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)

A novel ester of succinic acid (1,2,3-tri(methylsuccinyl)glycerol ester; 3SMG) was found to stimulate insulin release and to potentiate the insulinotropic action of gliquidone and repaglinide when administered intravenously to normal anaesthetized rats in a dose as low as 0.07 mumol g-1 body wt. The ester failed, however, to augment plasma insulin concentration when given enterally. The design of succinic acid esters of high insulinotropic potential might thus allow efficient stimulation of insulin secretion in non-insulin-dependent diabetes, without requiring unpractical high dosage and without running the risk of an undesirable increase in gluconeogenesis.
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PMID:Stimulation of insulin release and potentiation of the insulinotropic action of antidiabetic agents by 1,2,3-tri(methylsuccinyl)glycerol ester in anaesthetized rats. 944 27

Embryonic dysmorphogenesis has been blocked by antioxidant treatment in vivo and in vitro, suggesting that embryonic excess of reactive oxygen species (ROS) has a role in the teratogenic process of diabetic pregnancy. We report that the basal levels of ROS in dispersed rat embryonic cells in vitro, as determined by fluorescence of dichlorofluorescein (DCF), were not different in cells from control and diabetic pregnancy at day 10 or 12. Beta-hydroxybutyrate (beta-HB) and succinic acid monomethyl ester both augmented DCF fluorescence in cells from day 12 embryos of normal and diabetic rats but not from day 10 embryos. Cells of day 10 and day 12 embryos from normal and diabetic rats responded to increasing glucose concentrations with a dosage-dependent alleviation of DCF fluorescence. Day 10 embryonic cells exhibited high glucose utilization rates and high pentose phosphate shunt rates, but low mitochondrial oxidation rates. Moreover, in vitro culture of embryos between gestational days 9 and 10 in the presence of 20% oxygen induced an increased and glucose-sensitive oxidation of glucose compared with embryos not cultured in vitro. At gestation day 12, however, pentose phosphate shunt rates showed a decrease, whereas the mitochondrial beta-HB oxidation rates were increased compared with those at gestation day 10. This was paralleled by a lower expression of glucose 6-phosphate dehydrogenase- and phosphofructokinase-mRNA levels at day 12 than at day 10. On the other hand, H-ferritin mRNA expression at day 12 was high compared with day 10. None of the mRNA species investigated were affected by the diabetic state of the mother. It was concluded that beta-HB-induced stimulation of mitochondrial oxidative events may lead to the generation of ROS at gestational day 12, but probably not at day 10, when only a minute amount of mitochondrial activity occurs. Thus our results do not support the notion of diabetes-induced mitochondrial oxidative stress before the development of a placental supply of oxygen.
Diabetes 1998 Feb
PMID:Beta-hydroxybutyrate increases reactive oxygen species in late but not in early postimplantation embryonic cells in vitro. 951 22

Succinic acid esters are currently under investigation as possible insulinotropic tools in the treatment of noninsulin-dependent diabetes mellitus. The present article introduces three novel nutrient esters and aims mainly to explore, in both normal and GK rats, the secretory response to such esters when tested alone or in combination. It documents that in pancreatic islets from normal rats, methyl acetate (10 mM), which fails to augment basal insulin output, potentiates the secretory response to succinate dimethyl ester (also 10 mM). It also reveals that alpha-D-glucose pentaacetate (alpha GPA) (1.7 mM) stimulates insulin release in the absence of any other exogenous nutrient and even more so in the presence of succinate methyl ester. Moreover, the methyl esters of succinic acid (10 mM), when used together with either methyl acetate or alpha GPA, provoked insulin secretion in islets from diabetic GK rats incubated in the absence of D-glucose, although no significant secretory response of such islets could be detected when each of these agents was tested separately. These findings thus draw attention to the insulinotropic potential in type 2 diabetes of selected combinations of nutrient esters, including a D-glucose ester presumably able to enter into islet cells without requiring the intervention of a hexose carrier.
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PMID:Synergistic insulinotropic action of succinate, acetate, and glucose esters in islets from normal and diabetic rats. 954 40

