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 (0.00 seconds)

To investigate the role of the beta-cell in the occurrence of diabetes in obesity, longitudinal changes of insulin-gene expression and pancreatic insulin content were compared among genetically obese diabetic (Wistar fatty) rats, genetically obese nondiabetic (Zucker fatty) rats, and ventromedial hypothalamus (VMH)-lesioned obese rats. Plasma glucose levels were significantly elevated with age in Wistar fatty rats, whereas they were virtually unchanged in VMH-lesioned and Zucker fatty rats. Obesity and hyperinsulinemia were evident in VMH-lesioned rats 1 wk after the operation and in Zucker and Wistar fatty rats at 5 wk of age. In VMH-lesioned rats, the pancreatic preproinsulin I mRNA (pplmRNA) level and pancreatic insulin content markedly increased approximately two- to threefold (P less than 0.001) with the development of hyperinsulinemia, whereas sham-operated rats showed no significant change. In Zucker and Wistar lean rats, the pplmRNA level and pancreatic insulin content increased with age, corresponding to increases in body weight. In Zucker fatty rats, the pplmRNA level and pancreatic insulin content at 5 and 14 wk of age were significantly higher than those of lean littermates. The pplmRNA level in Zucker fatty rats at 14 wk of age reached 290% of that of their lean littermates (P less than 0.001). On the other hand, the pplmRNA level and pancreatic insulin content in Wistar fatty rats at 5 and 14 wk of age did not increase more than those of their lean littermates at the corresponding ages and were therefore significantly lower than in Zucker fatty rats, which had a higher grade of hyperinsulinemia at 14 wk of age.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Sep
PMID:Importance of imparied insulin-gene expression in occurrence of diabetes in obese rats. 169 58

To investigate further the role of cytokines in the pathogenesis of type I insulin-dependent diabetes mellitus, the effects of interleukin-1 beta (IL-1), tumour necrosis factor-alpha (TNF) and gamma-interferon (IFN) were tested on rat insulinoma INS-1 cells. Whereas TNF and IFN had, respectively, a minor or no effect on insulin production, IL-1 caused a time- and dose-dependent decrease in insulin release and lowered the insulin content as well as the preproinsulin mRNA content of INS-1 cells. Both IL-1 and TNF exerted a cytostatic effect, estimated by a decrease in [3H]thymidine incorporation, while only IL-1 decreased cell viability as measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The glutathione content of INS-1 cells was shown to be modulated by the presence of 2-mercaptoethanol in the culture medium, but was not affected by IL-1 or TNF. In conclusion, INS-1 cell culture is considered to be a useful model for studying the effect of cytokines on insulin-producing cells. The differentiated features of these cells will permit several questions to be addressed regarding the mechanism of action of IL-1 and eventually other cytokines, both at the level of gene expression and of intracellular signalling.
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PMID:Effects of cytokines on rat insulinoma INS-1 cells. 173 60

Insulin is both produced and degraded within the pancreatic Beta cell. Production involves the synthesis of the initial insulin precursor preproinsulin, which is converted to proinsulin shortly after (or during) translocation into the lumen of the rough endoplasmic reticulum. Proinsulin is then transported to the trans-cisternae of the Golgi complex where it is directed towards nascent secretory granules. Conversion of proinsulin to insulin and C-peptide arises within secretory granules, and is dependent upon their acidification. Granule contents are discharged by exocytosis in response to an appropriate stimulus. This represents the regulated secretory pathway to which more than 99% of proinsulin is directed in Beta cells of a healthy individual. An alternative route also exists in the Beta cell, the constitutive secretory pathway. It involves the rapid transfer of products from the Golgi complex to the plasma membrane for immediate release, with, it is supposed, little occasion for prohormone conversion. Even if delivered appropriately to secretory granules, not all insulin is released; some is degraded by fusion of granules with lysosomes (crinophagy). Each event in the molecular lifestyles of insulin and its precursors in the Beta cell will be seen to be governed by their own discrete functional domains. The identification and characterisation of these protein domains will help elucidate the steps responsible for delivery of proinsulin to secretory granules and conversion to insulin. Understanding the molecular mechanism of these steps may, in turn, help to explain defective insulin production in certain disease states including diabetes mellitus.
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PMID:Structural domains and molecular lifestyles of insulin and its precursors in the pancreatic beta cell. 176 34

