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)

Intracellular Na+ is approximately two times higher in diabetic cardiomyocytes than in control. We hypothesized that the increase in Na+i activates the mitochondrial membrane Na+/Ca2+ exchanger, which leads to loss of intramitochondrial Ca2+, with a subsequent alteration (generally depression) in bioenergetic function. To further evaluate this hypothesis, mitochondria were isolated from hearts of control and streptozotocin-induced (4 weeks) diabetic rats. Respiratory function and ATP synthesis were studied using routine polarography and 31P-NMR methods, respectively. While addition of Na+ (1-10 mM) decreased State 3 respiration and rate of oxidative phosphorylation in both diabetic and control mitochondria, the decreases were significantly greater for diabetic than for control. The Na+ effect was reversed by providing different levels of extramitochondrial Ca2+ (larger Ca2+ levels were needed to reverse the Na+ depressant effect in diabetes mellitus than in control) and by inhibiting the Na+/Ca2+ exchanger function with diltiazem (a specific blocker of Na+/Ca2+ exchange that prevents Ca2+ from leaving the mitochondrial matrix). On the other hand, the Na+ depressant effect was enhanced by Ruthenium Red (RR, a blocker of mitochondrial Ca2+ uptake, which decreases intramitochondrial Ca2+). The RR effect on Na+ depression of mitochondrial bioenergetic function was larger in diabetic than control. These findings suggest that intramitochondrial Ca2+ levels could be lower in diabetic than control and that the Na+ depressant effect has some relation to lowered intramitochondrial Ca2+. Conjoint experiments with 31P-NMR in isolated superfused mitochondria embedded in agarose beads showed that Na+ (3-30 mM) led to significantly decreased ATP levels in diabetic rats, but produced smaller changes in control. These data support our hypothesis that in diabetic cardiomyocytes, increased Na+ leads to abnormalities of oxidative processes and subsequent decrease in ATP levels, and that these changes are related to Na+ induced depletion of intramitochondrial Ca2+.
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PMID:Na+ effects on mitochondrial respiration and oxidative phosphorylation in diabetic hearts. 1139 24

The reason for the 3- to 4-h delay between a rise in plasma free fatty acid (FFA) levels and the development of insulin resistance remains unknown. In the current study, we have tested the hypothesis that the delay may be caused by the need for plasma FFAs to first enter muscle cells and to be re-esterified there before causing insulin resistance. To this end, we have determined intramyocellular triglyceride (IMCL-TG) content with proton nuclear magnetic resonance ((1)H-NMR) spectroscopy in healthy volunteers before and 4 h after lowering of plasma FFAs (with euglycemic-hyperinsulinemic clamping) or after increasing plasma FFAs (with lipid plus heparin infusions). Increasing plasma FFAs (from 516 to 1,207 micromol/l or from 464 to 1,857 micromol/l, respectively) was associated with acute increases in IMCL-TG from 100 to 109 +/- 5% (P < 0.05) or to 133 +/- 11% (P < 0.01), respectively, and with a significant increase in insulin resistance (P < 0.05 after 3.5 h). Lowering of plasma FFAs from 560 to 41 micromol/l was associated with a tendency for IMCL-TG to decrease (from 100 to 95 +/- 3%). Changes in plasma FFAs correlated linearly with IMCL-TG (r = 0.74, P < 0.003). The demonstration that acute changes in plasma FFAs were accompanied by corresponding changes in IMCL-TG and with the development of insulin resistance, taken together with previous reports of a close correlation between IMCL-TG and insulin resistance, supported the notion that accumulation of IMCL-TG is a step in the development of FFA-induced insulin resistance.
Diabetes 2001 Jul
PMID:Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. 1142 83

