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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a new complex oligosaccharide (Bay g 5421) of microbial origin on human intestinal alpha-glucosidehydrolase activity was tested in mucosal homogenate from human small bowel biopsy specimens. The alpha-glucosidehydrolase inhibitor (alpha-GHI) exerted a potent inhibitory effect on glucoamylase, sucrase, and maltase, was minimally effective on isomaltase, and did not affect trehalase and lactase activity. Kinetic analysis revealed a fully competitive type of inhibition with a Ki of 1.3 x 10(-6) M; thus the inhibitor had a 15,000-fold higher affinity to the enzyme sucrase than its natural substrate sucrose. The new compound may prove to be useful in the study of carbohydrate maldigestion and malabsorption and may possibly be of therapeutic benefit in diabetes and obesity.
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PMID:Inhibition of human intestinal alpha-glucosidehydrolases by a new complex oligosaccharide. 44 22

Inhibition of intestinal alpha-glucohydrolase activity is one approach for reducing the glycemic response from dietary carbohydrate and may prove useful for the treatment of diabetes mellitus. In this article, we describe the pharmacological properties of a time-dependent intestinal alpha-glucohydrolase inhibitor, MDL 73945. When preincubated 2 h with a rat intestinal mucosa preparation before substrate addition, MDL 73945 was a potent inhibitor of sucrase, maltase, glucoamylase, and isomaltase activities (MDL 73945 concentrations required to cause a 50% decrease in enzyme activity, 2 x 10(-7), 1 x 10(-6), 5 x 10(-6), and 8 x 10(-6) M, respectively); without preincubation, it was 10- to 500-fold less potent. In rats, a single oral dose of MDL 73945 administered simultaneously with 2 g/kg body wt sucrose resulted in a dose-dependent reduction in the area under the 0- to 3-h glycemic response curve, which was significant at 1 (45% reduction) and 3 (65% reduction) mg/kg. When administered 1 h before sucrose, the compound was more potent, with 0.3 mg/kg MDL 73945 significantly reducing the glycemic response to sucrose by 62%. A reduction in the glycemic response to sucrose was accompanied by reduced insulin secretion. MDL 73945 was slightly less effective against a starch load, with 3 and 10 mg/kg MDL 73945 administered 0.5 h before starch reducing the glycemic response by 39 and 52%, respectively. MDL 73945 was more effective against a sucrose load in streptozocin-administered rats than in control rats and was as effective after 16 daily doses as after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Jul
PMID:New potent alpha-glucohydrolase inhibitor MDL 73945 with long duration of action in rats. 206 Jul 19

The influences of glucose, the benzothiadiazide derivative diazoxide (an inhibitor of insulin release), and the potent non-glucose insulin secretagogue 3-isobutyl-1-methylxanthine (IBMX) on insulin secretion and the activities of 3 different lysosomal enzymes were studied in isolated mouse islets. We found that the increase in insulin secretion during a 4 hr incubation period in the presence of 16.7 mM glucose was accompanied by an increase in islet activities of the lysosomal enzymes acid amyloglucosidase and acid alpha-glucosidase. These alpha-1,4-glucoside splitting enzyme activities were increased by 45-55% (p less than 0.01). No influence by glucose was encountered for the activities of N-acetyl-beta-D-glucosaminidase or the non-lysosomal neutral alpha-glucosidase. Upon incubation with 0.2 mM diazoxide and glucose (16.7 mM) the glucose-induced insulin secretion was markedly suppressed and no significant increase in islet lysosomal enzyme activities was observed. On the other hand, insulin secretion induced by IBMX to the same magnitude as with 16.7 mM glucose, was accompanied by an increase in islet activity of N-acetyl-beta-D-glucosaminidase (p less than 0.05), whereas no apparent changes in acid amyloglucosidase and acid alpha-glucosidase activities could be detected. In conclusion, the determination of lysosomal enzyme activities in isolated mouse islets revealed that glucose was able to induce an increased activity of glucose producing glycogenolytic acid hydrolases under conditions when a concomitant insulin secretion occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1986 Oct
PMID:Insulin secretion and lysosomal enzyme activities in isolated mouse islets. Effects of glucose, diazoxide and isobutylmethylxanthine. 243 78

