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)

Hormonal regulation of L-serine dehydratase [L-serine hydro-lyase (deaminating), EC 4.2.1.13] was studied in primary cultures of adult-rat hepatocytes. The hepatocytes were isolated by collagenase perfusion and maintained in culture on collagen-gel/nylon-mesh substrata. L-Serine dehydratase activity was measured with [14C]threonine as substrate. The enzyme activity in hepatocytes of normal adult rats was low and declined rapidly in culture in L-15 medium containing 0.1 micro M-insulin and even more in the presence of glucose. L-Serine dehydratase activity in hepatocytes of rats with streptozotocin-induced diabetes was initially 20-fold higher than that of normal rats, but fell rapidly to a low value by 4 days in culture. Hormonal regulation of the enzyme activity was manifested by treatment of the cultured hepatocytes with insulin (0.1 micro M), glucagon (0.3 micro M), dexamethasone (10 micro M) and combinations of these hormones. Either glucagon or dexamethasone in the absence of insulin enhanced the activity of L-serine dehydratase, but failed to do so in the presence of insulin. Treatment with both hormones resulted in a 2-3-fold increase in enzyme activity in culture on days 3 and 4. Under conditions in which the enzyme activity was enhanced, glucose production by the cultured hepatocytes was concomitantly increased. Glucose production resulted in part from gluconeogenesis from pyruvate and not entirely from glycogenolysis. The gluconeogenic conditions of culture resulted in a decrease in cellular lipids in the cultured hepatocytes, as evidenced by ultrastructural studies.
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PMID:Increase of L-serine dehydratase activity under gluconeogenic conditions in adult-rat hepatocytes cultured on collagen gel/nylon mesh. 732 17

The free amino acid content of diaphragm muscles of control and diabetic rats was studied 5 days after the injection of streptozotocin. Muscles were prepared for analysis either immediately after sacrifice or following incubation in balanced salt solution containing 5.5 mM glucose, with or without an electron acceptor, 0.02 mM methylene blue. Diaphragms of diabetic rats contained significantly more free taurine, glutamate, and branched chain amino acids than the controls at sacrifice, and significantly less glutamine, serine, asparagine, lysine, arginine, histidine, threonine, citrulline, and carnosine. Alanine decreased in plasma of diabetic rats but not in diaphragms before incubation. Hemidiaphragms of diabetic rats produced less alanine and more glutamate during incubation than controls. After incubation they contained less than half as much alanine and glutamine and twice as much glutamate than the controls, having released approximately 40% less alanine and 25% more glutamate into the medium than the controls. Glutamine release was not significantly different between the two groups. Methylene blue increased the free alanine content in the tissue water as well as alanine release by control and by diabetic muscles; the glutamate content of muscles decreased concomitantly. The effects of methylene blue were greater in the diabetic group. Branched chain amino acid release by diabetic muscles decreased during incubation with methylene blue. Muscles of diabetic rats contained more alpha-ketoglutarate than the controls after incubation with or without methylene blue. Methylene blue increased the alpha-ketoglutarate content of muscles and its release into the medium, the effect being greater in diabetics than in controls. Hemidiaphragms from diabetic rats released less pyruvate during incubation than controls, while lactate release by the two groups was not significantly different. Incubation with methylene blue caused a marked increase in pyruvate release by diabetic muscles, and a lesser stimulation in controls; lactate release increased in both groups. After incubation the lactate/pyruvate ratio in muscles was lower in the methylene blue treated group. The in vitro effect of 0.02 mM phenazine methosulfate on alanine production was similar to that of methylene blue. The data is compatible with the hypothesis that the NADH/NAD ratio may exert a restraining effect on alanine production and release by muscle. The progressive increase in this ratio may play a role in the eventual deceleration of gluconeogenesis during a prolonged fast and may restrain this process in uncompensated diabetes.
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PMID:The effect of diabetes and the redox potential on amino acid content and release by isolated rat hemidiaphragms. 738 25