Selected esters of succinic acid are currently under investigation as insulinotropic tools for the treatment of non-insulin-dependent diabetes mellitus. The aim of the present study was to investigate, in isolated rat pancreatic islets, the insulin secretory response to ten novel esters of succinic acid. According to six different methods of comparison, the following hierarchy in insulinotropic potential was established: 4-tert-butyl-succinate < or = glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate < or = threitol-3-succinoyl-1,2,4-trimethylsuccinate < or = ethanediol-1,2-diethylsuccinate < or = glycerol-1,2-dimethylsuccinate < or = glycerol-3-hydroxy-1,2-dimethylsuccinate < or = arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate < or = threitol-1,2,4-trimethylsuccinate < or = ethanediol-1,2-dimethylsuccinate < propanediol-1,2-dimethylsuccinate. There was a close correlation (r = 0.823) between the insulinotropic potential and the minimal effective concentration, which ranged between the extreme values of 10 microM and 2.5 mM. In the presence of the esters, the concentration-response relationship for glucose-stimulated insulin release was changed from its typically sigmoidal shape to a hyperbolic pattern, with most agents enhancing insulin output at a low hexose concentration (2.8 mM) but failing to do so at a high glucose level (16.7 mM). Highly potent insulinotropic esters have several advantages over other antidiabetic agents in clinical use.
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PMID:Comparison between the insulinotropic potential of ten new esters of succinic acid. 957 Apr 52

Selected esters of succinic acid are currently under investigation as possible insulinotropic agents for the treatment of noninsulin-dependent diabetes mellitus. The aim of the present study was to investigate the effects of ten novel esters of succinic acid upon biosynthetic activity in rat pancreatic islets. In the absence of any other exogenous nutrient, glycerol-3-hydroxy-1,2-dimethyl succinate (0.5 mM), D-arabitol-5-hydroxy-1,2,3,4-tetramethylsuccinate (0.5 mM), and 4-tert-butylsuccinate (2.5 mM) exerted little or no effect upon L-[4-3H]phenylalanine incorporation into trichloroacetic acid-precipitable material. A modest but significant increase in biosynthetic activity to approximately 150% of basal value was found in the presence of L-threitol-1,2,4-trimethylsuccinate (2.0 mM) and ethanediol-1,2-diethylsuccinate (2.5 mM). A two- to five-fold increase in protein biosynthesis was observed in islets exposed to propanediol-1,2-dimethylsuccinate, glycerol-1,2-dimethylsuccinate-3-hydrogenosuccinate, L-threitol-3-succinoyl-1,2,4-trimethylsuccinate, glycerol-1,2-dimethylsuccinate or ethanediol-1,2-dimethylsuccinate (2.5 mM each), these esters being mentioned in order of increasing biological efficiency. There was a significant correlation between these results and the insulinotropic action of the same esters. The present findings thus reinforce the view that such esters act as nutrients in islet cells and, therefore, offer the advantage over pharmacological agents currently used for the treatment of type-2 diabetes in stimulating both the biosynthetic and secretory activity of insulin-producing B-cells.
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PMID:Stimulation of biosynthetic activity by novel succinate esters in rat pancreatic islets. 958 65

1. Selected esters of succinic acid are currently under investigation as potential insulinotropic tools in the treatment of non-insulin-dependent diabetes. At variance with the methyl esters of succinic acid used in most of the work so far conducted from this perspective, the monoethyl ester of succinic acid (EMS) offers the advantage of avoiding the undesirable generation of methanol by intracellular hydrolysis. In the present study, the metabolism and functional effects of EMS were investigated, therefore, in rat pancreatic islets. 2. At a 10 mM concentration, EMS enhanced insulin release from islets stimulated by 7-17 mM D-glucose but failed to do so at lower concentrations of the hexose. EMS was efficiently metabolized, as judged from the generation of 14CO2 by islets exposed to the monoethyl ester of either [1,4-14C] or [2, 3-14C]succinic acid. D-Glucose (6 mM) failed to affect the metabolism of EMS (10 mM), which itself failed to affect the metabolism of D-[5-3H]glucose or D-[U-14C]glucose. EMS also stimulated biosynthetic activity in the islets. It inhibited 86Rb and 45Ca outflow from prelabeled islets perfused in the absence of D-glucose but enhanced the efflux of the two cationic tracers in the presence of the hexose (7 mM). 3. It is concluded that the insulinotropic action of EMS is attributable, to a large extent, to its capacity to act as a nutrient in islet cells.
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PMID:Insulinotropic action of the monoethyl ester of succinic acid. 970 5

