Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.01 seconds)

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Care 1990 Sep
PMID:Monomeric insulins and their experimental and clinical implications. 222 10

Surface and intracellular membrane distribution and hormonal regulation of transcobalamin II receptor (TC II-R) activity and protein levels have been studied in an effort to understand its regulation of expression in the rat. TC II-R activity and the levels of the 62 kDa monomeric and 124 kDa dimeric forms of TC II-R were highest in the rat kidney and intestine, and in these tissues the receptor expression was not dependent upon the postnatal development of the rat. TC II-R expression was uniform in the various regions of the gut. Surface membrane distribution of TC II-R in the kidney revealed the expression of the 124 kDa dimer form of TC II-R in the apical and basolateral membranes in the ratio of 1:10. Further subcellular distribution of TC II-R in the kidney revealed the expression of the 124 kDa dimer in the intermicrovillar clefts and clathrin-coated vesicles and the 62 kDa monomer in the microsomes. Neither the monomer nor the dimer could be detected in the early endosomes or lysosomes. Membrane TC II-R activity and TC II-R protein levels and cobalamin (Cbl; vitamin B12) transport in vivo were inhibited by about 90% in adrenalectomized rats and all three returned to normal levels by oral treatment of these animals with cortisone acetate. In contrast, thyroidectomy or experimentally induced diabetes had no effect on TC II-R activity or Cbl transport. Based on these observations, we suggest that TC II-R expression is not developmentally or regionally regulated in rat renal and intestinal membranes and its expression in the kidney is asymmetrically distributed between the apical (10%) and basolateral (90%) membranes. In addition, our results also show that the dimerization of TC II-R is a post-microsomal event and that the expression of TC II-R and plasma Cbl transport is regulated by cortisone.
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PMID:Regulation of expression of transcobalamin II receptor in the rat. 757 28

We conducted a study to investigate the effect of parity on the following six serum markers used in screening for Down's syndrome, after adjusting them for ethnic group and maternal weight: alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and dimeric inhibin A. We aimed to estimate the effect of adjusting for any differences found on the screening performance. AFP, uE3, and hCG concentrations were available from 16,666 women with singleton pregnancies without Down's syndrome or neural tube defects and without insulin-dependent diabetes mellitus, who were screened between 15 and 22 weeks' gestational age. Stored serum samples were available on a subset of 1347 women and these were used to measure free alpha-hCG, free beta-hCG, and inhibin A. Serum concentrations were expressed as multiples of the median (MOM) for women of the same gestational age, weight, and ethnic group. Of the six markers, only hCG levels were affected by parity; hCG levels decreased by 3.1 per cent per previous birth (95 per cent confidence interval 2.2-4.0 per cent); there was no significant relationship between the number of previous abortions and hCG level after adjustment for the number of previous births. The effect of previous births on hCG was not due to maternal age. Only AFP was affected by maternal age, but the effect was small; levels increased by 4.4 per cent per 10 years of age (3.2-5.7 per cent). It is not worthwhile adjusting serum markers for parity or for maternal age in prenatal screening for Down's syndrome because their effect on the performance of screening is negligible.
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PMID:Serum markers for Down's syndrome in relation to number of previous births and maternal age. 887 78

Glutamic acid decarboxylase (GAD) is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). This was initially identified as a 64-65 kD molecule according to migration in gels after immunoprecipitation from pancreatic islets. We studied the antigenicity of two different radiolabelled preparations of GAD, derived either by affinity purification from porcine brain and known to contain GAD 65 and GAD 67, or by expression from a cDNA for human GAD 65 by rabbit reticulocyte lysate (RRL). Radiolabelled immunoprecipitated pellets from the reaction of potent antisera to GAD from patients with IDDM were examined by autoradiography after SDS-PAGE under reducing or non-reducing conditions. Also, preparations of porcine brain GAD were "depleted' of GAD by exposure to antisera, and then similarly re-examined. Autoradiography of radiolabelled GAD either affinity purified from porcine brain, or expressed by RRL, showed that the immunoprecipitated protein migrated under non-reducing conditions according to a M(r) of approximately 110-130 kD, corresponding to dimeric forms of monomeric GAD of approximately 55-65 kD. Depletion by immunoprecipitation of this minor higher M(r) component from preparations of GAD left, in the supernatant, an abundance of GAD of M(r) 64-65 kD corresponding to monomer that was completely non-reactive with potent IDDM sera. We conclude that IDDM sera react with the GAD molecule in a dimeric (or oligomeric) form. Our findings have general connotations for self-tolerance and autoimmunity.
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PMID:Diabetic sera react with the glutamic acid decarboxylase molecule in a dimeric-oligomeric form. 891 80