Diabetes is known to cause impaired endothelium-dependent relaxation of blood vessels. The purpose of this study was to determine whether this endothelial dysfunction is a permanent defect or is reversible after acute arginine supplementation in vitro or by surgical intervention in vivo using syngeneic pancreatic islet transplantation. Lewis rats were injected with streptozotocin to induce diabetes and were studied either 8 or 12 weeks later. Another group received syngeneic islets via intraportal injection at 8 weeks of diabetes and were allowed to become euglycemic for 4 weeks before study. Thoracic aortic rings were tethered in isolated muscle baths, contracted with a submaximal concentration of norepinephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator nitroglycerin. Relaxation to acetylcholine (but not nitroglycerin) was reduced in both 8- and 12-week diabetic rings compared with age-matched control rings. Preincubation of diabetic rings in vitro with L-arginine (but not D-arginine) restored relaxation to acetylcholine to normal to rings from 8-week but not 12-week diabetic animals. Plasma basic amino acids (arginine, lysine, and histidine) were reduced by diabetes, whereas other neutral or acidic amino acids were unchanged (phenylalanine, proline, and glutamate), reduced (serine, cysteine, threonine, tyrosine, tryptophan, and aspartate), or elevated (isoleucine, leucine, and valine). Islet transplantation restored to normal the changes in plasma amino acids. Elevation in blood glucose and total glycosylated hemoglobin in diabetic animals was normalized after islet transplantation. Furthermore, islet transplantation completely restored the defective endothelium-dependent relaxation to acetylcholine in diabetic rings.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Sep
PMID:Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes. 765 36

In response to insulin, several proteins are phosphorylated on tyrosine and on serine/threonine residues. Decreased phosphorylation of signaling peptides by a defective insulin receptor kinase may be a cause of insulin resistance. Accordingly, inhibition of the appropriate phosphatases might increase the phosphorylation state of these signaling peptides and thereby elicit increased glucose transport. The purpose of this study was to examine the effect of the serine/threonine phosphatase inhibitor okadaic acid and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate on 2-deoxyglucose transport in insulin-resistant human skeletal muscle. All three phosphatase inhibitors stimulated 2-deoxyglucose transport in insulin-resistant skeletal muscle. These data suggest that these compounds have bypassed a defect in at least one of the signaling pathways leading to glucose transport. Furthermore, maximal transport rates induced by the simultaneous presence of insulin and phosphatase inhibitor in insulin-resistant muscle were equal to insulin-stimulated rates in lean control subjects. However, both vanadate alone and vanadate plus insulin stimulated 2-deoxyglucose transport significantly more in insulin-sensitive tissue than in insulin-resistant tissue. These results demonstrate that although vanadate is able to stimulate glucose transport in insulin-resistant muscle, it is not able to normalize transport to the same rate achieved in insulin-sensitive muscle.
Diabetes 1995 Jun
PMID:Okadaic acid, vanadate, and phenylarsine oxide stimulate 2-deoxyglucose transport in insulin-resistant human skeletal muscle. 778 33

We have recently identified a new member of the Ras/GTPase superfamily termed Rad which has unique sequence features and is overexpressed in the skeletal muscle of humans with type II diabetes (Reynet, C., and Kahn, C. R. (1993) Science, 262, 1441-1444). When expressed in bacteria as a glutathione S-transferase fusion protein, Rad bound [alpha-32P]GTP quickly and saturably. Binding was specific for guanine nucleotides and displayed unique magnesium dependence such that both GTP and GDP binding were optimal at relatively high Mg2+ concentrations (1-10 mM). Rad had low intrinsic GTPase activity which was greatly enhanced by a GTPase-activating protein (GAP) activity present in various tissues and cell lines. Several known GAPs had no stimulatory effect toward Rad. Conversion of Ser to Asn at position 66 in Rad (equivalent to position 12 in Ras) resulted in a total loss of GTP binding. Mutation of Pro61 (equivalent to Gly12 in Ras) or Gln109 (equivalent to Gln61 in Ras) had no effect on Rad GTPase activity, whereas creation of a double mutation at these positions resulted in exceptionally high intrinsic GTPase activity. In vitro, Rad was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PK). Phosphopeptide mapping indicated two PKA phosphorylation sites near the COOH terminus. Rad also co-precipitated a serine/threonine kinase activity from extracts of various tissues and cell lines which catalyzed phosphorylation on Rad but was not inhibited by PKA inhibitor. Thus, Rad is a GTP-binding protein and a GTPase which has some structure/function similarities to Ras, but displays unique features. Rad may also be phosphorylated on serine/threonine residues by PKA and other kinases, as well as regulated by its own GAP which is present in many tissues and cell types.
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PMID:Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity. 787 54

