The rate of energy storage in adipose tissues is, at least in part, dependent on the concentration of nutrients and hormones in the blood. A delayed absorption of ingesta from the intestine should cause lower concentrations of fat, glucose and insulin and, thus, reduce the triglyceride storage rate. Non-selective agents retard the absorption irrespective of composition of food. Inhibitors of intestinal alpha-glucosidases delay the degradation of complex carbohydrates to absorbable monosaccharides and thus decrease the rate of their absorption. Inhibitors of pancreatic lipase interfere with the degradation of dietary triglycerides and decrease the postprandial triglyceride increment in blood and tissues. Recently a compound was found which inhibits the absorption of carbohydrates as well as triglycerides.
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Common bean (Phaseolus vulgaris L.) is a good source of protein, vitamins, minerals and complex carbohydrates. The objective was to compare protein profile, including anti-nutrient proteins, and potential bioactive peptides of improved common bean cultivars grown in Mexico and Brazil. Bean protein isolates (BPI) were prepared from 15 common bean cultivars and hydrolyzed using pepsin/pancreatin. Thirteen proteins were identified by SDS-PAGE and protein in-gel tryptic-digestion-LC/MS. Protein profile was similar among common bean cultivars with high concentrations of defense-related proteins. Major identified proteins were phaseolin, lectin, protease and α-amylase inhibitors. Lectin (159.2 to 357.9 mg lectin/g BPI), Kunitz trypsin inhibitor (inh) (4.3 to 75.5 mg trypsin inh/g BPI), Bowman-Birk inhibitor (5.4 to 14.3 μg trypsin-chymotrypsin inh/g BPI) and α-amylase inhibitor activity (2.5 to 14.9% inhibition relative to acarbose/mg BPI) were higher in Mexican beans compared to Brazilian beans. Abundant peptides were identified by HPLC-MS/MS with molecular masses ranging from 300 to 1500 Da and significant sequences were SGAM, DSSG, LLAH, YVAT, EPTE and KPKL. Potential bioactivities of sequenced peptides were angiotensin converting enzyme inhibitor (ACE), dipeptidyl peptidase IV inhibitor (DPP-IV) and antioxidant capacity. Peptides from common bean proteins presented potential biological activities related to control of hypertension and type-2 diabetes.
A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors.
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Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.
To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy.
We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea.
Lupine is a medicinal food plant with potential value in the management of diabetes. In white mice, extracts of seeds of the white lupine [Lupinus albus (L. termis L.)] were associated with increased tolerance to an oral glucose bolus. Antihyperglycemic activity was present in extracts of the whole seed but not extracts of the seed coat, and was not detected when glucose was administered intraperitoneally rather than orally. However, in contrast to results seen with the prescription drug, acarbose, lupine extract did not appear to increase the bulk or carbohydrate content of the feces. Antihyperglycemic activity was also seen in extracts of the tailcup lupine (L. caudatus) found in the Four Corners Region of the United States.
Diabetes is characterized by hyperphagia, polydipsia, polyuria, and elevations in blood and urinary glucose. It has also been documented that beta-adrenergic responsiveness is reduced in diabetes. The intestinal glucosidase inhibitor, acarbose (BAY G 5421), decreases postprandial glycemia by delaying carbohydrate absorption. The purpose of this study was to evaluate the effects of chronic acarbose treatment (20 and 40 mg/100 g of diet) on the metabolic and adrenergic parameters altered in streptozotocin (STZ) (50 mg/kg, intravenously [IV] )-induced diabetes. Metabolic parameters were measured daily for 8 weeks. Diabetic rats were hyperphagic, polydipsic, and polyuric within 1 week of STZ treatment. Acarbose treatment did not consistently effect the food intake but did reduce water intake, urinary output, blood glucose, and the urinary loss of glucose associated with STZ-induced diabetes. Adrenergic responses were assessed by monitoring the increase in tail skin temperature (TST) associated with administration of isoproterenol. Diabetic rats were less responsive than controls and acarbose treatment restored responses toward that of the controls. Additionally, 3H-NE release from the tail artery was elevated in the diabetic rat and restored to normal in the acarbose-treated animals. Collectively these data suggest that acarbose treatment is effective in reducing the severity of metabolic and autonomic complications associated with STZ-induced diabetes.
The medical application of pomegranate fruits and its peel is attracted human beings. The aim of the present study was to evaluate the in vitro α-Glucosidase inhibition, antimicrobial, antioxidant property and in vivo anti-hyperglycemic activity of Punica granatum (pomegranate) fruit peel extract using Caenorhabditis elegans.