Cytokine effects on permanent cell lines of transformed mouse pancreatic alpha- and beta-cells were compared. The beta-tumor cell 1 (beta TC1) line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat insulin II promoter) produced insulin predominantly, although small quantities of intracellular glucagon (100:1 insulin to glucagon) were detectable by radioimmunoassay. The alpha TC1 line (from an adenoma created in transgenic mice expressing the SV40 large T-antigen oncogene under control of the rat preproglucagon promoter) produced not only glucagon but also considerable quantities of insulin (4:1 glucagon to insulin) and preproinsulin mRNA. We therefore cloned alpha TC1 cells and obtained 12 glucagon-producing clonal cell lines that did not produce levels of insulin detectable by radioimmunoassay. Analysis by Northern blotting of total RNA from two lines, alpha TC1 clones 6 and 9, confirmed the absence of preproinsulin mRNA. No somatostatin or pancreatic polypeptide was detected by immunohistochemical staining in alpha TC1 clones 6 or 9 or beta TC1 cells. Rat recombinant gamma-interferon (IFN-gamma; 5-250 U/ml) or mouse recombinant interleukin 1 (IL-1; 1-25 U/ml) individually inhibited DNA synthesis in beta TC1 cells after 3 days of treatment. The two cytokines in combination acted synergistically to further depress DNA synthesis and increase cytotoxicity. In contrast, alpha TC1 clone 9 cells were not sensitive to inhibition of DNA synthesis by each cytokine individually, although glucagon synthesis was inhibited. The combination of these cytokines caused marked inhibition of DNA and glucagon syntheses in alpha TC1 clone 9 cells. alpha TC1 clone 9 cells were somewhat more resistant to the cytotoxic action of the combined cytokines than were beta TC1 cells. Incubation with 50 U/ml IFN-gamma induced class II MHC molecules (I-Ab, I-Ad, and I-Ed) and enhanced the constitutive expression of class I molecules (H-2Kb and H-2Kd) on the cell surfaces of beta TC1, uncloned alpha TC1, and alpha TC1 clones 6 and 9. Thus, these cell lines are heterozygous for MHC alleles derived from both parental strains used in the construction of the transgenic mice [C57BL/6J (H-2b) and DBA/2J (H-2d)]. Class II gene transcription induced by IFN-gamma was confirmed in beta TC1 and alpha TC1 clone 9 cells by Northern blot analysis with A alpha-, A beta-, E alpha, and E beta-DNA probes.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1990 Apr
PMID:Comparison of cytokine effects on mouse pancreatic alpha-cell and beta-cell lines. Viability, secretory function, and MHC antigen expression. 210 69

We recently described autoantibodies that stimulate the release of insulin from pancreatic beta-cells both in vitro and in vivo. The aim of this study was to establish whether islet cell-stimulating antibodies (ICSTAs) also increase islet cell preproinsulin mRNA content. Wistar rat islets, isolated by collagenase digestion, were exposed to 2.7 and 11.1 mM glucose. Insulin release increased 10-fold in response to the higher glucose concentration, and dot-blot analysis of islet mRNA with a rat preproinsulin cDNA probe showed a concomitant increase in mRNA levels. The globulin fractions of four test serums, three from patients with type I (insulin-dependent) diabetes and one from a patient with the insulin autoimmune syndrome, showed clear (5- to 8-fold) stimulation of insulin release. The nonglobulin fractions of these serums and both fractions of three control serums failed to stimulate secretion of insulin. The insulin mRNA content of islets incubated with the ICSTA globulin fractions was greatly increased compared with levels observed in islets treated with control serum globulin fractions. We conclude that ICSTAs not only can stimulate the release of insulin but also increase the preproinsulin mRNA content of islet cells.
Diabetes 1990 Oct
PMID:Increased preproinsulin mRNA in pancreatic islets incubated with islet cell-stimulating antibodies from serums of type I diabetic patients. 221 69

C57BL/KsJ (BKs) and CBA/J, but not C57BL/6J (B6) mice are susceptible to the diabetogenic action of the obesity gene, "diabetes" (db). BKs and CBA/J, but not B6 mice, constitutively express intracisternal type A particles (IAP), an endogenous class of retrovirus, in beta cells and in cortical thymocytes. IAP genetic expression in these cell types included production of the group-specific antigen, p73, as well as higher-molecular mass p73-related antigens (p114-120). We used islet culture techniques to show that both transcription and translation of IAP genomes in beta cells in enhanced by glucose. Maintenance of CBA/J islets for 48 h in 16.5 mM glucose-containing medium effected a fivefold induction of IAP protein synthesis in comparison to islets cultured in low- (5.5 mM) glucose medium. Analysis of RNA from 16.5 mM glucose-cultured islets revealed induction of 7.2 and 5.4 kbp transcripts known to code for p73 and the p114-120 polypeptides, respectively. This induction in CBA/J islets was 10-15-fold on a tissue basis, and 5-7-fold on an RNA basis. Glucose induction of preproinsulin mRNA levels was also analyzed in the same samples. Islets cultured in 16.5 mM glucose showed an eightfold higher level on a tissue basis, and a fourfold increase in terms of total recovered RNA. Comparison of these glucose-inducible parameters in islets isolated from the diabetes-susceptible BKs strain vs. the resistant B6 strain revealed that expression of the group-specific retroviral p73 antigen was limited to BKs beta cells. This inbred strain control of p73 expression was also found in cortical thymocytes, with B6 thymocytes producing a 117 kD component to the exclusion of p73, while both components were expressed in thymocytes from normal BKs mice. In comparison to normal BKs males, thymocytes from four week-old genetically diabetic (db/db) BKs males showed no change in labeling of p117, but showed a sharply diminished incorporation into p73. This suggested that accelerated thymic involution characteristic of db/db mice may entail selective elimination of p73-producing cells. The possibility that glucose-stressed BKs pancreatic beta cells are marked for autoimmune elimination by the elaboration of p73 or other IAP-related proteins is discussed.
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PMID:Glucose induces intracisternal type A retroviral gene transcription and translation in pancreatic beta cells. 307 15

