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)

Aldose reductase (EC 1.1.1.21) is implicated in the pathophysiology of diabetic complications. In this paper we determined the activities of aldose reductase and ATPases of the erythrocytes in 17 patients with Type 2 (non-insulin-dependent) diabetes mellitus (NIDDM). In the aldose reductase assay we used fluorometric method to avoid the disturbance of hemoglobin. With dihydronicotinamide adenine dinucleotide (NADH), we verified it was aldose reductase but not aldehyde reductase II that was activated in the erythrocytes of the patients with NIDDM. The aldose reductase activity of the erythrocytes in the patients was significantly higher (P less than 0.01) than that in the controls. The activity of Na+/K(+)-ATPase of the patients was significantly lower (P less than 0.01) than that of the controls. The activities of Ca(2+)-ATPase and Mg(2+)-ATPase on the erythrocyte membranes of the patients were similar to those of the controls. At the same time we measured the seven nucleotide concentrations in the erythrocytes of the patients. In this experiment we used ultrafiltration method, instead of acid precipitation to make it possible to determine dihydronicotinamide adenine dinucleotide phosphate (NADPH) and NADH. The concentrations of ATP, ADP and AMP were similar to those of the controls. The concentrations of NADPH, NAD+ and NADH in the erythrocytes of the patients were significantly lower (P less than 0.01, 0.05 and 0.05 respectively) than those of controls. The concentration of nicotinamide adenine dinucleotide phosphate (NADP+) in the patients was significantly higher (P less than 0.01) than that of controls.
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PMID:Activities of aldose reductase, ATPases, and nucleotide concentrations of erythrocytes in patients with type 2 (non-insulin-dependent) diabetes mellitus. 166 Dec 22

Insulin receptor tyrosine kinase activity solubilized from hind limb muscle of control and streptozocin-induced diabetic (STZ-D) rats (2-3 wk) was studied with the substrates histone H2B and poly glutamic acid-tyrosine (glu-tyr) (4:1). Basal and insulin-stimulated kinase activities were inhibited when high concentrations of either substrate were added before initiation of phosphorylation with ATP. Under these conditions, insulin-stimulated activities of diabetic- and control-derived receptor kinase toward H2B were similar at 0.008 mg/ml H2B. However, higher concentrations of H2B (0.04-1 mg/ml) progressively reduced the ratios of diabetic-derived to control-derived receptor kinase activities to approximately 0.5. When inhibition of receptor kinase activities was prevented by allowing maximal autophosphorylation of insulin receptors before addition of H2B, kinase activity of diabetic- and control-derived receptors was similar at all H2B concentrations. Diabetic-derived insulin-receptor tyrosine kinase activity toward poly glu-tyr (4:1) was not significantly different from that of control rats. Under conditions of substrate inhibition (0.4 mg/ml H2B), insulin receptor H2B kinase activity from muscles of rats with severe diabetes (85 mg/kg STZ, 7 days) was significantly decreased, whereas the same activity from rats with moderate diabetes (50 mg/kg STZ, 7 days) was not significantly different from control rats. Insulin receptor alpha,beta dimers were not detectable in muscle preparations from control or diabetic rats. The data suggest that the impairment of muscle-derived insulin-receptor tyrosine kinase activity associated with insulinopenic diabetes reflects, in part, enhanced inhibition by some substrates. If solubilized insulin receptors and the exogenous substrates studied model in vivo events, impaired signaling of the muscle insulin receptor in insulinopenic diabetes may depend on the type and concentration of intracellular tyrosine kinase substrates and the severity of the metabolic derangements.
Diabetes 1991 Dec
PMID:Skeletal muscle insulin-receptor kinase. Effects of substrate inhibition and diabetes. 166 94