Castanospermine-glucosides (CS-glcs) are new compounds which have been evaluated as glycohydrolase inhibitors in rats. 7-O-alpha-D-Glucopyranosyl-CS (7 alpha-glc-CS) and 8 alpha-glc-CS were potent sucrase inhibitors with IC50s of 40 and 30 nM, respectively. Their sucrase inhibition was poorly reversible. They were much weaker liver lysosomal alpha-glucosidase inhibitors with IC50s of 40,000 nM. 1 alpha-glc-CS and 8 beta-glc-CS were both weaker and less selective sucrase inhibitors. In vivo, 7 alpha-glc-CS and 8 alpha-glc-CS effectively reduced the glycemic response to an oral 2 g/kg sucrose load at doses less than or equal to 1 mg/kg. 8 alpha-glc-CS was effective when administered up to 4 hr before sucrose. The known glucohydrolase inhibitors 1-deoxynojirimycin and N-hydroxyethyl-1-deoxy-nojirimycin were also potent sucrase inhibitors (IC50s = 200 and 400 nM, respectively) but their sucrase inhibition was readily reversible in vitro and their in vivo duration of action was much shorter than for the CS-glcs. Among the glucohydrolase inhibitors tested, the prolonged in vivo duration of action could be predicted by poor reversibility from sucrase. These CS-glcs provide a new generation of sucrase inhibitors which may be useful in the treatment of diabetes mellitus.
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PMID:Castanospermine-glucosides are potent, selective, long-acting sucrase inhibitors. 267 17

To examine the function of islet lysosomal enzymes in islet hormone secretory mechanisms, we investigated the effects of the lysosomotropic drug chloroquine on islet lysosomal enzyme activities and basal as well as stimulated insulin and glucagon secretion. Chloroquine, added to islet homogenates, did not affect the activities of the lysosomal enzymes acid amyloglucosidase, acid alpha-glucosidase, or N-acetyl-beta-D-glucosaminidase. The activity of acid phosphatase, however, was inhibited at a high concentration of chloroquine (10(-3) M). When injected together with glucose, chloroquine (2 or 10 mumol/kg) inhibited the peak plasma insulin response. Similarly, at 24 hrs after chloroquine injection (100 mumol/kg), the plasma insulin response to glucose was reduced. In contrast, islets isolated from mice pretreated 24 hrs before with chloroquine, displayed glucose-stimulated insulin secretion in vitro that was not different from controls. Such islets showed, furthermore, enhanced activities of the enzymes acid phosphatase and neutral alpha-glucosidase but not of acid amyloglucosidase, acid alpha-glucosidase or N-acetyl-beta-D-glucosaminidase. Arginine-stimulated insulin response in vivo displayed a complex pattern; it was increased when arginine was injected together with chloroquine but decreased at 24 hrs after chloroquine administration. Arginine-stimulated glucagon secretion was not affected by chloroquine. We conclude that chloroquine pretreatment 24 hrs prior to glucose injection decreases glucose-stimulated insulin secretion in vivo by mechanisms that are not correlated to an inhibitory action on islet activities of glycogenolytic lysosomal enzymes.
Diabetes Res 1988 Nov
PMID:Islet hormone secretion and islet lysosomal enzyme activities in the mouse: effects of chloroquine. 307 44