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

The design of safe sweeteners is very important for people who are affected by diabetes, hyperlipemia, and caries and other diseases that are linked to the consumption of sugars. Sweet proteins, which are found in several tropical plants, are many times sweeter than sucrose on a molar basis. A good understanding of their structure-function relationship can complement traditional SAR studies on small molecular weight sweeteners and thus help in the design of safe sweeteners. However, there is virtually no sequence homology and very little structural similarity among known sweet proteins. Studies on mutants of monellin, the best characterized of sweet proteins, proved not decisive in the localization of the main interaction points of monellin with its receptor. Accordingly, we resorted to an unbiased approach to restrict the search of likely areas of interaction on the surface of a typical sweet protein. It has been recently shown that an accurate survey of the surface of proteins by appropriate paramagnetic probes may locate interaction points on protein surface. Here we report the survey of the surface of MNEI, a single chain monellin, by means of a paramagnetic probe, and a direct assessment of bound water based on an application of ePHOGSY, an NMR experiment that is ideally suited to detect interactions of small ligands to a protein. Detailed surface mapping reveals the presence, on the surface of MNEI, of interaction points that include residues previously predicted by ELISA tests and by mutagenesis.
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PMID:Probing the surface of a sweet protein: NMR study of MNEI with a paramagnetic probe. 1146 46

Simultaneous synthesis and breakdown of glycogen is called glycogen cycling. The extent of hyperglycemia and decreased glycogen stores in diabetes mellitus may relate in part to the extent cycling occurs. Four methods have been introduced to estimate its extent in liver in humans. 1) In the fasted state, the rate of net hepatic glycogenolysis, i.e., glycogen breakdown minus synthesis, is estimated using NMR, and the rate of glycogenolysis is estimated from deuterium labeling of blood glucose on (2)H(2)O ingestion. 2) The rate of glycogen synthesis is estimated from the rate of labeling of carbon 1 of glycogen on [1-(13)C]glucose infusion, monitored by NMR, and the rate of breakdown from the rate of disappearance of that labeling on unlabeled glucose infusion. 3) The rate of synthesis from glucose-1-P, formed by glycogenolysis, is measured by the decrease in the (3)H/(14)C ratio in acetaminophen glucuronide on acetaminophen and [2-(3)H,6-(14)C]galactose administration. 4) The rate of synthesis is estimated from the dilution of label from labeled galactose in its conversion to the acetaminophen glucuronide, and the rate of glycogenolysis is estimated from the amount of label in blood glucose. In the first method, the fate of glucose-6-P is assumed to be only to glycogen and glucose. In the second, only glucose-6-P molecules formed by breakdown that are not cycled back to glycogen are measured. In the third, (3)H is assumed to be removed completely during cycling, and only the molecules cycled back to glycogen are measured. In the fourth, galactose conversion to glucose is assumed to be via glycogen. Quantitations in all four methods depend on assuming the order in which the molecules deposited in glycogen are released.
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PMID:Methods for measuring glycogen cycling. 1150 Feb 95

Aqueous vanadate and aqueous tungstate have been known to mimic all or most of the actions of insulin in intact cell systems with respect to normalization of the blood glucose level. By carrying out oral administration in vivo experiments on the blood glucose level of streptozotocin (STZ)-induced diabetes (STZ mice), the insulin-mimetic (IM) effects of metal-oxide clusters of all-inorganic composition were examined using many types of polyoxometalates (POM) with and without vanadium substitution. Several homo-POM and vanadium-substituted POM showed hypoglycemic effects. The observed hypoglycemic effects indicated that POM with the Dawson structure [[alpha-P(2)W(18)O(62)](6-) (W-2), [alpha-P(2)W(17)V(V)O(62)](7-) (V-19) and [alpha-1,2,3-P(2)W(15)V(V)(3)O(62)](9-) (V-04)] are more effective than those with the Keggin structure [[alpha-PW(12)O(40)](3-) (W-1), [alpha-PW(11)V(V)O(40)](4-) (V-01), [alpha-1,2-PW(10)V(V)(2)O(40)](5-) (V-02), [alpha-1,2,3-PW(9)V(V)(3)O(40)](6-) (V-03) and [alpha-1,4,9-PW(9)V(V)(3)O(40)](6-) (V-13)]. The vanadate cluster [V(10)O(28)](6-) (V-15) also showed a hypoglycemic effect. (31)P and (51)V NMR measurements showed that the Dawson POM (W-2, V-04 and V-19) are stable in aqueous solution under the conditions used. The effect of all POM on the body weight of STZ mice was also examined. The decrease in body weight after administration of W-2 was much less than for V-19, V-04 and V-15. This suggests that not only monomeric tungstate and vanadate, but also the structure factors of tungstate and vanadate clusters, can play a significant role in their biological action.
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PMID:Insulin mimetic effect of a tungstate cluster. Effect of oral administration of homo-polyoxotungstates and vanadium-substituted polyoxotungstates on blood glucose level of STZ mice. 1158 83