A nested case-control study using stored serum samples collected as part of a prospective study of the outcome of pregnancy was performed to investigate concentrations of (dimeric) inhibin-A in maternal serum between 15 and 22 weeks of pregnancy in 126 pregnancies among 92 women with insulin-dependent diabetes mellitus (IDDM). Each IDDM pregnancy was matched with two control singleton pregnancies for gestational age (same completed week) and duration of sample storage (same calendar quarter). The median inhibin-A level in the IDDM pregnancies was 0.88 multiples of the median (MOM) for pregnancies without IDDM at the same gestational age (P = 0.05) (95 per cent confidence interval 0.78-1.00) or 0.91 MOM after adjustment for maternal weight. These results enable inhibin-A values to be adjusted so that prenatal screening for Down's syndrome can be performed using this marker in IDDM pregnancies as well as in non-diabetic pregnancies.
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PMID:Maternal serum inhibin-A in pregnancies with insulin-dependent diabetes mellitus: implications for screening for Down's syndrome. 893 61

New cellular-based reagents are needed to diagnose type I diabetes as well as to monitor the outcomes of clinical trials at early time points. Four new monoclonal antibodies (mAbs) have been shown to demonstrate reduced binding to lymphocytes from identical twins with long-term type I diabetes relative to that observed with lymphocytes from their twin partners without diabetes or from control subjects. Biochemical analysis revealed mAb 3G12EG recognized an unidentified 45-kDa protein, whereas mAb 2E8F1 and 5B6E11 did not appear to precipitate specific proteins as detected by SDS-PAGE. Electrophoresis under reducing and nonreducing conditions and peptide mapping revealed that mAb 8F410 recognizes a novel dimeric form of HLA class I molecule. Predictions from crystallography studies suggested previously this class I dimer as the optimal activation of a single CD8 T-cell. In B-cells from both normal and diabetic individuals, the class I dimer was minimally associated with beta2-microglobulin rapidly formed in the endoplasmic reticulum. These new reagents appear to be able to identify new lymphocyte surface phenotypes associated with diabetes expression in both fresh blood samples and Epstein-Barr virus-established cell lines.
Diabetes 1997 Mar
PMID:New monoclonal antibody diagnostic reagents for type I diabetes: differential lymphocyte surface antigen expression related to disease. 903 90

Increased concentration of circulating adhesion molecules in human serum have been described in different immune-mediated diseases. Recently, we proposed an immunomodulatory function of soluble forms of the intercellular adhesion molecule-1 (ICAM-1) during the pathogenesis of human Type I (insulin-dependent) diabetes mellitus. To test this hypothesis in nonobese diabetic (NOD) mice, a spontaneous animal model for human Type I diabetes, two recombinant forms of soluble murine ICAM-1 were generated, one monomeric soluble ICAM-1 containing all five extracellular Ig-like domains of ICAM-1 (rICAM-1) and one dimeric protein with the N-terminal extracellular domains fused to the constant regions of murine IgG2a (rICAM-1-Ig). Beginning at age 35 days prediabetic NOD mice received i. p. injections of 5 microg recombinant ICAM-1-proteins three times a week for 4.5 months. At day 170 diabetes development was reduced (p < 0.001) in NOD mice receiving rICAM-1 (8%) or rICAM-1-Ig (8%) treatment in comparison with sham treated animals (45%). After termination of therapy animals treated with multimeric rICAM-1-Ig were protected longer than animals treated with rICAM-1. Prevention of diabetes was associated with decreased infiltration of pancreatic islets by mononuclear cells. A selective downregulation of Th1-type cytokine expression was observed in a second set of experiments in which diabetes development was synchronised by cyclophosphamide. These data support the hypothesis that circulating forms of adhesion molecules have an immunomodulatory function and can intervene in islet inflammation.
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PMID:Soluble forms of intercellular adhesion molecule-1 inhibit insulitis and onset of autoimmune diabetes. 983 36