Specific binding of ADH by the membrane fraction of the kidney medulla was lower in the normal CBA mice than in mutant mice with nephrogenic diabetes. Gel filtration of the solubilized ADH receptors of mutants revealed the presence of an unidentified factor which caused cooperative binding of ADH. DEAE-chromatography revealed no difference between cytosolic cAMP receptors in normal and mutant animals. Assay of GTP-ase activity of the membrane fraction revealed that ADH increased this parameter in CBA mice but not in mutant animals. Cholera toxin significantly diminished membrane ATP-ase activity whereas membrane preparations from mutant mice developed a reactivity to ADH. GTP binding ability in these preparations was higher than inn intact ones. In CBA mice this ability increased dramatically. HPLC profiles of G-protein complexes with GNP were very different in CBA and mutant mice. Mutation seems to cause changes both in binding and in "cross-talk" link op-complex membrane receptor of ADH.
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PMID:[ADH and cAMP receptor binding in the kidney medulla of mice insensitive to ADH]. 166 85

To investigate the metabolic fates of glutamine in splenocytes from the BB rat with spontaneous immunologically mediated insulin-dependent diabetes, freshly isolated cells were incubated in Krebs-Ringer Hepes buffer with 1.0 mM-[U-14C]glutamine and 0, 4 mM- or 15 mM-glucose. (1) The major products of glutamine metabolism in splenocytes from normal and diabetic rats were ammonia, glutamate, aspartate and CO2. (2) The addition of glucose increased (P less than 0.01) glutamate production, but decreased (P less than 0.01) aspartate and CO2 production from glutamine, as compared with the values obtained in the absence of glucose. However, there were no differences in these metabolites of glutamine at 4 mM- and 15 mM-glucose. (3) At all glucose concentrations used, the productions of ammonia, glutamate, aspartate and CO2 from glutamine were all markedly increased (P less than 0.01) in splenocytes from diabetic rats. (4) Potential ATP production from glutamine in the splenocytes was similar to that from glucose, and was increased in cells from the diabetic rat. (5) ATP concentrations were increased (P less than 0.01) in diabetic-rat splenocytes in the presence of glutamine with or without glucose. (6) Our results demonstrate that glutamine is an important energy substrate for splenocytes and suggest that the increased glutamine metabolism may be associated with the activation of certain subsets of splenocytes in the immunologically mediated diabetic syndrome.
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PMID:Elevated glutamine metabolism in splenocytes from spontaneously diabetic BB rats. 167 65

The metabolism of glutathione and activities of its related enzymes were investigated in erythrocytes from patients with diabetes mellitus. A decrease in the levels of the reduced form of glutathione and an increase in the levels of glutathione disulfide were observed in erythrocytes from diabetics whose fasting plasma glucose was more than 140 mg/dl. The activity of glutathione reductase decreased in diabetics, while that of glutathione peroxidase did no change. ATP-depended outward transport of glutathione disulfide also decreased in diabetics. These data suggest that the increase in the levels of glutathione disulfide in erythrocyte from diabetics is brought about by the decreased transport activity of glutathione disulfide through the erythrocyte membrane together with a decrease in the activity of glutathione reductase. The activity of gamma-glutamylcysteine synthetase was significantly lower in diabetics than in normal controls. Glycated gamma-glutamylcysteine synthetase determined using a boronate affinity column chromatography was higher in diabetics than in normal controls. The rate of glutathione synthesis using (H3)-glycine decreased in diabetics. The decrease is the levels of reduced form of glutathione is erythrocytes of diabetics is thought to be brought about by impaired glutathione synthesis. In order to study the mechanism by which glutathione synthesis is impaired, gamma-glutamylcysteine synthetase was purified from human erythrocytes. The molecular weight of the purified enzyme was 60K. A single band was observed on SDS polyacrylamide gel electrophoresis. When the purified enzyme was incubated with glucose, the enzyme activity decreased dependent on the incubation time. These data suggest that the impaired glutathione synthesis in diabetics is brought by glycation of gamma-glutamylcysteine synthetase. As conclusion, glutathione metabolism is impaired in erythrocytes from diabetics which weaken the defence mechanism against oxidative stress in these patients.
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PMID:[Glutathione metabolism in erythrocytes from patients with diabetes mellitus]. 167 80