Small molecules with insulin mimetic effects and oral availability are of interest for potential substitution of insulin injections in the treatment of diabetes. We have searched databases for compounds capable of mimicking one epitope of the insulin molecule known to be involved in binding to the insulin receptor (IR). This approach identifies thymolphthalein, which is an apparent weak agonist that displaces insulin from its receptor, stimulates auto- and substrate phosphorylation of IR, and potentiates lipogenesis in adipocytes in the presence of submaximal concentrations of insulin. The various effects are observed in the 10(-5)-10(-3) M range of ligand concentration and result in partial insulin activity. Furthermore, analogues of the related phenol red and fluorescein molecules fully displace insulin from the IR ectodomain, however, without insulin agonistic effects. The interactions are further characterized by NMR, UV-vis, and fluorescence spectroscopies. It is shown that both fluorescence and UV-vis changes in the ligand spectra induced by IR fragments occur with Kd values similar to those obtained in the displacement assay. Nevertheless, insulin itself cannot completely abolish binding of the small molecules. Determination of the binding stoichiometry reveals multiple binding sites for ligands of which one overlaps with the insulin binding site on the receptor.
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PMID:Properties of small molecules affecting insulin receptor function. 1169 99

We have investigated the effect of alloxan on insulin secretion and glucose homeostasis in rats maintained on a 17% protein (normal protein, NP) or 6% protein (low protein, LP) diet from weaning (21 days old) to adulthood (90 days old). The incidence of alloxan diabetes was higher in the NP (3.5 times) than in the LP group. During an oral glucose tolerance test, the area under serum glucose curve was lower in LP (57%) than in NP rats while there were no differences between the two groups in the area under serum insulin curve. The serum glucose disappearance rate (Kitt) after exogenous insulin administration was higher in LP (50%) than in NP rats. In pancreatic islets isolated from rats not injected with alloxan, acute exposure to alloxan (0.05 mmol/L) reduced the glucose- or arginine-stimulated insulin secretion of NP islets by 78% and 56%, respectively, whereas for islets from LP rats, the reduction was 47% and 17% in the presence of glucose and arginine, respectively. Alloxan treatment reduced the glucose oxidation in islets from LP rats to a lesser extent than in NP islets (23% vs. 56%). In conclusion, alloxan was less effective in producing hyperglycemia in rats fed a low protein diet than in normal diet rats. This effect is attributable to an increased peripheral sensivity to insulin in addition to a better preservation of glucose oxidation and insulin secretion in islets from rats fed a low protein diet.
Physiol Chem Phys Med NMR 2001
PMID:Protein deficiency attenuates the effects of alloxan on insulin secretion and glucose homeostasis in rats. 1175 37

Glucose transport enhancers were searched for in Lagerstroemia speciosa, a Philippine local herbal medicine used for diabetes mellitus. Bioassay-guided fractionation of the aqueous acetone extract of the leaves afforded three active ellagitannins, lagerstroemin, flosin B and reginin A, identified by NMR and optical rotation. These compounds increased glucose uptake of rat adipocytes, and could be responsible for lowering the blood glucose level.
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PMID:Ellagitannins from Lagerstroemia speciosa as activators of glucose transport in fat cells. 1185 74

