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Curr Diabetes Rev. 2008 Nov; 4(4): 340-56
Eleftheriadou I, Grigoropoulou P, Katsilambros N, Tentolouris N
Postprandial lipemia has emerged as an independent risk factor for coronary artery disease. In this systematic review we examined the effect of the medications used for the management of diabetes, obesity and dyslipidemia on postprandial lipemia. It should be mentioned that no standardization exists for a test meal and for the duration of observation postprandially to allow for direct comparisons between the published studies. Type 2 diabetes mellitus and insulin resistance are associated with enhanced postprandial lipemia. Insulin is effective in reducing both fasting and post prandial total triglyceride levels as well as triglycerides contained in the triglyceride-rich lipoprotein sub-fractions. Additionally, the newer rapid-acting insulin analogues seem to be more effective in the reduction of postprandial lipemia than the short-acting human insulins. Acarbose ameliorates postprandial lipemia and reduces the atherogenic chylomicron and very low density lipoprotein remnants. Metformin reduces both fasting and postprandial triglyceridemia, fasting and post-prandial free fatty acids and may increase the concentrations of the high density lipoprotein cholesterol. Sulfonylureas reduce fasting and postprandial triglyceride levels while data on the effect on high density lipoprotein levels are inconsistent. The effect of meglitinides on postprandial lipid metabolism is neutral. Rosiglitazone decreases fasting and postprandial free fatty acids but has no significant effect on fasting and postprandial triglycerides. Pioglitazone has additional beneficial effects on lipid metabolism because it reduces postprandial free fatty acids, fasting and postprandial triglycerides and increases high density lipoprotein cholesterol levels. Limited available data suggest that glucagon-like peptide-1 analogues and vildagliptin reduce postprandial lipemia through reduction of intestinally-derived triglycerides. No data exist on the effect of sitagliptin on postprandial lipemia. Orlistat improves postprandial lipemia by reducing the absorption of the dietary fat; no data exist on the effect of sibutramine and rimonabant on the metabolism of lipids in the postprandial state.
J Biol Chem. 2008 Nov 3;
Kitamura M, Okuyama M, Tanzawa F, Mori H, Kitago Y, Watanabe N, Kimura A, Tanaka I, Yao M
SusB, an 84kDa alpha-glucoside hydrolase involved in the starch utilization system (sus) of Bacteroides thetaiotaomicron, belongs to glycoside hydrolase family 97 (GH97). We have determined the enzymatic characteristics and the crystal structures in free and acarbose-bound form at 1.6 A resolution. SusB hydrolyzes the alpha-glucosidic linkage, with inversion of anomeric configuration liberating the beta-anomer of glucose as the reaction product. The substrate specificity of SusB, hydrolyzing not only alpha-1,4-glucosidic linkages but also alpha-1,6-, alpha-1,3-, and alpha-1,2-glucosidic linkages, is clearly different from other well-known glucoamylases belonging to GH15. The structure of SusB was solved by the single-wavelength anomalous diffraction method with sulfur atoms as anomalous scatterers using in-house X-ray source. SusB is comprised of three domains; the N-terminal, catalytic and C-terminal domains. The structure of SusB-acarbose complex shows a constellation of carboxyl groups at the catalytic center; Glu(532) is positioned to provide protonic assistance to leaving group departure, with Glu(439) and Glu(508), both positioned to provide base-catalyzed assistance for inverting nucleophilic attack by water. A structural comparison with other glycoside hydrolases revealed significant similarity between the structure of the catalytic domain of SusB and those of alpha-retaining glycoside hydrolases belonging to GH27, 36, and 31 despite the differences in catalytic mechanism. SusB and the other retaining enzymes appear to have diverged from a common ancestor and individually acquired the functional carboxyl groups during the process of evolution. Furthermore, sequence comparison of the active site based on the structure of SusB indicates that GH97 includes both retaining and inverting enzymes.
Antidiabetic Indian Plants: a Good Source of Potent Amylase Inhibitors.
