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)

A radioimmunoassay for the GLUT1 glucose transporter was developed with a synthesized peptide based on the sequence of the cDNA for GLUT1. A peptide corresponding to the COOH-terminal domain of the GLUT1 glucose transporter (Thr-Pro-Glu-Glu-Leu-Phe-His-Pro-Leu-Gly-Ala-Asp-Ser-Gln-Val) was synthesized and conjugated to keyhole limpet hemocyanin through the NH2-terminal of the peptide. An antibody was raised against this complex and affinity purified with the immobilized peptide. A second peptide, with tyrosine residue added to the NH2-terminal of the above peptide, was synthesized and used as a standard and iodinated for preparation of the radioactive ligand. The assay is highly reproducible, sensitive, and specific for the COOH-terminal domain of the GLUT1 glucose transporter. It has no cross-reactivity with the other glucose-transporter isoforms GLUT2 and GLUT4. Furthermore, the results obtained with this radioimmunoassay on the number of glucose transporters in human erythrocytes were in good agreement with previous studies based on cytochalasin B binding, suggesting that this radioimmunoassay is able to quantify the number of glucose transporters. The assay is completed within 4 h and can be used for simultaneous measurement of GLUT1 in many samples. In addition, it can be applied to the measurement of GLUT1 in several types of tissue.
Diabetes 1991 Mar
PMID:Peptide-based radioimmunoassay specific for GLUT1 glucose transporter. 199 71

To determine whether the responses of muscle protein metabolism to insulin and amino acids in patients with insulin-dependent diabetes mellitus (IDDM) were different from those in nondiabetic subjects, leg tissue kinetics of [15N]phenylalanine and [1-13C]leucine and its metabolites were measured in eight insulin-withdrawn IDDM patients and eight nondiabetic subjects during basal insulinemia and during infusion of insulin (0.29 nmol.min-1.m-2). The diabetic patients were studied in the absence of amino acids, and both groups were studied during infusion of a mixed-amino acid solution (AA). In the diabetic patients, insulin alone and combined with additional AA reduced leg tissue phenylalanine release by 42 and 41%, respectively (both P less than 0.05), but uptake was unchanged. Leg tissue leucine oxidation was unchanged by insulin alone but was increased (P = 0.012) fourfold during insulin infusion with additional AA. In the nondiabetic subjects, insulin with AA infusion increased leg tissue phenylalanine uptake (45.7 +/- 7.5 to 73.1 +/- 7.3 nmol.min-1.100 g-1, P less than 0.01). Insulin-stimulated glucose uptake in the diabetic patients (1.60 +/- 0.28 mumol.min-1.100 g-1, P = 0.04). These results suggest that, in IDDM patients, 1) infusion of insulin fails to stimulate muscle protein synthesis even when combined with a substantially increased provision of AA, and 2) compared with nondiabetic subjects, muscle protein synthesis as well as glucose uptake exhibit blunted responses to insulin.
Diabetes 1991 Apr
PMID:Effects of insulin and amino acids on leg protein turnover in IDDM patients. 201 51

The cholecystokinin-tetrapeptide (CCK4) analogs Trp-Pro-Asp-Phe-NH2 (3) and Trp-Pro-Asp-Phe-(4'-NO2)-NH2 (4) were found to be nearly equipotent to cholecystokinin-octapeptide (CCK8) in potentiating glucose-induced insulin secretion from islets of Langerhans isolated from rat pancreas. This stimulatory action was found to be dose-dependent and, in the case of 4, to exhibit a biphasic dose-response curve; i.e., at concentrations greater than 1.0 nM, the stimulating effect of 4 is reversed. These results suggest that conformational restriction of CCK4 and/or modification of the phenylalanine residue could produce more potent analogs capable of stimulating insulin release. Such compounds could have potential therapeutic utility in the treatment of non-insulin-dependent diabetes mellitus (NIDDM).
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PMID:Stimulation of insulin secretion from pancreatic islets by the cholecystokinin-tetrapeptide analogs Trp-Pro-Asp-Phe-NH2 and Trp-Pro-Asp-Phe(4'-NO2)-NH2. 213 65

Rat neutrophil chemotactic responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene (LT) B4, and lipopolysaccharide-activated serum (LPS-AS) were quantitatively assessed using the micropore filter system. Cells were suspended in either normal or diabetic rat serum for testing. Diabetic donor serum did not affect migration of neutrophils in a concentration gradient of the synthetic chemotactic agents. In contrast, the migratory responses to LPS-AS were significantly less than normal in this circumstance. Summation of effects was observed when FMLP and LPS-AS, or LTB4 and LPS-AS were simultaneously added to the test chamber, with cells suspended in normal serum. Suspended in diabetic rat serum neutrophils responded normally to the synthetic chemoattractants but the response to the activated serum was blocked. Cells previously incubated in the presence of diabetic donor serum then transferred to a culture medium for testing, presented reduced migratory responses to LPS-AS. Supramaximal, inhibitory concentrations of FMLP and LTB4, did not influence the response of neutrophils to LPS-AS. In vivo, suppression of cellular emigration to an inflamed area was observed from the early stages of the diabetic state. The inhibitory activity of chemotaxis in diabetes mellitus was previously reported to be associated with a protein factor in plasma of the animals. It is suggested that the inhibitory factor of chemotaxis in diabetes mellitus interacts with neutrophil receptors for complement-derived chemoattractants to induce blockade of cell-oriented locomotion either in vitro or in vivo.
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PMID:Inhibition of leukocyte chemotaxis by serum factor in diabetes mellitus: selective depression of cell responses mediated by complement-derived chemoattractants. 216 2