The pattern of pancreatic islet lysosomal enzyme activities was investigated in adult obese mice (aged 5-7 months), old obese mice (aged 9-17 months) and aged-matched old "obese" mice suffering from excessive weight loss. A series of lean NMRI mice of comparable age was included as controls. It was observed that the islet activity of the glucose producing glycogenolytic hydrolase, acid amyloglucosidase, was excessively high in the adult obese mouse, being about 10 times higher than in the adult lean mouse. This high activity was reduced by about 65% in the islets of old obese mice and by about 80% in old mice suffering from weight loss. When glycogen and maltose were compared as substrates for the alpha-1,4-glucoside splitting activity, the ratio, glycogen splitting/maltose splitting activity in adult obese mice (1.68) showed amyloglucosidase predominance, whereas the ratio in old obese mice (0.67), and in old mice suffering from weight loss (0.79) revealed a significant change in this relation. The extremely elevated plasma insulin levels in the adult obese mice were reduced by about 65% in old obese mice and by about 95% in old mice with excessive weight loss and thus displaying the same pattern as islet amyloglucosidase activity. Further, in normoglycemic obese mice a highly significant correlation (r = 0.85; p less than 0.001) was found between islet acid amyloglucosidase activity and the actual insulin secretory rate as reflected by the plasma insulin concentrations. The activity of islet N-acetyl-beta-D-glucosaminidase showed an activity pattern opposite to that of acid amyloglucosidase.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1986 Jan
PMID:Differential changes in islet lysosomal enzyme activities in aging obese hyperglycemic mice. 308 67

The glucose-producing amylolytic activity in pancreatic islet tissue was characterized with regard to its properties with glycogen (amyloglucosidase) and maltose (maltase) as substrate, its optimum activity in islets from different strains of mice (NMRI, CBA and C-57BL) and after fasting, and its relation to the insulin secretory response after different secretagogues in vivo. Additionally the effects and fate of injected fungal acid amyloglucosidase were assessed. In the pancreatic islets of NMRI mice both the glycogen-splitting activity and the maltose-splitting activity displayed latency and an acid pH-optimum of about 5.0. After differential centrifugation a significant part of amyloglucosidase activity was found to be confined to the mitochondrial-lysosomal fraction. In crude islet homogenate the apparent Km for maltose at pH 5.0 was 2.1 mM. No Km for glycogen could be given because of complex kinetics in the presence of this substrate. The maltase activity was about 30% lower than the amyloglucosidase activity in islet tissue from NMRI mice. The reverse pattern was observed in the liver. Moreover, the liver amyloglucosidase activity was only one fourth of that of the islet tissue. The amyloglucosidase but not the maltase activity in islet tissue from CBA mice was lower than in islets from NMRI mice. Both activities were very low in islets from C-57 mice. A 24 hr fasting period reduced the amyloglucosidase but not the maltase activity in islets from NMRI mice. The insulin secretory response in vivo to an i.v. arginine load in the different strains and after fasting displayed the same pattern as the islet amyloglucosidase activity, whereas the insulin response following a glucagon injection was largest in the C-57 strain and unaffected by the fasting state. Pretreatment of mice with 0.05 mumol/kg of highly purified fungal amyloglucosidase, moderately (about 35%) enhanced the insulin secretory response to arginine, did not affect the response to glucagon, and greatly (about 100%) enhanced the response to glucose and tolbutamide. Moreover, treatment of mice with lysosomal stabilizers (glucocorticoids) reduced the insulin response to sulphonylureas and glucose, had no effect on the insulin response to beta-adrenergic and cholinergic stimulation, and increased ACTH-induced insulin release. A lysosomal labilizer (progesterone) enhanced the insulin response induced by glucose and tolbutamide.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Res 1986 Jan
PMID:Islet amyloglucosidase activity: some characteristics, and its relation to insulin secretion stimulated by various secretagogues. 308 68