Evid Based Complement Alternat Med. 2008 Jun 27;
Bhat M, Zinjarde SS, Bhargava SY, Kumar AR, Joshi BN
Diabetes is known as a multifactorial disease. The treatment of diabetes (Type II) is complicated due to the inherent patho-physiological factors related to this disease. One of the complications of diabetes is post-prandial hyperglycemia (PPHG). Glucosidase inhibitors, particularly alpha-amylase inhibitors are a class of compounds that helps in managing PPHG. Six ethno-botanically known plants having antidiabetic property namely, Azadirachta indica Adr. Juss.; Murraya koenigii (L.) Sprengel; Ocimum tenuflorum (L.) (syn: Sanctum); Syzygium cumini (L.) Skeels (syn: Eugenia jambolana); Linum usitatissimum (L.) and Bougainvillea spectabilis were tested for their ability to inhibit glucosidase activity. The chloroform, methanol and aqueous extracts were prepared sequentially from either leaves or seeds of these plants. It was observed that the chloroform extract of O. tenuflorum; B. spectabilis; M. koenigii and S. cumini have significant alpha-amylase inhibitory property. Plants extracts were further tested against murine pancreatic, liver and small intestinal crude enzyme preparations for glucosidase inhibitory activity. The three extracts of O. tenuflorum and chloroform extract of M. koenigi showed good inhibition of murine pancreatic and intestinal glucosidases as compared with acarbose, a known glucosidase inhibitor.
J Mol Biol. 2008 Oct 14;
Ragunath C, Manuel SG, Venkataraman V, Sait HB, Kasinathan C, Ramasubbu N
Human salivary alpha-amylase (HSAmy) has three distinct functions relevant to oral health: (1) hydrolysis of starch, (2) binding to hydroxyapatite (HA), and (3) binding to bacteria (e.g., viridans streptococci). Although the active site of HSAmy for starch hydrolysis is well-characterized, the regions responsible for bacterial binding are yet to be defined. Since HSAmy possesses several secondary saccharide-binding sites in which aromatic residues are prominently located, we hypothesized that one or more of the secondary saccharide-binding sites harboring the aromatic residues may play an important role in bacterial binding. To test this hypothesis, the aromatic residues at five secondary binding sites were mutated to alanine to generate six mutants representing either single (W203A, Y276A, and W284A), double (Y276A/W284A and W316A/W388A), or multiple [W134A/W203A/Y276A/W284A/W316A/W388A; human salivary alpha-amylase aromatic residue multiple mutant (HSAmy-ar)] mutations. The crystal structure of HSAmy-ar as an acarbose complex was determined at a resolution of 1.5 A and compared with the existing wild-type acarbose complex. The wild-type and the mutant enzymes were characterized for their abilities to exhibit enzyme activity, starch-binding activity, HA-binding activity, and bacterial binding activity. Our results clearly showed that (1) mutation of aromatic residues does not alter the overall conformation of the molecule; (2) single or double mutants showed either moderate or minimal changes in both starch-binding activity and bacterial binding activity, whereas HSAmy-ar showed significant reduction in these activities; (3) starch-hydrolytic activity was reduced by 10-fold in HSAmy-ar; (4) oligosaccharide-hydrolytic activity was reduced in all mutants, but the action pattern was similar to that of the wild-type enzyme; and (5) HA binding was unaffected in HSAmy-ar. These results clearly show that the aromatic residues at the secondary saccharide-binding sites in HSAmy play a critical role in bacterial binding and in starch-hydrolytic functions of HSAmy.
J Enzyme Inhib Med Chem. 2008 Oct 27; 1
Sengupta S, Mukherjee A, Goswami R, Basu S
Tinospora cordifolia, used in anti-diabetic herbal drug preparations, was reported [12] to contain an alpha-glucosidase inhibitor, characterized as saponarin (apigenin-6-C-glucosyl-7-O-glucoside). The leaf extract had appreciable antioxidant and hydroxyl radical scavenging activities and contained the flavonoid in the range of 32.1 +/- 1.5-45.5 +/- 3.5 mg/g of dry solid. Saponarin showed mixed competitive inhibition on activities of alpha-glucosidase and sucrase of different origins. IC(50), Ki and ki' values determined were 48 muM, 8 muM and 19.5 muM respectively for intestinal maltase and 35 muM, 6 muM and 13 muM respectively for intestinal sucrase. When given orally to maltose-fed rat, saponarin showed hypoglycemic activity in the range of 20-80 mg/kg compared to 100-200 mg/kg for acarbose as reported [27].