Several lines of evidence suggest that phagocyte-mediated oxidative processes are involved in damage to pancreatic islet cells of Type I insulin-dependent diabetes mellitus (IDDM). This hypothesis, however, has not yet been explored at the clinical onset of IDDM. Similarly, the possibility that cyclosporine A (Cy-A) might exert a selective influence on these phagocyte-mediated oxidative reactions has also not yet been investigated as compared to a placebo. The present study tested both hypotheses in 32 patients with recently diagnosed IDDM who were part of the recent French multicenter randomized therapeutic trial of Cy-A. The production of reactive oxygen intermediates (ROI) by circulating polymorphonuclear (PMN) and mononuclear (MN) phagocytes was determined by luminol-dependent chemiluminescence (CL), both directly within microamounts of whole blood and in purified PMN or MN phagocyte suspensions. Lastly, CL production was measured in the absence (resting CL) and the presence of a panel of particular and soluble phagocyte membrane-stimulating agents. We found that on entry into the trial, i.e. within less than 2 months of the clinical onset of IDDM, patients had normal whole blood CL production in the absence of a stimulating agent and upon phagocytic challenge with latex or opsonised zymosan particles. By contrast, whole blood CL responses to soluble stimuli such as phorbol myristate acetate (PMA), concanavalin A (Con-A) and F Met-Leu-Phe (FMLP) were significantly higher than in the control group of 52 normal subjects (P less than 0.01). In purified PMN and MN phagocyte suspensions, both resting and stimulated CL productions were normal, regardless of the type of stimulating agent. After 3 months of treatment, whole blood CL responses to Con-A and FMLP returned to almost normal levels in patients treated with Cy-A (15 cases) but not in those receiving the placebo (17 cases); PMA-induced CL responses were also decreased, but this was found in both groups of patients. In purified phagocyte suspensions we detected no effect of Cy-A on PMN, whereas MN phagocytes from Cy-A-treated patients showed reduced CL responses to FMLP but not to other stimuli. Altogether, these results demonstrate for the first time that the capacity of circulating PMN and MN phagocytes to generate ROI is normal at the clinical onset of IDDM and suggest that circulating substances increase oxidative responses to soluble, but not particulate, stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phagocyte oxidative metabolism in cyclosporine- or placebo-treated patients with insulin-dependent (type I) diabetes mellitus of recent onset. 218 53

Studies on naturally occurring and man-made mutations in the insulin gene have provided new insights into insulin biosynthesis, action, and metabolism. Ten families have been identified in which one or more members have single-point mutations in their insulin genes that result in amino acid substitutions within the proinsulin molecule. Six of these cause the secretion of biologically defective insulin molecules due to changes within the A or B chains. Replacing A3-Val with Leu, B24-Phe with Ser, or B25-Phe with Leu results in molecules that have essentially normal immunoreactivity but greatly reduced insulin-receptor-binding potency. Individuals with these mutations have a syndrome of mild diabetes or glucose intolerance, which is inherited in an autosomal-dominant mode and is associated with hyperinsulinemia and altered insulin-C-peptide ratios. Although affected individuals are heterozygous and coexpress both normal and abnormal molecules, the elevated circulating insulin consists mainly of the biologically defective form, which accumulates because it fails to be rapidly metabolized via receptor-mediated endocytosis. Four additional families have mutations that are associated with relatively asymptomatic hyperproinsulinemia. A point mutation affecting proinsulin occurs in 3 of the 4 families, leading to replacement of Arg-65 by His, which prevents recognition of the C-peptide-A-chain dibasic cleavage site by the appropriate beta-cell processing protease and results in the circulation of a type II proinsulin intermediate form (des 64, 65 HPI). Members of a fourth family with hyperproinsulinemia have a substitution of B10-His with Asp, resulting in a proinsulin that exhibits markedly altered subcellular sorting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Care 1990 Jun
PMID:Lessons learned from molecular biology of insulin-gene mutations. 219 46

