8 ml X min-1 X kg-1), and their hypoglycaemic effects (11.2%, 3% and 0.3%) were markedly reduced compared with their lipogenic potencies in vitro (80%, 30% and 13%, respectively). A low dose infusion of insulin or an equipotent dose of one of the dimers significantly prolonged the effects of an insulin bolus on plasma glucose but not on non-esterified fatty acids. The apparent distribution space (106.4 +/- 11.9 ml/kg) and clearance rate (14.7 +/- 0.5 ml X min-1 X kg-1) of an insulin bolus were significantly reduced by one dimer (44.5 +/- 8.4 ml/kg and 10.7 +/- 2.8 ml X min-1 X kg-1) but not by the equipotent insulin infusion (102.7 +/- 8.2 ml/kg and 16.4 +/- 0.07 ml X min-1 X kg-1). The apparent partial competitive antagonism of insulin by the dimers that has been reported in vitro can be observed in vivo, in that antagonism of insulin metabolism was directly demonstrated with one of the dimers.

Animals↗
PubMed1995

Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs.

Insulin analogues with relatively greater effect on hepatic glucose production than peripheral glucose disposal could offer a more physiological approach to the treatment of diabetes mellitus. The fact that proinsulin exhibits this property to a minor degree may suggest that analogues with increased molecular size may be less able than insulin to obtain access to peripheral receptor sites. Covalent insulin dimers have previously been shown to possess lower hypoglycaemic potencies than predicted by their in vivo receptor binding affinities. Reduced rates of diffusion to peripheral target tissues might be an explanation for the lower in vivo potency compared to insulin. To test the relative hepatic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-3H]glucose tracer infusions were used in anaesthetised greyhounds to establish dose-response curves for rates of hepatic glucose production and glucose disposal with insulin, N alpha B1, N alpha B'1,-suberoyl-insulin dimer, and N epsilon B29, N epsilon B'29,-suberoyl-insulin dimer. With N alpha B1, N alpha B'1,-suberoyl-insulin dimer molar potencies relative to insulin were 68%, (34-133) (mean and 95% fiducial limits), for inhibition of hepatic glucose production and 14.7%, (10.3-20.9) for glucose disposal. With N epsilon B29,N epsilon B'29,-suberoyl-insulin dimer potencies were 75%, (31-184) and 2.5%. (1.5-4.3), for inhibition of hepatic glucose production and for glucose disposal, respectively. The demonstration that both dimers exhibit a significantly greater effect on glucose production than on glucose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells.

Analysis of Variance↗