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)

This study examined pancreatic allograft function in transplanted diabetic juvenile pigs. The grafts were transplanted with ligated, occluded (Ethibloc) or open ducts. No immunosuppression was used. Irreversible and permanent diabetes was induced by streptozotocin. Graft function was assessed by measuring glucose tolerance and insulin production during an i.v. glucose tolerance test. The fractional growth rate of the transplanted host was used to evaluate the long-term consequence of transplantation. Normal glucose tolerance was achieved in 50%, and a slight impairment in 10% of the animals. In 35%, no detectable graft function was observed. Duct-ligated and Ethibloc-occluded grafts had a significantly lower function rate within the first week compared with grafts with open ducts. The fractional growth rate was significantly decreased in animals receiving grafts with occluded ducts. This was probably not due to different insulin production. No graft failures were observed within the first week in open-duct graft transplantations. Graft failures were associated with elevated serum alpha-amylase and were probably due to vascular impairment. Normal glucose tolerance in transplanted pigs was associated with elevated levels of normal insulin and C-peptide in peripheral blood, concomitant with low levels of proinsulin. Our results show that a pancreatic graft should be transplanted with open ducts. Obstructed ducts lead to an increased frequency of graft failure, while the transplanted hosts with such functioning grafts show retarded growth due to unidentified factors.
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PMID:Pancreas transplantation in streptozotocin-diabetic juvenile pigs. Evaluation of function among duct-ligated, duct-occluded, and nonligated allografts. 636 37

The native or modified alpha-amylase inhibitor Hoe 467A - isolated from the culture medium of Streptomyces tendae 4158 - and overlapping peptides were degraded by the automatic Edman technique. The oxidized or aminoethylated or oxidized and maleoylated inhibitor was digested with trypsin and the native inhibitor with pepsin. Further digestion with Staphylococcus aureus proteinase was also carried out. After peptic digestion two cystin peptides were isolated, which allowed the establishment of the disulfide bonds. The alpha-amylase inhibitor is a polypeptid consisting of 74 amino-acid residues with a molecular mass of 7958 Da. The inhibitor is composed of all naturally occurring amino acids except methionine and phenylalanine and shows no sequence homology to known inhibitors. The clinical and pharmacological importance in respect to the inhibitors ability for inactivation of human salivary and pancreatic alpha-amylase is discussed. Especially the proteinase resistance of the inhibitor enables a clinical application in human (e.g. Diabetes mellitus) per os.
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PMID:[The primary structure of the alpha-amylase inhibitor Hoe 467A from Streptomyces tendae 4158. A new class of inhibitors]. 660 9

A rapid method is proposed for isolating the two main components of human pancreatic alpha-amylase (HPA I and HPA II). The isoelectric point of HPA I (7.2), the main component, was determined using an isoelectrofocusing method and found to differ from that of HPA II (6. 6). The molecular mass of HPA I (55862+/-5 Da) and that of HPA II (55786+/-5 Da) were determined by performing mass spectrometry and found to be quite similar to that of the protein moiety calculated from the amino acid sequence (55788 Da), which indicates that the human amylase is not glycosylated. The structure of both HPA I and HPA II was further investigated by performing limited proteolysis. Two fragments with an apparent molecular mass of 41 kDa and 14 kDa were obtained by digesting the isoforms with proteinase K and subtilisin, whereas digestion with papain yielded two cleaved fragments with molecular masses of 38 kDa and 17 kDa. Proteinase K and subtilisin susceptible bonds are located in the L8 loop (A domain), while the papain cut which occurs in the presence of the calcium chelator EDTA is in the L3 loop (B domain). The kinetics of the inhibition of HPA I and HPA II by acarbose, a drug used to treat diabetes and obesity, were studied using an amylose substrate. The Lineweaver-Burk primary plots of HPA I and HPA II, which did not differ significantly, indicated that the inhibition was of the mixed non-competitive type. The secondary plots gave parabolic curves. All in all, these data provide evidence that two acarbose molecules bind to HPA. In conclusion, apart from the pI, no significant differences were observed between HPA I and HPA II as regards either their molecular mass and limited proteolysis or their kinetic behavior. As was to be expected in view of the high degree of structural identity previously found to exist between human and porcine pancreatic amylases, the present data show that the inhibitory effects of acarbose on the kinetic behavior of these two amylases are quite comparable. In particular, the process of amylose hydrolysis catalyzed by HPA as well as by PPA in both cases requires two carbohydrate binding sites in addition to the catalytic site.
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PMID:The human pancreatic alpha-amylase isoforms: isolation, structural studies and kinetics of inhibition by acarbose. 977 2

