Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the relation between activities of islet glycogenolytic alpha-glucosidehydrolases and insulin secretion induced by glucose and 3-isobutyl-1-methylxanthine (IBMX) by means of suppressing 1) insulin release (Ca2+ deficiency) and 2) islet alpha-glucosidehydrolase activity (selective inhibition by the deoxynojirimycin derivative miglitol). Additionally, the in vivo insulin response to both secretagogues was examined. We observed that, similar to glucose-induced insulin release, islet glycogenolytic hydrolases (acid amyloglucosidase, acid alpha-glucosidase) were highly Ca2+ dependent. Acid phosphatase, N-acetyl-beta-D-glucosaminidase, or neutral alpha-glucosidase (endoplasmic reticulum) was not influenced by Ca2+ deficiency. In Ca2+ deficiency IBMX-induced insulin release was unaffected and was accompanied by reduced activities of islet alpha-glucosidehydrolases. Miglitol strongly inhibited glucose-induced insulin release concomitant with a marked suppression of islet alpha-glucosidehydrolase activities. Direct addition of miglitol to islet homogenates suppressed acid amyloglucosidase [half-maximal effective concentration (EC50) approximately 10(-6) M] and acid alpha-glucosidase. Acid phosphatase and N-acetyl-beta-D-glucosaminidase were unaffected. The miglitol-induced inhibition of glucose-stimulated insulin release was dose dependent (EC50 approximately 10(-6) M) and displayed a remarkable parallelism with the inhibition curve for acid amyloglucosidase. The in vivo insulin secretory response to glucose was markedly reduced in dystrophic mice (low amyloglucosidase), whereas the response to IBMX was unaffected. In summary, islet glycogenolytic hydrolases are Ca2+ dependent, and acid amyloglucosidase is directly involved in the multifactorial process of glucose-induced insulin release. In contrast the mechanisms of IBMX-stimulated insulin secretion operate independently of these enzymes. The effects of miglitol, a drug currently used in diabetes therapy, deserves further investigation.
 ...
PMID:Ca2+ deficiency, selective alpha-glucosidehydrolase inhibition, and insulin secretion. 768 25

The drugs used to treat diabetes mellitus are diverse and involve several classes. However, these drugs can be roughly separated into hypoglycaemic agents, such as insulin and the sulphonylureas, and antihyperglycaemic agents, such as the biguanides, the alpha-glucosidase inhibitors and troglitazone. Reports of insulin overdose are rare. The major effects of insulin overdose are secondary to the insult to the CNS produced by hypoglycaemia. The mainstay of insulin overdose management is glucose replacement therapy. Sulphonylureas are the most commonly used oral antihyperglycaemic agents in the management of type 2 (non-insulin-dependent; NIDDM) diabetes mellitus. Sulphonylureas primarily cause serum glucose reduction by stimulating the release of preformed insulin from the pancreatic islets. The mainstay of sulphonylurea overdose management is glucose replacement therapy, and in severe cases, reduction of insulin release. In the large majority of patients intravenous glucose supplementation will be sufficient to maintain euglycaemia. Repaglinide, a meglitinide analogue, is a new nonsulphonylurea oral hypoglycaemic agent. In overdose, this drug may produce prolonged hypoglycaemia similar to the sulphonylureas. The primary problem with biguanide overdose is the potential for lactic acidosis. The management of biguanide overdose is largely supportive and directed at correcting the metabolic acidosis along with associated complications. The alpha-glucosidase inhibitors, acarbose, voglibose and miglitol competitively and reversibly inhibit the alpha-glucosidase enzymes (glucoamylase, sucrase, maltase and isomaltase) in the brush border in the small intestine, which delays the hydrolysis of complex carbohydrates. They appear unlikely to produce hypoglycaemia in overdose, but abdominal discomfort and diarrhoea may occur. Troglitazone is the first thiazolidinedione antidiabetic drug available. There are no data on overdose, probably because of its very recent introduction. Overdoses with antidiabetic drugs produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare when treatment is initiated early. The management of the hypoglycaemic drugs (insulin and sulphonylureas) is based primarily on restoring and maintaining euglycaemia via intravenous dextrose supplementation. In the case of the sulphonylureas, reduction of insulin secretion via pharmacological intervention may also be necessary. With biguanides the main risk appears to be cardiovascular collapse secondary to profound acidosis. The management focus is on restoring acid-base balance with hyperventilation and the use of insulin to shift the utilisation of glucose from the nonoxidative pathway to the oxidative pathway. Use of haemodialysis has shown equivocal results but may be valuable in metformin overdose.
 ...
PMID:Management of antidiabetic medications in overdose. 982 53

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.
 ...
PMID:Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors. 1142 50

