Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sulfonylureas are a class of oral hypoglycemic agents used to treat type II diabetes mellitus, and tolbutamide is a "first generation" member of this family. It is a nonpolar, weakly acidic drug that binds to serum albumin in the circulation. In the present study, we have examined the interactions of tolbutamide with human serum albumin by isothermal titration calorimetry and heteronuclear multiple-quantum coherence NMR spectroscopy. Calorimetric titrations revealed that tolbutamide binds to albumin at three independent sites with the same or comparable affinity. This result was independently confirmed by NMR experiments which resolved three resonances at 1H chemical shifts of 2.07, 2.11 and 2.14 ppm, corresponding to [methyl-13C]tolbutamide bound to three discrete binding sites. The binding affinity quantitated by calorimetry (Kd = 21 +/- 9 microM at pH 7.4, 37 degrees C) was approximately 5 times lower than the most frequently reported value. Tolbutamide titrations of albumin complexed with three other drugs whose binding sites have been localized by X-ray crystallography (salicylate, clofibric acid, and triiodobenzoic acid) demonstrated direct competition for common binding sites. NMR experiments with samples containing [methyl-13C]tolbutamide and these competing drugs permitted assignment of the resonances at 2.07 and 2.14 ppm to tolbutamide bound to the aspirin sites in albumin subdomains IIIA and IIA, respectively. These findings permit the first assignment of tolbutamide binding sites to specific locations on the albumin molecule within the context of the recently published crystal structure of human serum albumin. In addition, this information provides a molecular basis for predicting unfavorable drug interactions involving tolbutamide in patients with type II diabetes.
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PMID:Localization of tolbutamide binding sites on human serum albumin using titration calorimetry and heteronuclear 2-D NMR. 761 18

Alterations of cell ion content have been reported acutely after oral glucose ingestion, and chronically in subjects with hypertension and noninsulin dependent diabetes mellitus (NIDDM). We have hypothesized that these ionic abnormalities, elevated cytosolic free calcium (Cai), and suppressed intracellular pH (pHi) and free magnesium (Mgi), common to both of these syndromes, may explain their frequent clinical coincidence. To investigate the potential role of glucose in this process, we utilized 19F- and 31P-NMR spectroscopy to measure Cai, Mgi, and pHi in normal human red blood cells before and 60, 120, and 180 min after in vitro incubation with glucose (15 mmol/L) and equimolar concentrations of the glucose analogs, L-glucose, 2-deoxyglucose, and 3-O-methylglucose. At each point in time (from t = 0 to t = 60, 120, 180 min), glucose induced significant (P < .05) elevations in Cai (27.2 +/- 2.2 to 68.3 +/- 7.2, 70.7 +/- 10.5, 59.8 +/- 10.1 nmol/L), while suppressing pHi (7.28 +/- 0.02 to 7.22 +/- 0.03, 7.23 +/- 0.03, 7.22 +/- 0.03), and Mgi (206 +/- 10 to 151 +/- 7, 131 +/- 7, 143 +/- 5 mumol/L). This glucose induced ionic effect was dose dependent, significant elevations in Cai being observed at 10 and 15 mmol/L, but not at the other concentrations tested. It was also specific, no changes in Cai being observed with any of the glucose analogs tested. Thus, hyperglycemia per se elevates Cai and suppresses Mgi and pHi in normal human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ionic basis of hypertension in diabetes mellitus. Role of hyperglycemia. 851 65