This study examines the effect of moderate intake of red wine, tannic acid, or ethanol during a meal in type 2 diabetic patients and the influence of tannic acid on the digestibility of starch by alpha-amylase. Thirty non-insulin-dependent diabetes mellitus (NIDDM) patients aged 53 +/- 6 years were studied (in vivo study) 10 of whom received red wine (200 mL), 10 tannic acid (150 mg), and 10 ethanol (16 g) with their midday meal (600 calories, 65 g carbohydrate, 20 g lipid, and 34 g protein). All patients were tested on two occasions (water or placebo v wine, alcohol, or tannic acid). The influence of tannic acid (0.25, 0.5, and 1 mg) on the digestibility of starch (100 mg) by alpha-amylase (100 U) was tested in vitro by sequential incubation at 37 degrees C (in vitro study). The maximum glucose excursion after lunch was 2.6 +/- 0.8 mmol/L at 90 minutes (T90) for water and 1.8 +/- 0.9 mmol/L at T90 for red wine taken with the meal. The values at T60 and T90 were significant (P < .01). Comparable results were obtained with tannic acid alone (nonalcoholic component of wine): the maximum glucose excursion after lunch was 2.76 +/- 0.9 mmol/L at T120 for placebo and 1.97 +/- 0.9 mmol/L at T90 for tannic acid (P < .01); no difference in glucose and insulin excursion was observed between water and ethanol. No interaction between tannic acid and starch was observed in the in vitro experiments, although after preincubation of alpha-amylase with tannic acid, digestion was slowed in a dose-dependent manner (6.1 +/- 1.1 minutes for 0.25 mg tannic acid and 13.1 +/- 1.59 minutes for 1 mg tannic acid). Drinking red wine with a meal did not increase blood glucose in NIDDM patients, and led to a slight decrease in some instances. The effect appeared to be mediated by the nonalcoholic compounds in wine such as tannic acid. Ethanol itself had no effect on plasma glucose or insulin levels.
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PMID:Effects of red wine, tannic acid, or ethanol on glucose tolerance in non-insulin-dependent diabetic patients and on starch digestibility in vitro. 1048 61

Scientific advances in the 19th and 20th centuries led to the discovery of insulin, the fundamental therapeutic means for treatment of diabetes mellitus type 1 at the onset of the twenties, to the introduction of sulfonylurea derivatives and biguanides in the fifties and sixties. The discovery of the principle of radioimmunoassay at the end of the fifties made it possible to investigate insulin secretion and to achieve a more accurate understanding of the pathogenesis of type 1 and 2 diabetes. Understanding of insulin resistance made it possible to introduce an euglycaemic hyperinsulin clamp at the end of the seventies. Insulin resistance was presented in context with metabolic syndrome X. Insulin is administered at the break of the millenium in subcutaneous injections, insulin dispensers and insulin pumps, experimentally also by the intraperitoneal and inhalatory route. In the nineties in the practice of diabetes 1 therapy ultrashort-term and finally als long-term insulin analogues were developed. For type 2 diabetes mellitus inhibitors of alpha-amylase were introduced and as a quite new group of oral antidiabetics thiazolidindiones. The possibility of 24-hour monitoring of the blood sugar level by means of a subcutaneous glucose sensor was introduced. The end of the century is characterized also by attempts to administer growth factors in the treatment of non-patent vascular obstructions in the diabetic foot syndrome. In mice and rats transformation of the ductal cell of the exocrine pancreas to the Langerhans islet cell proved successful. Further progress in diabetology will depend, similarly as in the rest of medicine, in particular on advances in cellular and molecular biology and genetics, as well as advances in microelectronics and new materials. Emphasis on the community understanding of this disease and consequential primary prevention of diabetes and secondary prevention of its complications are important.
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PMID:[Diabetology at the threshold of the 21st century]. 1139 67

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.
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PMID:Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors. 1142 50