In Poland like in other countries we observe an increasing number of diabetes mellitus cases with about half of the patients in whom the disease remains undiagnosed. Therefore it seems necessary to improve early diagnoses and prevention of the disease. The aim of the study was to assess the efficiency of a 3-month non-pharmacological intervention based on diet and increased physical activity in patients with newly diagnosed diabetes type 2 (diagnosis based on oral glucose tolerance test (OGTT), WHO 1999). We investigated 37 newly diagnosed diabetic type 2 patients, 16 men (aged 52.4 +/- 5.4) and 21 women (aged 51.0 +/- 5.7). Anthropometric and biochemical measurements were performed before and after intervention. Two-kilometres Walking Test with an intermediate estimation of VO2max and fitness index (FI) was performed before and after intervention. Total abdominal fat volume (measured from diaphragm to pubis): visceral fat volume (VFV) and subcutaneous fat volume (SFV) (mm3) were assessed according to the standard protocol of NMR abdominal examination. Patients completed 12 weeks of supervised intervention focused on weight reduction, increase of physical activity, changes of nutritional habits. Students t-test, Mann-Whitney test and Spearman's correlation were used for statistical analysis. In women the average weight reduction was 4.7 kg (5.8% of initial body weight), whereas in men 5.9 kg (5.9% of initial body weight). In women VO2 max increased from 23.7 +/- 6.4 to 24.9 +/- 4.8 (ns), and fitness index increased from 78.7 +/- 11.7 to 83 +/- 14.7 (ns). In men VO2 max increased from 22.5 +/- 6.7 to 26.6 +/- 8.6 (ns) and fitness index increased from 55.1 +/- 12.5 to 64.8 +/- 13.7 (p < 0.05). In women the level of fasting glycaemia decreased from 6.47 +/- 1.2 to 4.84 mmol/l +/- 0.6 (p < 0.01) and the level of glycaemia at 120 minutes of OGTT decreased from 13.2 +/- 2.5 to 6.76 +/- 2.7 mmol/l (p < 0.01). The decrease of plasma glucose was accompanied by the decrease of fasting insulin from 19.2 +/- 15.5 to 8.53 +/- 93.2 uj/ml (p < 0.01) and in 120 minutes of OGTT from 148.8 +/- 86.2 to 58.4 +/- 41.0 uj/ml (p < 0.01). In men the level of fasting glycaemia decreased from 8.63 +/- 2.0 to 7.07 mmol/l +/- 2.4 (p < 0.05) and the level of glycaemia at 120 minutes of OGTT decreased from 15.76 +/- 3.2 do 9.3 +/- 5.7 mmol/l (p < 0.01). The decrease of plasma glucose was accompanied by the decrease of fasting insulin from 21.99 +/- 12.6 to 10.1 (3.8 uj/ml (p < 0.05) and at 120 minutes of DGTT from 81.5 +/- 52.7 do 41.6 +/- 21.0 uj/ml (p < 0.05). After the intervention 45% of the patients (57% of women and 31% of men) were non-diabetic (correct OGTT). In men visceral fat volume (VFV) was greater than in women (7642.6 +/- 1774.6 and 4789.9 +/- 1242.0 mm3 respectively (p < 0.01). Subcutaneous fat volume (SFV) was smaller in men than in women (7116.5 +/- 2048.5), in men and 10533.9 +/- 3478.3 respectively (p < 0.01). In women and men a strong (p < 0.01) correlation between waist circumference and visceral fat volume (VFV) (r = 0.573 (p < 0.01) and r = 0.833 (p < 0.01) respectively) and subcutaneous fat volume (SFV) (r = 0.900 (p < 0.01) and r = 0.790 (p < 0.01) respectively) was found. The results of the study confirm that in newly diagnosed diabetic type 2 patients body weight reduction and increased physical activity result in the improvement of biochemical indices. In about one half of patients the early phase of the disease might be reversible due to weight reduction and increased physical activity. The non-pharmacological intervention should be the first intervention undertaken in newly diagnosed diabetic type 2 patients.
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PMID:[The efficacy of non-pharmacological intervention in obese patients with newly diagnosed diabetes mellitus type II]. 1192 96


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