Magnesium ions (Mg2+) are pivotal in the transfer, storage and utilization of energy; Mg2+ regulates and catalyzes some 300-odd enzyme systems in mammals. The intracellular level of free Mg2+ ([Mg2+]i) regulates intermediary metabolism, DNA and RNA synthesis and structure, cell growth, reproduction, and membrane structure. Mg2+ has numerous physiological roles among which are control of neuronal activity, cardiac excitability, neuromuscular transmission, muscular contraction, vasomotor tone, blood pressure and peripheral blood flow. Mg2+ modulates and controls cell Ca2+ entry and Ca2+ release from sarcoplasmic and endoplasmic reticular membranes. Since the turn of this century, there has been a steady and progressive decline of dietary Mg intake to where much of the Western World population is ingesting less than an optimum RDA. Geographic regions low in soil and water Mg demonstrate increased cardiovascular morbidity and mortality. Dietary deficiency of Mg2+ results in loss of cellular K+ and gain of cellular Na+ and calcium ions (Ca2+). Blood normally contains Mg2+ bound to proteins, Mg2+ complexed to small anion ligands and free ionized Mg2+ (IMg2+). Most clinical laboratories only now assess the total Mg, which consists of all three Mg fractions. Estimation of the IMg2+ level in serum or plasma by analysis of ultrafiltrates (complexed Mg + IMg2+) is somewhat unsatisfactory, as the methods employed do not distinguish the truly ionized form from Mg2+ bound to organic and inorganic anions. Because the levels of these ligands can vary significantly in numerous pathological states, it is desirable to directly measure the levels of IMg2+ in complex matrices such as whole blood, plasma and serum. Using novel ion selective electrodes (ISE's), we have found that there is virtually no difference in IMg2+, irrespective of whether one samples whole blood, plasma or serum. These data demonstrate that the mean concentration of IMg2+ in blood is about 600 mumoles/litre (0.54-0.65 mmol/L, 95% Cl); 65-72% of total Mg being free or biologically-active Mg2+. Use of the NOVA and KONE ISE's for IMg2+ on plasma and sera from patients with a variety of pathophysiologic and disease syndromes (e.g., long-term renal transplants, liver transplants, during and before cardiac surgery, ischemic heart disease [IHD], headaches, pregnancy, neonatal period, non-insulin dependent diabetes (NIDDM), end-stage renal disease [ESRD], hemodialyse [HEM], and continuous ambulatory peritoneal dialysis (CAPD), hypertension, myocardial infarction [AMI] and after excessive dietary intake of Mg), has revealed interesting data. The results indicate that long-term renal transplant patients, headache, pregnant, NIDDM, ESRD, HEM, CAPD, AMI, hypertensive, and IHD subjects exhibit, on the average significant depression in IMg2+ but not TMg. Use of 31P-NMR spectroscopy on red blood cells, from several of these disease states, to assess free intracellular Mg ([Mg2+]i demonstrates a high correlation (r = 0.5-0.8) between IMg2+ and [Mg2+]i. Increased dietary load of Mg, for only 6 days, in human volunteers, resulted in significant elevations in serum IMg2+ but not TMg. Correlations between the clinical course of several of the above disease syndromes and the fall in IMg2+ and [Mg2+]i were found. The ICa2+/IMg2+ ratio appears, from our data, to be an important guide for signs of peripheral vasoconstriction, ischemia or spasm and possibly atherogenesis. Overall, our data point to important uses for ISE's for IMg2+ in the diagnosis and treatment of disease states.
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PMID:Role of magnesium in patho-physiological processes and the clinical utility of magnesium ion selective electrodes. 886 38

In this review, the results of a series of NMR experiments investigating glucose storage and synthesis in NIDDM patients and normal controls have been summarized. These have shown: 1. The deficit in nonoxidative glucose disposal in NIDDM subjects results from a defect in the muscle glycogen synthesis pathway. 2. Reduced activity of glucose transporter/hexokinase step in this pathway accounts for the reduced rate of glycogen synthesis in NIDDM patients. 3. This reduced activity of GT/Hk is a genetic defect present before the clinical onset of disease in prediabetic descendants of diabetic parents. 4. In muscle from normal, healthy subjects the rate of glycogen synthesis is controlled by the glucose transport/hexokinase activity step and not by the activity of the muscle glycogen synthase enzyme. 5. Hepatic gluconeogenesis is responsible for most hepatic glucose production during an overnight fast in both normal and NIDDM subjects, and increases in gluconeogenic flux are responsible for the increased rate of hepatic glucose production in NIDDM subjects. 6. In contrast to human muscle, where glycogenesis ceases at rest, in the liver gluconeogenesis and glycogenolysis are always active. Numerous previous studies were considered prior to embarking in each of these NMR experiments. In the original research articles we published, the earlier studies were discussed in terms of the relevant literature. Here, however, I have chosen to present the NMR data as simply as possible, in the hope of exposing the significance of these studies by disentangling the results from the complexities of NMR methodology.
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PMID:Nuclear magnetic resonance studies of glucose metabolism in non-insulin-dependent diabetes mellitus subjects. 889 70