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Among 40,537 who met the inclusion criteria, 17,519 (43.2%) had insulin initiated over a median follow-up period of 58.6 months. The rate of insulin initiation due to 1% increase in A1c increased by 33.6%, 28.8%, 24.2%, 19.7%, 15.4% for patients exposed to 0, 1, 2, 3, 4 classes of oral-glucose-lowering agents. A higher insulin initiation rate was also associated with younger age, more comorbidities, non-Hispanic white race/ethnicity, obesity, longer diabetes duration, and attending endocrinology clinics.
Transferred nuclear Overhauser effect (trNOE) experiments have been performed to investigate the conformations of the competitive inhibitors, methyl 5'-thio-4-N-alpha-maltoside 3a and methyl 5'-thio-4-S-alpha-maltoside 4 when bound to the catalytic subunit of the enzyme glucoamylase. These NMR data suggest that, although each of the free ligands populates two conformational families, both heteroanalogues are bound by the enzyme in conformations in the area of the global energy minimum. These conformations have been used as initial points for docking into the active site of the enzyme taken from a X-ray crystal structure of the related glucoamylase-D-gluco-dihydroacarbose 2 complex. Minimization of the resulting complexes has yielded structures for the bound complexes. Corroboration of the structures is provided by fast T(1)(rho)-relaxation effects for certain ligand protons as a result of close contacts with protons in the enzyme active site. The results auger well for the combined use of transferred NOE spectroscopy and molecular modeling based on X-ray crystal structures of complexes of suitable congeners for the rapid analysis of ligand-receptor interactions.
We recently encountered a 96-year-old Japanese woman who suffered from frequent hypoglycemia. Endocrinological and imaging data eliminated the possibility of insulinoma, whereas oral glucose tolerance testing revealed impaired glucose tolerance and subsequent reactive hypoglycemia. The patterns between insulin or C-peptide secretions and glucose excursions demonstrated that the discrepancy occurred in the late postprandial stage. Administration of small doses of alpha-glucosidase inhibitor (alpha-GI) dramatically inhibited the rapid rise and subsequent precipitous fall of plasma glucose. Reactive hypoglycemia may be one of the important cause of hypoglycemia in the elderly, and alpha-GI could effectively and safely prevent such hypoglycemic attacks in those patients.
The effects of alpha-, beta- and gamma-cyclodextrins on the amylose and maltopentaose hydrolysis catalysed by porcine pancreatic alpha-amylase (PPA) were investigated. The results of the statistical analysis performed on the kinetic data using the general initial velocity equation of a one-substrate reaction in the presence of one inhibitor indicate that the type of inhibition involved depends on the substrate used: the inhibition of amylose hydrolysis by alpha-, beta- and gamma-cyclodextrin is of the competitive type, while the inhibition of maltopentaose hydrolysis is of the mixed noncompetitive type. Consistently, the Lineweaver-Burk plots intersect on the vertical axis when amylose is used as the substrate, while in the case of maltopentaose, the intersection occurs at a point located in the second quadrant. The inhibition of the hydrolysis therefore involves only one abortive complex, PPA-cyclodextrin, when amylose is used as the substrate, while two abortive complexes, PPA-cyclodextrin and PPA-maltopentaose-cyclodextrin, are involved with maltopentaose. The mixed noncompetitive inhibition thus shows the existence of one accessory binding site. In any case, only one molecule of inhibitor binds to PPA. In line with these findings, the difference spectra of PPA produced by alpha-, beta- and gamma-cyclodextrin indicate that binding occurs at a tryptophan and a tyrosine residue. The corresponding dissociation constants and the inhibition constants obtained using the kinetic approach are in the same range (1.2-7 mM). The results obtained here on the inhibition of maltopentaose hydrolysis by cyclodextrin are similar to those previously obtained with acarbose as the inhibitor [Alkazaz, M., Desseaux, V., Marchis-Mouren, G., Prodanov, E. & Santimone, M. (1998) Eur. J. Biochem. 252, 100-107], but differ from those obtained with amylose as the substrate and acarbose as inhibitor [Alkazaz, M., Desseaux, V., Marchis-Mouren, G., Payan, F., Forest, E. & Santimone, M. (1996) Eur. J. Biochem. 241, 787-796]. It is concluded that the hydrolysis of both long and short chain substrates requires at least one secondary binding site, including a tryptophan residue.
Forty-eight subjects (26 males, aged 61 +/- 8 years) with early type 2 diabetes (baseline hemoglobin A(1c) < or = 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11-dehydro-thromboxane (TX)B(2) (marker of in vivo platelet activation) and 8-iso-prostaglandin (PG)F(2alpha) (marker of in vivo lipid peroxidation) excretion rate, 2-h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE).