The polyacetate esters of certain non-nutrient monosaccharides, such as L-glucose and 2-deoxy-D-glucose, were recently reported to display positive insulinotropic action and, hence, proposed as possible tools for stimulation of insulin release in non-insulin-dependent diabetes. In the present study, the secretory response to four carbohydrate esters was compared in islets of both normal and hereditary diabetic Goto-Kakizaki rats. Three major findings are documented. First, in islets exposed to the dimethyl ester of succinic acid (10.0 mmol/l), D-mannoheptulose hexaacetate (1.7 mmol/l) was found to stimulate insulin release in both normal and diabetic rats. Second, relative to the control value recorded in the sole presence of the succinic acid ester, the increments in insulin output evoked by D-mannoheptulose hexaacetate, alpha-L-glucose pentaacetate and beta-D-glucose pentaacetate (all 1.7 mmol/l) were not lower and, on occasion, even higher in diabetic rats than in control animals. Last, the sole exception to such a rule was encountered in islets exposed to beta-L-glucose pentaacetate, in which case the hexose moiety of the ester might mimic the inhibitory effect of alpha-D-glucopyranose upon phosphorylase a-catalyzed glycogenolysis in islets from diabetic rats. These findings reinforce the concept that the insulinotropic action of monosaccharide esters is not solely attributable to the catabolism of their carbohydrate moiety but also to a direct effect of the esters themselves upon a yet unidentified receptor system. They also provide further support to the possible use of the esters of non-nutrient monosaccharides as insulinotropic tools in type-2 diabetes.
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PMID:Insulinotropic action of the polyacetate esters of two non-nutrient monosaccharides in normal and diabetic rats. 985 50

Both alpha- and beta-D-glucose pentaacetate (1.7 mM each) augmented, to almost the same extent, insulin release caused by succinic acid dimethyl ester (10.0 mM) in rat pancreatic islets. The secretory response to these hexose esters largely exceeded that evoked by unesterified D-glucose tested at the same concentration (1.7 mM). The release of insulin provoked by succinic acid dimethyl ester was inhibited, however, by alpha-D-galactose pentaacetate, whilst being unaffected by beta-D-galactose pentaacetate (each also 1.7 mM). It appears, therefore, that the insulinotropic action of hexose esters is not attributable solely to the catabolism of their carbohydrate moiety, but may also involve a receptor system that displays anomeric specificity and can be directly activated or inhibited by the esters themselves. Hence, it is proposed that selected esters of non-nutrient monosaccharides may represent new tools to either stimulate insulin release in diabetes or prevent excessive hormonal secretion in situations of hyperinsulinemia.
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PMID:Opposite effects of D-glucose pentaacetate and D-galactose pentaacetate anomers on insulin release evoked by succinic acid dimethyl ester in rat pancreatic islets. 1007 7

The nutritional value of glycerol-1,2,3-tris(methylsuccinate), a novel ester of succinic acid with high insulinotropic efficiency both in vitro and in vivo, was assessed in both fed and starved rats. The infusion of the ester, given in a daily amount (1.2 micromol. g body wt-1) well in excess of what could result from its repeated intravenous administration as an insulinotropic agent in non-insulin-dependent diabetes (0.07 micromol. g body wt-1 for each administration), failed to prevent the fall in body weight, liver and muscle glycogen contents, and plasma d-glucose or insulin concentration, as well as the increase in plasma free fatty acid and beta-hydroxybutyrate concentrations caused by starvation. The sole indications that the ester may serve, to a limited extent, as an alternative nutrient in starved rats consisted in a somewhat higher weight of both liver and paraovarian adipose tissue and somewhat higher activity of liver glucokinase in rats receiving the ester than in animals infused with saline. The low nutritional value of this ester thus answers the objection of its possible role as an extrapancreatic nutrient or gluconeogenic precursor in the perspective of its use as an insulinotropic tool in type 2 diabetes.
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PMID:Assessment of the nutritional value of glycerol-1,2, 3-tris(methylsuccinate) in fed and starved rats. 1038 33

Hereditarily diabetic Goto-Kakizaki rats were infused for 5 min with saline, containing as required nateglinide or mixed molecules (HD154 and HD166) with both a nateglinide moiety and a succinic acid ester moiety. The dose of these agents given intravenously amounted to 5.0 nmol/g body weight in all cases. All agents provoked a comparable early increase in plasma insulin concentration. However, HD154 and HD166, but not nateglinide itself, also caused a secondary rise in plasma insulin concentration 30 min after their infusion. It is proposed that mixed molecules formed of both a hypoglycemic sulfonylurea or meglitinide analog and a succinic acid ester may be better able than the antidiabetic agents themselves to evoke a sustained stimulation of insulin release in non-insulin-dependent diabetes.
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PMID:Stimulation of insulin release in hereditarily diabetic rats by mixed molecules formed of nateglinide and a succinic acid ester. 1060 76


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