A Xenopus oocyte expression system was used to examine how glucose transporters (GLUT 2 and GLUT 3) and glucokinase (GK) activity affect glucose utilization. Uninjected oocytes and low rates of both glucose transport and phosphorylation; expression of GLUT 2 or GLUT 3 increased glucose phosphorylation approximately 20-fold by a low Km, endogenous hexokinase at glucose concentrations < or = 1 mM, but not at higher glucose concentrations. Coexpression of functional GK isoforms with GLUT 2 or 3 increased glucose utilization approximately an additional two- to threefold primarily at the physiologic glucose concentrations of 5-20 mM. The Km for glucose of both the hepatic and beta cell isoforms of GK, determined in situ, was approximately 5-10 mM when coexpressed with either GLUT 2 or GLUT 3. The increase in glucose utilization by coexpression of GLUT 3 and GK was dependent upon glucose phosphorylation since two missense GK mutations linked with maturity-onset diabetes, 182: Val-->Met and 228:Thr-->Met, did not increase glucose utilization despite accumulation of both a similar amount of immunoreactive GK protein and glucose inside the cell. Coexpression of a mutant GK and a normal GK isoform did not interfere with the function of the normal GK enzyme. Since the coexpression of GK and a glucose transporter in oocytes resembles conditions in the hepatocyte and pancreatic beta cell, these results indicate that increases in glucose utilization at glucose concentrations > 1 mM depend upon both a functional glucose transporter and GK.
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PMID:Coexpression of glucose transporters and glucokinase in Xenopus oocytes indicates that both glucose transport and phosphorylation determine glucose utilization. 792 12

During the past two decades epidemiological, clinical and laboratory studies have confirmed the existence of the diabetic heart in some patients with diabetes mellitus. The diagnosis was made in patients in whom other known etiological factors, such as coronary artery disease, alcoholism or hypertensive cardiovascular disease, were ruled out. The newer concept of the diabetic hypertensive heart is clinically based on a higher incidence of congestive heart failure caused by extensive myocardial involvement. In patients with hypertension and hypertension associated with diabetes, the intramyocardial arterioles present medial hypertrophy and a diminished lumen, increased periarteriolar fibrosis, accumulation of fibrillar collagen and patent extramural coronary arteries. Such confirmatory findings have been previously seen in experimental animals and in patients with diabetes and no hypertension. In the genetically diabetic rat, diabetes may be prevented by neonatal thymectomy, suggesting the existence of an autoimmune deficiency syndrome. Furthermore, conversion of Ala 776 into Thr 776 on the polyprotein by a point mutation results in loss of diabetogenicity. Abnormalities in systole and diastole related to lowering of CK-M and CK-B mRNA levels are normalized following insulin therapy. Identification of the genetic factors in the diabetic heart may lead to the identification of its pathogenic mechanisms.
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PMID:Unravelling the conundrums of the diabetic heart diagnosed in 1876: prelude to genetics. 795 32