Glutamic acid decarboxylase (GAD) is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). Two GAD isoforms exist, GAD65 and GAD67, which differ mostly in the first 100 amino acids of the amino terminus. IDDM sera are predominantly reactive with GAD65 but autoepitopes have been localised only to regions of GAD65 highly homologous with GAD67. In this study we investigated the contribution of the amino terminus to the IDDM epitope on GAD65, in order to test whether this region of GAD could explain the difference in reactivity between GAD65 and GAD67. A recombinant hybrid GAD molecule consisting of amino acids 1-101 of GAD67 and 96-585 of GAD65 was constructed and a truncated GAD65 was also constructed consisting of amino acids 98-585 of GAD65. The reactivity with the hybrid GAD molecule, GAD65 and GAD67, and truncated GAD65 was examined by radioimmunoprecipitation using 50 IDDM sera with known reactivity to purified porcine brain GAD. Over 90% of the IDDM sera were reactive with the hybrid GAD molecule confirming that the amino terminus of GAD65 does not contribute to the autoepitope and that the IDDM epitope is localised to the middle and carboxyl terminal domains of GAD65. Furthermore, evidence is presented that autoantibodies to GAD65 in IDDM sera react with an epitope formed on a dimeric configuration of the molecule.
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PMID:Autoantigenic reactivity of diabetes sera with a hybrid glutamic acid decarboxylase GAD67-65 molecule GAD67(1-101)/GAD65(96-585). 989 8

Hepatocyte nuclear factor 1alpha (HNF1alpha) is an atypical dimeric homeodomain-containing protein that is expressed in liver, intestine, stomach, kidney, and pancreas. Mutations in the HNF1alpha gene are associated with an autosomal dominant form of non-insulin-dependent diabetes mellitus called maturity-onset diabetes of the young (MODY3). More than 80 different mutations have been identified so far, many of which involve highly conserved amino acid residues among vertebrate HNF1alpha. In the present work, we investigated the molecular mechanisms by which MODY3 mutations could affect HNF1alpha function. For this purpose, we analyzed the properties of 10 mutants resulting in amino acid substitutions or protein truncation. Some mutants have a reduced protein stability, whereas others are either defective in the DNA binding or impaired in their intrinsic trans-activation potential. Three mutants, characterized by a complete loss of trans-activation, behave as dominant negatives when transfected with the wild-type protein. These data define a clear causative relationship between MODY3 mutations and functional defects in HNF1alpha trans-activation. In addition, our analysis sheds new light on the structure of a homeoprotein playing a key role in pancreatic beta cell function.
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PMID:Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. 1058 42

Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha). Here, we describe the crystal structure of the HNF-1alpha dimerization domain at 1.7 A resolution and assess its structural plasticity. The crystal's low solvent content (23%, v/v) leads to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold crystallographic symmetry axis. The dimers define a novel intertwined four-helix bundle (4HB). Each protomer contains two alpha-helices separated by a sharp non-canonical turn. Dimer-related alpha-helices form anti-parallel coiled-coils, including an N-terminal "mini-zipper" complementary in structure, symmetry and surface characteristics to transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains (five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar intertwined dimer exists in solution. Comparison of structures obtained in multiple independent crystal forms indicates that the mini-zipper is a stable structural element, whereas the C-terminal alpha-helix can adopt a broad range of orientations. Segmental alignment of the mini-zipper (mean pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of 0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 A C(alpha) rmsd displacement) is observed in the DCoH-bound peptide. Diabetes-associated mutations perturb distinct structural features of the HNF-1alpha domain. One mutation (L12H) destabilizes the domain but preserves structural specificity. Adjoining H12 side-chains in a native-like dimer are predicted to alter the functional surface of the mini-zipper involved in DCoH recognition. The other mutation (G20R), by contrast, leads to a dimeric molten globule, as indicated by its 1H-NMR features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn configuration enables specific interactions between the mini-zipper and the C-terminal coiled-coil.
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PMID:The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. 1143 29


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