J Ethnopharmacol. 2008 Oct 28; 119(3): 478-81
Tshikalange TE, Meyer JJ, Lall N, Muñoz E, Sancho R, Van de Venter M, Oosthuizen V
ETHOPHARMACOLOGICAL RELEVANCE: The plants selected in this study are used traditionally in the treatment of sexually transmitted diseases and traditional healers interviewed claimed these plants can also help AIDS patients. AIM: To evaluating the in vitro anti-HIV properties of selected plants in various bioassays. MATERIALS AND METHODS: The extracts were evaluated for their inhibition against alpha-glycohydrolase, reverse transcriptase and viral proteins (NF-kappaB and Tat) which play a significant role in the HIV life cycle. RESULTS: Terminalia sericea extract (IC(50)=92mg/ml) exhibited a considerable alpha-glucosidase inhibitory activity which was better than acarbose (IC(50)=131mg/ml) under our assay conditions. In the reverse transcriptase assay, T. sericea also showed good inhibitory activity (IC(50)=43mg/ml), which was higher than that of the reference drug, Adriamycin (IC(50)=100mg/ml). The ethyl acetate extract of Elaeodendron transvaalense exhibited the most potent inhibitory activity in both the NF-kappaB and Tat assays with inhibitory activity of 76% and 75% respectively at a concentration of 15mg/ml. The acetone and chloroform extracts of E. transvaalense and Zanthoxylum davyi also showed good activity in the NF-kappaB and Tat assays.
[Cardiovascular risk and cardiometabolic risk: an epidemiological evaluation]
G Ital Cardiol (Rome). 2008 Apr; 9(4 Suppl 1): 6S-17S
Vanuzzo D, Pilotto L, Mirolo R, Pirelli S
On the basis of a critical literature review, this article deals with the concepts of global cardiovascular risk and cardiometabolic risk, pointing out their links but also their unresolved issues and discussing their usefulness in clinical practice. The global cardiovascular risk is the probability of suffering from a coronary event or stroke in a given period of time and in this sense it is an absolute risk, generally reported as percentage at 10 years. Usually risk functions are used, derived from longitudinal studies of healthy people at baseline. They consider some factors that are coherently linked with events in population analyses: among these there are some metabolic factors (total cholesterol, HDL cholesterol, fasting blood glucose), some biological factors (blood pressure) and some lifestyle factors (tobacco smoking), all modifiable beyond those non-modifiable like age and gender. The chosen factors must be independent at multivariate analysis, simple and standardized to measure, and contribute to significantly increase the risk-function predictivity. To be reliable, these risk functions must be derived from the same population where they will be later administered. For this reason the Italian Progetto CUORE, in the longitudinal study section, built a database of risk factors from longitudinal comparable studies started between the mid '80s and '90s and followed up the participants for cardiovascular mortality and morbidity to estimate the Italian global cardiovascular risk (first coronary or cerebrovascular event) for men and women. Two tools have been produced, the risk charts and a score software (see www.cuore.iss.it). The ongoing epidemics of obesity and diabetes and the fact that diabetes is associated with classical risk factors like hypertension and dyslipidemia induced the American Diabetes Association and the American Heart Association to launch a "call to action" to prevent both cardiovascular disease and diabetes. In this paper, as cardiometabolic risk factors were considered those "closely related to diabetes and cardiovascular disease: fasting/postprandial hyperglycemia, overweight/obesity, elevated systolic and diastolic blood pressure, and dyslipidemia". The association among the cardiometabolic risk factors has been known for a long time, and much of their etiology has been ascribed to insulin resistance. Also, the fact that these "metabolic" abnormalities can cluster in many individuals gave rise to the term "metabolic syndrome", a construct embraced by many organizations but questioned by other authors. From an epidemiological point of view the metabolic syndrome seems to increase modestly the cardiovascular risk, whereas in non-diabetic individuals it predicts diabetes much more efficiently. Many studies have compared the performance of the classical cardiovascular evaluation tools (the Framingham risk score, the SCORE charts, the Progetto CUORE score) and metabolic syndrome in cardiovascular disease prediction. Usually in people at high risk the presence of the metabolic syndrome does not improve the risk, whereas in people at lower risk its presence increases significantly the chances of cardiovascular disease. Many studies have shown that positive lifestyle interventions markedly reduce the rate of progression of type 2 diabetes. Also some drugs were tested for diabetes prevention, usually in people with impaired glucose tolerance. Oral diabetes drugs considered together (acarbose, metformin, flumamine, glipizide, phenformin) were less effective than lifestyle interventions, with different results among the drugs; the antiobesity drug orlistat gave similar results to lifestyle interventions. In Italy an appropriate approach to cardiovascular disease and diabetes prevention may be that of first evaluating the global cardiovascular risk using the charts or the score software of the Progetto CUORE, because high-risk subjects (> or =20%) must be treated aggressively independently of the presence of the metabolic syndrome; as a second step the metabolic syndrome may be sought, because it increases the risk; finally some attention should be paid to non-diabetic hyperglycemic individuals.