We analyzed the structural correlates underlying the insulin-dependent selection of the specific anti-insulin IgG1 kappa mAb13-producing cell clone, derived from a patient with insulin-dependent diabetes mellitus treated with recombinant human insulin. First, we cloned the germ-line genes that putatively gave rise to the expressed VH and V kappa segments and used them to generate the full (unmutated) "germ-line revertant" of the "wild-type" (somatically mutated) mAb13, using recombinant PCR methods and an in vitro human C gamma 1 and C kappa expression system. The full "germ-line revertant" bound insulin specifically and in a dose-saturable fashion, but with a relative avidity (AVrel) more than three-fold lower than that of its wild-type counterpart (Avrel, 1.69 x 10(-8) vs 4.91 x 10(-9) g/microliters). Second, we established, by reassorting wild-type and germ-line revertant forms of the mAb13 VH and V kappa segments, that the increased Avrel for insulin of mAb13 when compared with its full "germ-line revertant" counterpart was entirely dependent on the mutations in the VH not those in the V kappa chain. Third, we determined, by site-directed mutagenesis experiments, that of the three mutations in the mAb13 VH segment (Ser-->Gly, Ser-->Thr, and Ser-->Arg at positions 31, 56, and 58, respectively), only Arg58 was crucial in increasing the mAb13 Avrel (from 1.44 x 10(-8) to 5.14 x 10(-9) g/microliters) and affinity (Kd, from 189 to 59 nM) for insulin. The affinity enhancement mediated by the VH segment Arg58 residue reflected about a threefold decrease in dissociation rate constant (Koff, from 4.92 x 10(-3) to 1.54 x 10(-3) s-1) but not an increase in association rate constant (Kon, from 2.60 x 10(4) to 2.61 x 10(4) M-1 s-1), and it contrasted with the complete loss of insulin binding resulting from the substitution of the VH segment Asn52 by Lys. The present findings suggest that human insulin, a self Ag, has the potential to recruit a natural autoantibody-producing cell precursor expressing a specific surface receptor for Ag in unmutated configuration, and drive it through affinity maturation. They also show that binding of insulin by such a receptor can be enhanced or completely abrogated by a single amino acid change.
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PMID:A human anti-insulin IgG autoantibody apparently arises through clonal selection from an insulin-specific "germ-line" natural antibody template. Analysis by V gene segment reassortment and site-directed mutagenesis. 799 43

Glut2, the facilitative glucose transporter isoform expressed in pancreatic beta cells, is believed to play a role in glucose-stimulated insulin secretion. Two polymorphisms that result in amino acid substitutions have been reported in the human Glut2 gene (Tanizawa, Y., Riggs, A. C., Chiu, K. C., Janssen, R. C., Bell, D. S. H., Go, R. P. C., Roseman, J. M., Acton, R. T., and Permutt, M. A. (1994) Diabetologia 37, 420-427). A threonine 110-->isoleucine substitution was present at equal frequency in diabetic and control populations, and a valine 197-->isoleucine substitution was discovered in a single allele of a patient with non-insulin-dependent diabetes. The effect of these amino acid changes on glucose transport activity was tested by expression of the mutant proteins in Xenopus oocytes. The polymorphism at threonine 110 had no effect on the expression of Glut2 protein or the uptake of 2-deoxyglucose. Remarkably, however, the highly conservative valine 197-->isoleucine amino acid change abolished transport activity of the Glut2 transporter expressed in Xenopus oocytes. This represents the first known dysfunctional mutation in a human facilitative glucose transporter protein. The presence of this mutation in a diabetic patient suggests that defects in Glut2 expression may be causally involved in the pathogenesis of non-insulin-dependent diabetes.
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PMID:A mutation in the Glut2 glucose transporter gene of a diabetic patient abolishes transport activity. 802 28

Mutations were screened for in the glucokinase gene of 25 Japanese patients with Type 2 (non-insulin-dependent) diabetes mellitus. Each exon was scanned by electrophoresis of enzymatically amplified DNA segments under non-denaturing conditions and variants were sequenced. A variant pattern was detected in exon 5 of one patient. Direct sequencing of this exon revealed a single nucleotide substitution in codon 188 (GCT-->ACT) of one of two alleles resulting in the mutation of Ala188-->Thr, an invariant residue in the sequence of all mammalian glucokinases and hexokinases. This mutation was not found in 40 normal control subjects. The proband had been diagnosed with Type 2 diabetes at the age of 62 years. Four other members of her family have the same mutation and all have Type 2 diabetes or impaired glucose tolerance. The youngest age at diagnosis of Type 2 diabetes in these other members was 13 years, suggesting that her pedigree was maturity-onset diabetes of the young (MODY). All subjects with the Thr188 mutation show a decreased insulin secretory response during oral glucose tolerance testing. Mutations in the glucokinase gene associated with Type 2 diabetes have been previously identified in Caucasian (French and British) subjects. This study indicates that mutations in this gene are also implicated in the development of Type 2 diabetes in Asians. Further studies are required to determine the frequency of mutations in glucokinase among Japanese patients with Type 2 diabetes.
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PMID:Type 2 (non-insulin-dependent) diabetes mellitus associated with a mutation of the glucokinase gene in a Japanese family. 831 48


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