Gruppuso et al. [Gruppuso, P.A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. & Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into lambda-WES and recombinants containing the two insulin alleles, lambda MD41 and lambda MD51, were isolated by plaque hybridization. DNA sequencing of lambda MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambda MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC----GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results, along with the linkage analysis of Elbein et al. [Elbein, S.C., Gruppuso, P., Schwartz, R., Skolnick, M. & Permutt, M.A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin.
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PMID:A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. 347 Jul 84

Insulin resistance is a characteristic feature of non-insulin dependent diabetes mellitus (NIDDM) due to target tissue defects in insulin action. Abnormalities of cellular insulin action can be divided into receptor and post-receptor defects. Patients with impaired glucose tolerance are insulin resistant due to decreased insulin receptors resulting in decreased insulin sensitivity and rightward shifted in vivo dose response curves. Patients with NIDDM are insulin resistant due to a combination of receptor and post-receptor defects. The greater the severity of the diabetes (greater fasting hyperglycemia) the greater the post-receptor defect, and in those patients with more significant fasting hyperglycemia the post-receptor defect is the predominant abnormality leading to the insulin resistant state. At least one of the abnormalities underlying this post-receptor defect involves a decrease in glucose transport system activity in freshly isolated adipocytes. This defect in glucose transport, is not expressed in cultured fibro-blasts, indicating that the abnormality in glucose disposal seen in vivo and in glucose transport seen in freshly isolated cells is an acquired phenomenon. Consistent with this, the post-receptor defect is partially reversible by insulin therapy, which leads to a 50-70% reversal of the reduced rates of in vivo glucose disposal and in vitro glucose transport. Insulin resistance also exists in poorly controlled IDDM patients, due to a postreceptor defect in insulin action. This insulin resistance is not present in well controlled IDDM patients, and is completely reversible when poorly controlled patients are treated with intensive insulin therapy. Insulin is produced in the pancreatic beta cell as the primary biosynthetic product preproinsulin. This peptide is rapidly converted to proinsulin (MW approximately 9000). Proinsulin is converted to insulin (MW approximately 6000) plus C-peptide in the secretory granule with a small amount (approximately 5 percent) of the proinsulin remaining unconverted. After a brief time in the peripheral circulation (half-life six to 10 minutes), insulin interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is the promotion of overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states including Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). Since insulin travels from the beta cell through the circulation to the target tissues, abnormalities at any of these loci can influence the ultimate action of the hormone. These abnormalities, all
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PMID:Insulin resistance in non-insulin dependent (type II) and insulin dependent (type I) diabetes mellitus. 389 63

A complementary DNA (cDNA) library was prepared from messenger RNA (mRNA) isolated from Syrian hamster islets. Bacterial colonies containing hamster preproinsulin cDNA were identified by cross-hybridization with the human preproinsulin gene. The sequences of two of these established the complete sequence of Syrian hamster preproinsulin mRNA and predicted the sequence of the protein. Hamster preproinsulin is 110 amino acids and possesses 90.0% and 82.7% identity with the corresponding proteins of rats (either I or II) and human beings, respectively. Analysis of the hybridization of hamster preproinsulin cDNA to restriction endonuclease digests of hamster DNA suggests that there is only a single preproinsulin gene in this rodent, in contrast to rats and mice, which possess two nonallelic genes.
Diabetes 1984 Mar
PMID:Sequence of a cDNA encoding Syrian hamster preproinsulin. 636 63

The human insulin domains, signal peptide, B-chain, C-peptide, and A-chain, were highly expressed in Escherichia coli as recombinant proteins N-terminally fused to glutathione-S-transferase and a histidine-hexapeptide. The recombinant proteins were purified from insoluble cell fraction by affinity chromatography using metal chelating matrix, which was charged with Ni+2 ions. ELISA screening for autoantibodies directed to preproinsulin were performed with sera from patients with recently diagnosed insulin-dependent diabetes mellitus in order to localize the antigenic epitopes within the human preproinsulin. Of the patients, 14% had developed autoantibodies that recognized either the recombinant C-peptide or the signal peptide. No reaction was observed with the A-chain or B-chain.
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PMID:Mapping of antigenic epitopes within the recombinant human preproinsulin related to insulin-dependent diabetes mellitus. 751 60


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