Metabolic potency of des-(B26-B30)-insulin-B25-amide, [TyrB25]des- (B26-B30)-insulin-B25-amide and [HisB25]des-(B26-B30)-insulin-B25-amide was studied in anaesthetized rats. Compared to insulin, full potency for des-(B26-B30)-insulin-B25-amide and an enhanced potency for both substituted analogues has been described previously on rat adipocytes in vitro. Hypoglycaemic effects following i.v. injection of all of these analogues were almost identical to those of native insulin with a half-maximal effective dose of approximately 3 nmol.kg-1. Stimulation of glucose metabolism during euglycaemic hyperinsulin-/analogueaemic clamp studies was indistinguishable from that of the native hormone with a maximal stimulation of approximately 19 mg.kg-1.min-1 and half-maximal effective hormone concentrations of approximately 1 pmol.ml-1. Analogue action on individual peripheral tissues estimated by the uptake of 2-deoxyglucose as well as stimulation of lipogenesis in epididymal fat was not different to that of insulin. These data demonstrate that C-terminal amidation of des-(B26-B30)-insulin results in a shortened molecule with full in vivo metabolic potency. When substituting phenylalanine in position B25 by tyrosine or histidine, the insulin-identical potency is preserved.
Diabetes Res Clin Pract 1990 Jul
PMID:In vivo metabolic activity of des-(B26-B30)-insulin-B25-amide and related analogues in the rat. 222 26

The potencies of several opioid agonists are reduced in diabetic animals and in animals made hyperglycemic via injections of glucose. In this report we examined the effects of streptozotocin-induced diabetes on the feeding responses to centrally administered opioid agonists with differing receptor selectivities. The selective mu receptor agonist Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAGO) caused a larger increase in intake in diabetic rats than in controls. In both groups feeding responses were greater on the fourth day of daily injections than on the first day. The delta receptor agonist [D-Ser2,Leu5]-enkephalin-Thr6 (DSLET) stimulated intake in controls but not in diabetics. However, the elevated baseline and large variability in intake of the diabetics in this experiment prevent drawing a conclusion on diabetes-induced changes in the potency of this peptide. No differences between controls and diabetics were apparent in the feeding responses to U50, 488H, a selective kappa receptor agonist. These data suggest that diabetes may differentially affect the classes of opioid receptors or the binding of ligands to these receptors.
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PMID:Effects of streptozotocin-induced diabetes on feeding stimulated by centrally administered opioid agonists. 254 90

Insulin binds to a receptor on the cell surface, thereby triggering a biological response within the target cell. Mutations in the insulin receptor gene can render the cell resistant to the biological action of insulin. We have studied a family in which two sisters have a genetic form of insulin-resistant diabetes mellitus. The technique of homozygosity mapping has been used to demonstrate that the mutation causing diabetes in this consanguineous family is genetically linked to the insulin receptor gene. The two insulin-resistant sisters are homozygous for a mutation encoding substitution of valine for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. Transfection of mutant insulin receptor cDNA into NIH3T3 cells demonstrated that the Val382 mutation impaired post-translational processing and retarded transport of the insulin receptor to the plasma membrane. Thus, the mutation causes insulin resistance by decreasing the number of insulin receptors on the surface of the patients' cells.
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PMID:A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes. 257 22

The degradation of intracellular protein and other cytoplasmic macromolecules in liver is an ongoing process that regulates cytoplasmic mass and provides amino acids for energy and other metabolic uses early in starvation. Cellular proteins are conveniently divided into two general classes according to readily discernable differences in average rates of turnover. A short-lived class, having a half-life of approximately 10 min, comprises about 0.6% of total protein. Its degradation is not physiologically controlled, and the mechanism is probably nonlysosomal in nature. The second or long-lived group, with an average half-life 250 times greater, constitutes more than 99% of the cell's protein. By contrast, its breakdown is strongly regulated, and the site of catabolism is believed to be the vacuolar-lysosomal system. Cytoplasmic sequestration by lysosomes can be divided into two categories; macro- and microautophagy. The first is induced by amino acid and/or insulin deprivation. Amino acids are considered to be primary regulators, since they can control this process over the full range of induced proteolysis in the absence of hormones. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in myocytes. Micrautophagy differs from the former in that the cytoplasmic "bite" is smaller and the uptake process is not acutely regulated. However, the latter does decrease during starvation in parallel with basal proteolysis, effects that might be linked to the loss of endoplasmic reticulum. The primary control of macroautophagy is accomplished through a small group of direct regulators (Leu, Tyr/Phe, Gln, Pro, Met, His, and Trp) and a specific coregulatory action of alanine. As a group, regulatory amino acids produce direct inhibitory responses in the perfused rat liver that are identical to those of the complete amino acid mixture at 0.5x and 4x (times) normal plasma concentrations. However, they lose effectiveness almost completely within a narrow zone centered at normal levels, a loss that can be abolished by the addition of alanine at its normal plasma concentration (0.5 mM). At this level, alanine does not inhibit directly. Interestingly, this zonal loss is also eliminated by insulin. Glucagon, though, specifically blocks the initial inhibition evoked by 0.5x amino acid mixtures and thus induces maximal rates of protein degradation at normal amino acid concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1989 Feb
PMID:Mechanism and regulation of protein degradation in liver. 264 36


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