Like acarbose, A. capillus-veneris as well as chlorogenic acid, with respective IC50 values (mg/mL) of 0.8 ± 0.0 and 0.2 ± 0.0, were identified as in vitro potent dual inhibitors of α-amylase/α-glucosidase. Unlike guar gum, A. capillus-veneris had no glucose diffusion hindrance capacity. Equivalent to orlistat, A. capillus-veneris and its phytoconstituents inhibited PL in vitro with an ascending order of PL- IC50 values (μg/mL): ferulic acid; 0.48 ± 0.06 < ellagic acid; 13.53 ± 1.83 < chlorogenic acid; 38.4 ± 2.8 < A. capillus-veneris; 1600 ± 100. Incomparable to acarbose or metformin and glipizide, A. capillus-veneris (125, 250 and 500 mg/kg b.wt) lacked antihyperglycaemic efficacies in acute starch- or glucose-evoked postprandial hyperglycaemia increments in normoglycaemic overnight fasting rats. Superior to atorvastatin; A. capillus-veneris exerted significant antiobesity (p < 0.001) with marked triacylglycerol-reducing capacities (p < 0.001) in comparison to rats fed with HCD for 10 weeks.
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Acarbose (AC) and Sitagliptin (STGP) are oral hypoglycemic agents currently used either alone or in conjunction with human diabetic (Type 2) patients. AC has been used with diabetic cats, but not STGP thus far. Therefore, the objective of this study was to determine the potential use of AC or STGP alone and in combination for diabetic cats, by observing their effect on short-term post-prandial serum glucose, insulin, and incretin hormone (active glucagon-like peptide-1 (GLP-1) and total glucose dependent insulinotropic polypeptide (GIP)) concentrations in five healthy cats, following ingestion of a meal with maltose. All treatments tended (p<0.10; 5-7.5% reduction) to reduce postprandial glucose area under the curve (AUC), with an accompanying significant reduction (p<0.05, 35-45%) in postprandial insulin AUC as compared to no treatment. Meanwhile, a significant increase (p<0.05) in postprandial active GLP-1 AUC was observed with STGP (100% higher) and combined treatment (130% greater), as compared to either AC or no treatment. Lastly, a significant reduction (p<0.05) in postprandial total GIP AUC was observed with STGP (21% reduction) and combined treatment (7% reduction) as compared to control. Overall, AC, STGP, or combined treatment can significantly induce positive post-prandial changes to insulin and incretin hormone levels of healthy cats. Increasing active GLP-1 and reducing postprandial hyperglycemia appear to be the principal mechanisms of combined treatment. Considering the different, but complementary mechanisms of action by which AC and STGP induce lower glucose and insulin levels, combination therapy with both these agents offers great potential for treating diabetic cats in the future.
Fraction 2 of A. caudatum and fraction 4 of C. argentea has shown highest α-amylase and α-glucosidase inhibitory potential with IC₅₀ values of 0.241, 0.211 and 0.294, 0.249 mg/ml, respectively, which was comparable with acarbose (0.125 and 0.93 mg/ml). Whereas, extracts and remaining fractions of both the plants have shown lesser activity.
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α-Glucosidase inhibitor has considerable potential as a diabetes mellitus type 2 drug because it prevents the digestion of carbohydrates. The search for the constituents reducing α-glucosidase activity led to the finding of active compounds in the fruiting body of Ganoderma lucidum. The CHCl(3) extract of the fruiting body of G. lucidum was found to show inhibitory activity on α-glucosidase in vitro. The neutral fraction, with an IC(50) of 88.7 μg/ml, had stronger inhibition than a positive control, acarbose, with an IC(50) of 336.7 μg/ml (521.5 μM). The neutral fraction was subjected to silica gel column chromatography and repeated p-HPLC to provide an active compound, (3β,24E)-lanosta-7,9(11),24-trien-3,26-diol (ganoderol B). It was found to have high α-glucosidase inhibition, with an IC(50) of 48.5 μg/ml (119.8 μM).
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The aim of the study was to evaluate the efficacy and safety of acarbose in patients with Type 1 diabetes mellitus (DM).