Diabetes Metab Res Rev. 2008 Nov; 24(8): 611-6
Nijpels G, Boorsma W, Dekker JM, Kostense PJ, Bouter LM, Heine RJ
BACKGROUND: We hypothesized that acarbose would delay conversion from impaired glucose tolerance (IGT) to type 2 diabetes by alleviating postprandial hyperglycaemia. Our study's main objective was to investigate the effect of acarbose in IGT-persons on their 2-h plasma glucose level and beta-cell function. SUBJECTS AND METHODS: The study included a random sample of 45-70-year-old residents of Hoorn, Netherlands, with mean fasting plasma glucose < 7.8 mmol/L and mean 2-h plasma glucose of 8.6-11.1 mmol/L (measured by two successive oral glucose tolerance tests). After a qualification period, participants were randomized to acarbose treatment or placebo. Insulin secretion and insulin sensitivity were measured by hyperglycaemic clamp. After a 3-year treatment, analyses were performed of both the intention-to-treat and the per-protocol groups. RESULTS: Of the 12 093 residents who received postal invitations, 118 participants were randomized. The mean difference of the post-load plasma glucose after 3 years, was - 1.16 mmol/L (95% CI: - 2.03; - 0.17). The absolute risk reduction for diabetes was 6% (95% CI: - 9; 21). No effect was seen on insulin secretion and insulin sensitivity. CONCLUSIONS: In patients with IGT, treatment with acarbose was associated with beneficial effects on 2-h plasma glucose levels but not with improvement of beta-cell function. Copyright (c) 2008 John Wiley & Sons, Ltd.
J Microbiol Biotechnol. 2008 Aug; 18(8): 1401-7
Oh SW, Jang MU, Jeong CK, Kang HJ, Park JM, Kim TJ
The roles of conserved amino acid residues (Val329-Ala330- Asn331-Glu332), constituting an extra sugar-binding space (ESBS) of Thermus maltogenic amylase (ThMA), were investigated by combinatorial saturation mutagenesis. Various ThMA mutants were firstly screened on the basis of starch hydrolyzing activity and their enzymatic properties were characterized in detail. Most of the ThMA variants showed remarkable decreases in their hydrolyzing activity, but their specificity against various substrates could be altered by mutagenesis. Unexpectedly, mutant H-16 (Gly-Leu-Val-Tyr) showed almost identical hydrolyzing and transglycosylation activities to wild type, whereas K-33 (Ser-Gly-Asp-Glu) showed an extremely low transglycosylation activity. Interestingly, K-33 produced glucose, maltose, and acarviosine from acarbose, whereas ThMA hydrolyzed acarbose to only glucose and acarviosine-glucose, which proposes that the substrate specificity, or hydrolysis or transglycosylation activity of ThMA can be modulated by combinatorial mutations near the ESBS.
J Biol Chem. 2008 Oct 17; 283(42): 28641-8
Woo EJ, Lee S, Cha H, Park JT, Yoon SM, Song HN, Park KH
TreX is an archaeal glycogen-debranching enzyme that exists in two oligomeric states in solution, as a dimer and tetramer. Unlike its homologs, TreX from Sulfolobus solfataricus shows dual activities for alpha-1,4-transferase and alpha-1,6-glucosidase. To understand this bifunctional mechanism, we determined the crystal structure of TreX in complex with an acarbose ligand. The acarbose intermediate was covalently bound to Asp363, occupying subsites -1 to -3. Although generally similar to the monomeric structure of isoamylase, TreX exhibits two different active-site configurations depending on its oligomeric state. The N terminus of one subunit is located at the active site of the other molecule, resulting in a reshaping of the active site in the tetramer. This is accompanied by a large shift in the "flexible loop" (amino acids 399-416), creating connected holes inside the tetramer. Mutations in the N-terminal region result in a sharp increase in alpha-1,4-transferase activity and a reduced level of alpha-1,6-glucosidase activity. On the basis of geometrical analysis of the active site and mutational study, we suggest that the structural lid (acids 99-97) at the active site generated by the tetramerization is closely associated with the bifunctionality and in particular with the alpha-1,4-transferase activity. These results provide a structural basis for the modulation of activities upon TreX oligomerization that may represent a common mode of action for other glycogen-debranching enzymes in higher organisms.