The syntheses of two selenium analogues (10 and 11) of the naturally occurring sulfonium ion, salacinol (3), are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 2,3,5-tri-O-benzyl-1,4-anhydro-4-seleno-D-arabinitol at the least hindered carbon of benzyl- or benzylidene-protected D- or L-erythritol-1,3-cyclic sulfate. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as a solvent in the coupling reaction proves to be beneficial. Enzyme inhibition assays indicate that 10 is a better inhibitor (K(i) = 0.72 mM) of glucoamylase than 3, which has a K(i) value of 1.7 mM. In contrast, 11 showed no significant inhibition of glucoamylase. Compounds 10 and 11 showed no significant inhibition of barley-alpha-amylase or porcine pancreatic-alpha-amylase.
 ...
PMID:Synthesis of selenium analogues of the naturally occurring glycosidase inhibitor salacinol and their evaluation as glycosidase inhibitors. 1210 2

The synthesis of analogues of the naturally occurring glycosidase inhibitor, salacinol, in which the D-arabinitol ring has been replaced by D-lyxitol or D-ribitol, is described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata, which are traditionally used in India and Sri Lanka for the treatment of Type II diabetes. The synthetic strategy relies on the nucleophilic attack of 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-lyxitol or 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-ribitol at the least hindered carbon of the benzylidene-protected L-cyclic sulfate derived from L-erythritol. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective inhibitors of MGA and demonstrates the importance of the d-arabinitol configuration in the heterocyclic ring for effective inhibition.
 ...
PMID:Synthesis of D-lyxitol and D-ribitol analogues of the naturally occurring glycosidase inhibitor salacinol. 1619 22

Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol with cyclic sulfate derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium sulfate derivatives of D-glucose, D-galactose, D-arabinose, and D-xylose that are of interest in their own right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the low micromolar range, of approximately the same magnitude as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.
 ...
PMID:Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: new glycosidase inhibitors. 1643 29

Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes.
 ...
PMID:A new class of glucosidase inhibitor: analogues of the naturally occurring glucosidase inhibitor salacinol with different ring heteroatom substituents and acyclic chain extension. 1659 95

The synthesis of two novel amino acids, nitrogen analogues of the naturally occurring glycosidase inhibitor, salacinol, containing a carboxylate inner salt are described, along with the crystal structure of one of these analogues in the active site of Drosophila melanogaster Golgi mannosidase II (dGMII). Salacinol, a naturally occurring sulfonium ion, is one of the active principals in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino l- or d-arabinitol at the least hindered carbon of 5,6-anhydro-2,3-di-O-benzyl-l-ascorbic acid to yield coupled adducts. Deprotection, stereoselective catalytic reduction, and hydrolysis of the coupled products give the target compounds. The compound derived from d-arabinitol inhibits dGMII, one of the critical enzymes in the glycoprotein processing pathway, with an IC(50) of 0.3mM. Inhibition of GMII has been identified as a target for control of metastatic cancer. An X-ray crystal structure of the complex of this compound with dGMII provides insight into the requirements for an effective inhibitor. The same compound inhibits recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with a K(i) value of 21microM.
 ...
PMID:Synthesis, enzymatic activity, and X-ray crystallography of an unusual class of amino acids. 1701 Jun 21

The synthesis of aza- and thia-spiroheterocycles and the attempted synthesis of spiro sulfonium compounds related to salacinol are described. The binding of the nanomolar inhibitor swainsonine to Drosophila Golgi alpha-mannosidase II (dGMII) involves a large contribution of interactions between the six-membered ring of the inhibitor and the hydrophobic pocket within the enzyme active site. Salacinol, a naturally occurring sulfonium ion, is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. Spiro aza- and thia-heterocycles and a spiro analogue of salacinol were designed with the expectation that the hydrocarbon portions would make hydrophobic contributions to binding. The former sets of compounds were synthesized successfully but the salacinol analogue proved to be elusive. The stereochemistry of the final compounds was determined by means of 1D-NOESY experiments. The aza- and thia-heterocycles were not effective inhibitors of Golgi alpha-mannosidase II or human maltase glucoamylase.
 ...
PMID:Synthesis of aza- and thia-spiroheterocycles and attempted synthesis of spiro sulfonium compounds related to salacinol. 1766 86

This Highlight describes the detailed approach used to determine the absolute stereochemistry of the stereogenic centers in the acyclic side chain of kotalanol, a naturally occurring glucosidase inhibitor isolated from the plant Salacia reticulata. The plant extract itself is used in Ayurvedic medicine for the treatment of Type 2 diabetes. We highlight the syntheses of proposed candidates based on structure-activity relationships, the total synthesis of kotalanol, and crystallographic studies of kotalanol and its de-O-sulfonated derivative complexed with recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the breakdown of glucose oligomers into glucose.
 ...
PMID:Towards the elusive structure of kotalanol, a naturally occurring glucosidase inhibitor. 2033 33


<< Previous 1 2 3 Next >>