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To investigate the source of the maltose unit in acarbose, feeding experiments using 3H- or 2H-labeled maltose or maltotriose were carried out with resting cells of Actinoplanes sp. SN223/29. It was found by experiments with [6"-3H]- and [1-3H]maltotriose that a maltose unit from the nonreducing end of maltotriose is incorporated into acarbose more efficiently than from the reducing end. However, experiments with [6"-2H]- and [2-2H]maltotriose showed that maltose from either the reducing end or from the nonreducing end of maltotriose was incorporated into acarbose. The results established that acarbose is formed from maltotriose by two routes; (1) Sixty percent of the acarbose are formed by attachment of maltose, produced by removing a glucose exclusively from the nonreducing end of maltotriose, to the pseudodisaccharide core unit. (2) The other 40% of the acarbose are formed by direct attachment of maltotriose to the core unit followed by loss of the terminal glucose from the reducing end. Furthermore, it was observed that there is no scrambling of label between the two glucose moieties of acarbose, that maltotriose is a comparably efficient precursor of acarbose as is maltose, and that the core unit is enriched up to 50% from the 2H-glucose liberated from the deuterated maltotrioses.
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We investigated 77 patients (mean age 58.7 years, mean BMI 27.3 kg/m2), treated by diet alone for at least 4 weeks. The subjects were randomized into three treatment groups for 16 weeks: 100 mg t.i.d. acarbose (n = 25) or 1 mg t.i.d. glibenclamide (n = 27) or one t.i.d. placebo (n = 25). Before and after therapy, the levels of fasting plasma glucose, glycosylated haemoglobin, fasting insulin, plasma glucose and insulin 1 h after a standardized breakfast were measured and insulin sensitivity determined by euglycaemic hyperinsulinaemic clamp test.
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Diabetes and peripheral neuropathy were induced in Wistar rats by injection of streptozotocin (45 mg/kg/intraperitoneally). The roots, stem and leaves of Calotropis procera were sequentially extracted with petroleum ether, chloroform, ethyl acetate and methanol. All the extracts were assessed by oral administration at 100 and 250 mg/kg in streptozotocin diabetic rats. The following compounds were used as positive controls: insulin NPH (1 IU/kg/day), metformin (500 mg/kg/day), glibenclamide (2.5 mg/kg/day) and a combination of acarbose (20 mg/kg/day) with methylcobalamine (500 µg/kg/day). In contrast, the streptozotocin induced untreated diabetic rats termed as negative control. Thermal hyperalgesia, mechanical hyperalgesia and tactile allodynia were evaluated in all groups of streptozotocin diabetic rats to assess the extent of neuropathy by Eddy׳s hot plate, tail immersion, Randall-Selitto and Von Frey hair tests. The basal nociceptive thresholds were assessed in week 4 of post streptozotocin injection. All groups received their treatment on a regular basis from 28 to 42 days following a confirmation of diabetic neuropathy. The nociceptive thresholds were assessed in all groups in week 5 and 6. The histopathology of pancreas and biochemical estimations of plasma insulin and glycosylated haemoglobin (HbA1C%) levels were also performed in week 6 of post streptozotocin injection.
Melanocytes play an important role in maintaining epidermal homeostasis by producing melanin and protecting the skin from harmful environmental factors. However, excessive up- or down-regulation of melanin production often causes hyper- or hypo-pigmented disorders, respectively, which affect the patient's quality of life. Therefore, various strategies for modulating melanin levels have been developed by the pharmaceutical and cosmetic industries. We reported previously that voglibose, which is a well-known anti-hyperglycemic agent, could be used as an anti-melanogenic agent by inhibiting α-glucosidase activity and reducing tyrosinase protein levels. Of the other representative anti-hyperglycemic agents, acarbose showed less anti-melanogenic activity despite its potent anti-hyperglycemic efficacy. In this study, we report that acarbose exhibited considerable anti-melanogenic activity when melanocytes were co-treated with acarbose and a digestible sugar, such as maltose. Simultaneous treatment with maltose augmented the inhibitory effect of acarbose on α-glucosidase activity by enhancing its stability under physiological conditions, leading to the down-regulation of tyrosinase. These results suggest that the co-treatment of anti-hyperglycemic agents with hydrolysable sugars may be a useful tool for reducing glucosidase-associated melanogenesis as a potent sugar-based anti-melanogenic regimen.
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A series of novel tetracyclic oxindole derivatives were synthesized via tandem Suzuki coupling-Michael addition reaction catalyzed by palladium. Twenty derivatives were designed and synthesized in 6-8 steps in 8-20% overall yields. Their structures were confirmed by (1)H, (13)C NMR and LC/MS. These compounds were evaluated for α-glucosidase inhibitory activity in vitro. Compounds 7c, 7d, 7e, 7g, 7h, and 7i exhibited IC50 values of 32.3, 12.1, 15.7, 29.0, 16.0, and 4.8 μM, respectively, with potency all higher than that of the control standard acarbose (IC50=115.8 μM). Molecular docking studies revealed the existence of potential hydrogen bonding and hydrophobic interaction between the enzyme and the active compound 7i.