MDL 25,637 is a novel compound designed as a transition-state inhibitor of alpha-glucohydrolases. This compound inhibits rat intestinal sucrase, maltase, isomaltase, glucoamylase and trehalase activities at micromolar concentrations. It is a much weaker inhibitor of alpha-amylase and lactase. Inhibition of sucrase was competitive with sucrose. In mice, MDL 25,637 inhibited the rise in serum glucose after a sucrose or starch load but not after a glucose load. MDL 25,637 also reduced the glycemic response to sucrose in rats. The drug was most effective when administered 0 to 30 min before the sucrose load and was as effective in streptozotocin-treated rats as in normals. The inhibition by MDL 25,637 of intestinal glucohydrolases is an effective means of reducing the hyperglycemic response to an oral sucrose or starch load and, as such, warrants further investigation as a potential drug for the treatment of diabetes mellitus.
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PMID:Inhibition of intestinal disaccharidases and suppression of blood glucose by a new alpha-glucohydrolase inhibitor--MDL 25,637. 329 22

The pattern of islet lysosomal enzyme activities, islet insulin concentration and the plasma levels of insulin and glucose were studied in freely fed mice after the in vivo administration of diazoxide in doses known to induce crinophagy in islet beta-cells. After diazoxide treatment at time 0 and at 18 hr, the plasma glucose levels at 20 hr were markedly enhanced from 6.6 +/- 0.2 mmol/l (controls) to 27.2 +/- 2.7 mmol/l (diazoxide). Inhibition of insulin secretion by diazoxide was reflected in the insulinogenic index, which was reduced by approximately 40% (p less than 0.01) in the diazoxide-treated animals, who also displayed an increased concentration of islet insulin (+50%; p less than 0.01). Moreover, we found that the activities of certain lysosomal enzymes in islet tissue were markedly increased following diazoxide treatment. Thus the activities of the acid phosphatase, (+57%; p less than 0.02) the hexosaminidase N-acetyl-beta-D-glucosaminidase, (+52%; p less than 0.001), and the carboxyl proteinase cathepsin D (+41%; p less than 0.001), were all enhanced after diazoxide, whereas the activity of another lysosomal enzyme, the glycogen hydrolysing acid amyloglucosidase, was not altered by diazoxide treatment. The present data thus indicate that the morphological observation of diazoxide-induced crinophagy in pancreatic beta-cells has a biochemical correlate in enhanced levels of certain islet lysosomal enzyme activities known to participate in degradative processes. The results also suggest that islet lysosomal enzyme activities and/or lysosome populations can be modulated by a relative independence from each other.
Diabetes Res 1987 Oct
PMID:Biochemical determination of islet lysosomal enzyme activities following crinophagy-stimulating treatment with diazoxide in mice. 332 35

The pattern of islet lysosomal enzyme activities and the plasma levels of insulin and glucose were studied in adult obese hyperglycemic mice (aged 6-8 months) after in vivo administration of the lysosomotropic drug suramin. After suramin administration, 5.2 mumol/mouse, at time 0 and at 18 hr, the plasma insulin levels in the obese mice gradually decreased and were reduced by about 85% at 20 hr. At the same time point the suramin-induced inhibition of insulin secretion was reflected by a notable (250%) increase in islet insulin content. A negative correlation (r = -0.81; p less than 0.01) was observed between plasma insulin level and islet insulin storage. The plasma glucose levels were not affected by the drug. Furthermore, it was observed that the islet activity of the glucose producing glycogenolytic hydrolase, acid amyloglucosidase, which is excessively high in the obese mouse, was markedly reduced by suramin (about 70%) at 20 hr. A good correlation (r = 0.88; p less than 0.001) was found to exist between the islet acid amyloglucosidase activity and the plasma insulin concentration in controls and suramin-treated mice. When glycogen was replaced by maltose or 4-methylumbelliferyl-alpha-D-glucoside as substrate for the acid alpha-1,4-glucoside splitting activity the inhibitory effect of suramin was less pronounced (about 50%). The ratio, glycogen splitting/maltose splitting activity in islet tissue was reduced by suramin from 1.25 +/- 0.12 (control) to 0.69 +/- 0.06 (p less than 0.005). The neutral, nonlysosomal alpha-1,4-glucoside splitting activity was not affected by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1985 Jul
PMID:Islet lysosomal enzyme activities and plasma insulin levels in obese hyperglycemic mice following injection of the lysosomotropic drug suramin. 393 59


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