The NIDDM patient, willingly with high blood pressure and atheroma, has frequently an abnormal renal function. Must a renal artery stenosis (RAS) be searched as a determining or favorising cause? We have searched RAS by color duplex scan, in 60 consecutive NIDDM patients with altered renal function (creatinine clearance < or = 60 mL/min). Metabolic blood pressure (ABPM), cardiovascular and renal investigations have been realised. The population was composed of 22F/38M with middle age: 70.7 +/- 6.2 yrs, diabetic duration: 11.6 +/- 8 yrs, the plasma creatinine was: 161 +/- 78 mumol/L and clearance: 40 +/- 13 mL/min. Thirty eight had albuminuria, 28 had plasma creatinine > or = 150 mumol/L. All patients had high blood pressure. Significative RAS (> or = 70%) was detected in 15 patients (25%) by color duplex scan and proved with arteriography (n = 10) or angio NMR (n = 5). Twelve (80%) had unilateral stenosis (4 thrombosis), 3 (20%) bilateral stenosis. Renal US lead the diagnosis in 10 patients (66%): unilateral or bilateral hypotrophy. Those 15 patients had these following characteristics: 4F/11M (sex R : 0.36), middle age: 70.8 +/- 7.2 yrs, diabetic duration: 14.3 +/- 7.5 yrs, HbA1c was at 8.4 +/- 2%, 8 (53%) patients require insuline and 5 have retinopathy, plasma creatinine was at 169 +/- 6 mumol/L; 32% of patients with plasma creatinine > or = 150 mumol/L had RAS (n = 9/60%), creatinine clearance was at 38 +/- 12 mL/min (7/47% < or = 30 mL/min), 9 (60%) had macroalbuminuria and 5 (33%) microalbuminuria. All hypertensive patients were treated (mean SBP: 148 +/- 16, mean DBP: 82 +/- 7 mmHg) and had 62 +/- 28% SBP escape and 33 +/- 19% DBP escape. Ten had severe hypertension (at least 3 hypotensive drugs), 12 received CEI; 8 (53%) were smokers; 14 (93%) had one or more macroangiopathies (10/66% coronary heart diseases, 7/46% lower limbs arteritis, 6/40% carotid atheroma); 13 of these macroangiopathies are severe. In conclusion, renal failure (especially evolutive and/or treated with CEI) in NIDDM must call up a RAS (25%) specially in elderly males with a long diabetes duration, severe hypertension and macroangiopathies. This patient profile must lead to a color duplex scan to confirm the diagnosis already suspected by the renal echography.
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PMID:[Renal artery stenosis and chronic renal failure in NIDDM]. 974 69

Carbon nuclear magnetic resonance (13C NMR) spectroscopy and phosphorus (31p) NMR spectroscopy have been used to help define the contribution of insulin-stimulated muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals and the extent to which this process is defective in patients with type 2 (non-insulin-dependent) diabetes. Assessments of the response to hyperglycemic-hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)-associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms of insulin resistance can be addressed through combination therapy with agents that reverse the principal pathophysiologic defects of type 2 diabetes. The biguanide metformin appears to lower glucose by suppressing hepatic glucose production, whereas the thiazolidinedione troglitazone appears to increase glucose clearance by peripheral tissues. The two agents together have been shown to provide better glucose control than either drug alone, without stimulating insulin secretion.
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PMID:Cellular mechanisms of insulin resistance in humans. 1041 51

Psacalium decompositum was investigated for antihyperglycemic compounds using diabetic ob/ob mice as a model for type 2 diabetes. In vivo bioassay-guided fractionation of an aqueous extract from the roots of P. decompositum led to the isolation of two new eremophilanolides, 3-hydroxycacalolide (1a) and epi-3-hydroxycacalolide (1b). A 1:1 mixture of 1a/1b exhibited antihyperglycemic activity when tested at 1.09 mmol/kg in ob/ob mice. The known furanoeremophilanes, cacalone (2a) and epicacalone (2b), were also isolated from the aqueous extract and were inactive. The known furanoeremophilane, cacalol (3), was isolated from a CH2Cl2 extract of P. decompositum roots and possessed antihyperglycemic activity. The relative stereochemistry in 1a and 1b was assigned 3R,5S and 3S,5S, respectively, based on ROESY data, 3J H-H values, and molecular mechanics calculations. Complete 13C and 1H NMR chemical shifts were assigned for 1a, 1b, 2a, 2b, and 3, and several revisions in 13C NMR assignments for 2a and 3 were made. Results from the conformational analysis of 1a, 1b, 2a, and 2b indicate that each compound exists in one major conformation in solution with H3-12 in a pseudoaxial position.
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PMID:Antihyperglycemic sesquiterpenes from Psacalium decompositum. 1047 9