We review the role of ion channels in regulating insulin secretion from pancreatic beta-cells. By controlling ion permeability, ion channels at the membrane play a major role in regulating both electrical activity and signal transduction in the beta-cell. A proximal step in the cascade of events required for stimulus-secretion coupling is the closure of ATP-sensitive K+ channels, resulting in cell depolarization. Of particular relevance is the finding that this channel is directly regulated by a metabolite of glucose, which is the primary insulin secretagogue. In addition, this channel, or a closely associated protein, contains the sulfonylurea-binding site. Another K+ channel, the Ca2(+)-activated K+ channel, may be involved in cell repolarization to create homeostasis. Voltage-dependent Ca2+ channels are activated by cell depolarization and regulate Ca2+ influx into the cell. By controlling cytosolic free-Ca2+ levels ([Ca2+]i), these channels play an important role in transducing the initial stimulus to the effector systems that modulate insulin secretion. The link between a rise in [Ca2+]i and the terminal event of exocytosis is the least-understood aspect of stimulus-secretion coupling. However, phosphorylation studies have identified substrate proteins that may correspond to those involved in smooth muscle contraction, suggesting an analogy in the processes of stimulus secretion and excitation contraction. The advent of new methodology, particularly the patch-clamp technique, has fostered a more detailed characterization of the beta-cell ion channels. Furthermore, biochemical and molecular approaches developed for the structural analysis of ion channels in other tissues can now be applied to the isolation and characterization of the beta-cell ion channels. This is of particular significance because there appear to be tissue-specific variations in the different types of ion channels. Given the importance of ion channels in cell physiology, a knowledge of the structure and properties of these channels in the beta-cell is required for understanding the abnormalities of insulin secretion that occur in non-insulin-dependent diabetes mellitus. Ultimately, these studies should also provide new therapeutic approaches to the treatment of this disease.
Diabetes Care 1990 Mar
PMID:Ion channels and insulin secretion. 168 32

So far, only freshly isolated cells or short-term cultures have been used to study ion-channel activity in pancreatic nontumor beta-cells. We report a procedure for the long-term cultivation of pancreatic endocrine cells to study the relationship between ion channels and insulin secretion. Using thimerosal to suppress fibroblastoid cell proliferation and a preliminary 2-day cell exposure to alternating normal (5.6 mM) and high (16.7 mM) glucose levels, we observed a significant secretory responsiveness of the cells to a glucose challenge for at least 4 wk in culture. Cells also responded to glucose or other secretagogues, such as quinine and the sulfonylurea glyburide, with membrane voltage oscillations. In the cell-attached configuration of the patch-clamp technique, a 65-pS-conductance K+ channel was observed, which was inhibited by glucose, quinine, and glyburide. In the inside-out configuration, the activity of this channel was suppressed by ATP applied to the cytoplasmic side of the membrane. A K+ channel with a conductance of 200 pS was also observed, which was activated by intracellular Ca2+. A 13-pS-conductance glucose-insensitive K+ channel was present in both cell-attached and inside-out patch recordings. Even after 3 wk, the characteristics of these currents and channels were comparable to those reported by other investigators with freshly dissociated or short-term-cultured beta-cells from neonatal and adult rats and adult mice. Therefore, the neonatal rat endocrine cell culture characterized herein provides an improved model for long-term investigations combining secretion and electrophysiological studies.
Diabetes 1990 Nov
PMID:Long-term culture of neonatal rat pancreatic endocrine cells as model for insulin-secretion and ion-channel studies. 169 28