Camelids produce functional antibodies devoid of light chains and CH1 domains. The antigen-binding fragment of such heavy chain antibodies is therefore comprised in one single domain, the camelid heavy chain antibody VH (VHH). Here we report on the structures of three dromedary VHH domains in complex with porcine pancreatic alpha-amylase. Two VHHs bound outside the catalytic site and did not inhibit or inhibited only partially the amylase activity. The third one, AMD9, interacted with the active site crevice and was a strong amylase inhibitor (K(i) = 10 nm). In contrast with complexes of other proteinaceous amylase inhibitors, amylase kept its native structure. The water-accessible surface areas of VHHs covered by amylase ranged between 850 and 1150 A(2), values similar to or even larger than those observed in the complexes between proteins and classical antibodies. These values could certainly be reached because a surprisingly high extent of framework residues are involved in the interactions of VHHs with amylase. The framework residues that participate in the antigen recognition represented 25-40% of the buried surface. The inhibitory interaction of AMD9 involved mainly its complementarity-determining region (CDR) 2 loop, whereas the CDR3 loop was small and certainly did not protrude as it does in cAb-Lys3, a VHH-inhibiting lysozyme. AMD9 inhibited amylase, although it was outside the direct reach of the catalytic residues; therefore it is to be expected that inhibiting VHHs might also be elicited against proteases. These results illustrate the versatility and efficiency of VHH domains as protein binders and enzyme inhibitors and are arguments in favor of their use as drugs against diabetes.
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PMID:Three camelid VHH domains in complex with porcine pancreatic alpha-amylase. Inhibition and versatility of binding topology. 1196 Sep 90

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.
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PMID:Synthesis of selenium analogues of the naturally occurring glycosidase inhibitor salacinol and their evaluation as glycosidase inhibitors. 1210 2

The ability to control carbohydrate digestion is useful in the treatment of diabetes mellitus and obesity. In the present study, we examined whether recently developed 4(2)-O-beta-D-galactosyl maltobionolactone (LG2O) having anti-amylase activity is able to control postprandial blood glucose concentration in mice. In addition, we tried to determine how LG2O regulates carbohydrate delivery in the gut lumen by conducting in vivo and in vitro studies. Male non-diabetic ddY mice and KK-A(y) mice, a spontaneously diabetic strain, had free access to a carbohydrate rich diet supplemented with LG2O (3 or 10 g/kg) for 0.5 hr, and blood glucose concentration was measured. LG2O suppressed any steep increase in postprandial blood glucose concentration in both ddY and KK-A(y) mice. Corresponding to the blood glucose response, LG2O also markedly suppressed any increase in postprandial plasma insulin concentration. After ingestion of the diet, LG2O produced a 1.5-3.5 fold increase in the gut contents and reducible sugar content in the small intestine but not in the stomach. Although alpha-amylase activity in the stomach was much lower compared with the activity in the small intestine, LG2O still strongly inhibited alpha-amylase activity in the stomach. In contrast, LG2O had little or no influence on alpha-amylase activity in the proximal intestine. From the in vitro carbohydrate digestion stimulation, LG2O at 7.5 mM decreased glucose production by 75% for dextrin, 25% for alpha-starch and 60% for raw starch. In conclusion, administration of LG2O inhibits carbohydrate digestion in the gut, and produces significant improvements in both blood glucose and insulin response following ingestion as part of the diet, and this evidence provides support for its therapeutic potential in treating diabetes mellitus and obesity.
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PMID:Control of postprandial hyperglycaemia by galactosyl maltobionolactone and its novel anti-amylase effect in mice. 1212 61

Banaba [Lagerstroemia speciosa (L.) Pers.] has been used as a folk medicine for diabetes in the Philippines. Using bioassay-guided separation, valoneaic acid dilactone (1) was isolated from the leaves as a potent alpha-amylase inhibitor. A simple and efficient method for the quantitative determination of valoneaic acid and its derivatives in Banaba extract was established. Valoneaic acid exists as the structural part of the polyphenols, which like flosin A, reginin A, and lagerstroemin, are characteristic constituents of Banaba. These derivatives were hydrolyzed to valoneaic acid by HCl and extracted with 2-butanone. This extract was subjected to HPLC analysis, and the contents of valoneaic acid determined as the whole valoneaic acid contents. Using this method, the whole valoneaic acid contents were measured in eight Banaba leaf decoctions. The alpha-amylase-inhibiting activities of the decoctions were dependent on the whole valoneaic acid contents. In addition, a strong linear correlation was observed between the whole valoneaic acid contents and total polyphenol contents. This analytical procedure is applicable to the chemical evaluation of Banaba.
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PMID:[Isolation and quantitative analysis of the alpha-amylase inhibitor in Lagerstroemia speciosa (L.) Pers. (Banaba)]. 1287 43


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