Vanadium has well-documented blood-glucose-lowering properties both in vitro and in vivo. The design of new oxovanadium(IV) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biguanides, most importantly metformin, are oral hypoglycemic agents used today to treat type 2 diabetes mellitus. In this study, biguanide, metformin, and phenformin, all biguanides, were coordinated to oxovanadium(IV) to form potential insulin-enhancing compounds. Highly colored, air-stable, bis(biguanidato)oxovanadium(IV), [VO(big)2], bis(N'N'-dimethylbiguanidato)oxovanadium(IV), [VO(metf)2], and bis(beta-phenethyl-biguanidato)oxovanadium(IV), [VO(phenf)2], were prepared. Solvation with dimethylsulfoxide occurred with VO(metf)2 to form a six-coordinate complex. Precursor ligands and oxovanadium(IV) coordination complexes were characterized by infrared spectroscopy, mass spectrometry, elemental analyses, magnetic susceptibility, and, where appropriate, 1H NMR spectroscopy. Biological testing with VO(metf)2, a representative compound, for insulin-enhancing potential included acute (72 h) administration, both by intraperitoneal (i.p.) injection and by oral gavage (p.o.) in streptozotocin (STZ)-diabetic rats. VO(metf)2 administration resulted in significant blood-glucose lowering at doses of 0.12 mmol kg-1 i.p. and 0.60 mmol kg-1 p.o. (previously established as ED50 doses for organically chelated oxovanadium(IV) complexes); however, no positive associative effects due to the presence of biguanide in the complex were apparent.
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PMID:Vanadyl-biguanide complexes as potential synergistic insulin mimics. 1060 40

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by (13)C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.
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PMID:Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue. 1507 88

Troglitazone (TGZ), the first glitazone used for the treatment of type II diabetes mellitus and removed from the market for liver toxicity, was shown to bind covalently to microsomal protein and glutathione (GSH) following activation by cytochrome P450 (P450). The covalent binding of (14)C-TGZ in dexamethasone-induced rat liver microsomes was NADPH-dependent and required the active form of P450; it was completely inhibited by ketoconazole (10 microM) and GSH (4 mM). The covalent binding in P450 3A4 Supersomes (9.2 nmol of TGZ Eq/nmol P450) was greater than that with P450 1A2 (0.7), 2C8 (3.7), 2C19 (1.4), 2E1 (0.6), and 2D6 (1.1) and 3A5 (3.0). The covalent binding in liver microsomes from rats pretreated with dexamethasone (5.3 nmol of TGZ Eq bound/nmol P450) was greater than that from rats pretreated with vehicle (3.5), beta-naphthoflavone (0.4), phenobarbital (1.1), or pyridine (2.5). A TGZ-GSH adduct was detected by liquid chromatography-tandem mass spectrometry and radioactivity detection with a deprotonated quasi-molecular ion [M-H](-) at m/z 745, with fragment ions at m/z 438 (deprotonated TGZ moiety), and at m/z 306 (deprotonated GSH moiety). The TGZ-GSH adduct was determined to be 5-glutathionyl-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-thiazolidine-2,4-dione based on collision-induced dissociation fragmentation, and one- and two-dimensional NMR analysis of the isolated adduct. The synthetic 5-hydroxy TGZ and the benzylidene derivative of TGZ did not react with GSH or GSH ethyl ester. The mechanisms for metabolic activation of TGZ may involve an ultimate reactive sulfonium ion which could be formed from an initial sulfoxide followed by a formal Pummerer rearrangement, or a C5 thiazolidinedione radical or a sulfur cation radical.
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PMID:Metabolic activation of troglitazone: identification of a reactive metabolite and mechanisms involved. 1515 56


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