Methodological developments in recent years, particularly patch clamp technology and the techniques of molecular biology, have advanced our knowledge of the molecular basis of synaptic transmission. The review is a brief summary of some findings concerning the ion channels that respond to hormones transmitters, or change in cell membrane potential, and of advances in our understanding of transmitter storage and release. Ion channels have been found to be targets for several drugs in clinical use, including anaesthetics, bensodiazopines, so-called calcium antagonists and the sulphonylureas used in the treatment of diabetes. The latter drugs have been shown to interact specifically with a potassium channel regulated by ATP (adenosine triphosphate). In pancreatic beta-cells, this channel controls membrane potential and insulin release under physiological conditions; in several other cells, it is activated under hypoxic or ischaemic conditions.
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PMID:[Ion channels--the molecular background of neural transmission]. 171 16

This study used 10-nm gold particles with 5-7 insulin molecules attached (Au10-Ins) to investigate the site of interaction of insulin with the nuclear envelope during insulin uptake into intact isolated nuclei. Despite its size, and in the absence of ATP, Au10-Ins entered nuclei through the nuclear pore and associated with the heterochromatin. Because Au10-Ins is essentially gold-bovine serum albumin (Au-BSA) with a few insulin molecules attached, the effect of insulin and other growth factors on the nuclear accumulation of BSA coupled to 10-, 15-, and 24-nm-diam colloidal gold particles (Au10-BSA, Au15-BSA, and Au24-BSA) was determined. The Au-BSA complexes were excluded from nuclei in the absence of insulin. Insulin (0.5-100 ng/ml) caused a dose-dependent accumulation of Au10-BSA in the nucleus. The nuclear membrane was shown to be intact by several criteria, therefore, accumulation of Au-BSA occurred via the nuclear pore and was not due to leakage across or through the membrane. Uptake of 15- and 24-nm Au-BSA molecules was not affected by insulin, suggesting the hormone had a limited effect in increasing the functional diameter of the nuclear pores. Glucagon, epidermal growth factor, platelet-derived growth factor, insulinlike growth factor I, and insulin A or B chains did not stimulate the accumulation of Au10-BSA. The insulin-stimulated accumulation of Au10-BSA was blocked by concanavalin A, mimicked by wheat-germ agglutinin, and did not require ATP. The Au10-BSA in the nucleus was associated with heterochromatin, suggesting it bound to a nuclear element.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Feb
PMID:Insulin stimulates accumulation and efflux of macromolecules in isolated nuclei from H35 hepatoma cells. 173 9

We review some key aspects of the maturation of stimulus-secretion coupling and the regulation of DNA replication in the fetal beta-cell. During fetal life, the beta-cell shows a poor insulin response to glucose, although it responds to several other nonnutrient stimuli. However, chronic exposure to glucose in excess of basal levels can induce maturation of the stimulus-secretion coupling. Studies of glucose metabolism and the transmembrane flow of K+ and Ca2+ indicate that the attenuated glucose-stimulated insulin release is due to an immature glucose metabolism resulting in impaired regulation of ATP-sensitive K+ channels in the plasma membrane of the fetal beta-cell. In late fetal life, glucose is also a strong stimulus to beta-cell replication, and metabolism of glucose is a prerequisite for this process. Glucose stimulates proliferation by recruiting beta-cells from a resting state into a proliferative compartment composed of cells in an active cell cycle. The proliferative compartment comprises less than 10% of the total islet cell population even at maximal stimulation. The proliferation of fetal beta-cells is also regulated by several peptide growth factors such as growth hormone, insulinlike growth factor I, and platelet-derived growth factor. The observation that glucose can both induce precocious maturation of the stimulus-secretion coupling and stimulate proliferation of the fetal beta-cell explains the intrauterine hyperinsulinemia and beta-cell hyperplasia of the offspring of diabetic mothers with relatively mild hyperglycemia. However, severe hyperglycemia, at least when induced in rats, seems to retard rather than stimulate beta-cell growth.
Diabetes 1991 Dec
PMID:Functional maturation and proliferation of fetal pancreatic beta-cells. 174 74


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