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)

Pretreatment with n-butanol (10 mmol/kg i.p.) 30 minutes before alloxan (100 mg/kg) protects mice from the permanent hyperglycemic effects (measured at 72 hours) of the diabetogenic agent. This dose of n-butanol caused an elevation of serum glucose at 30 minutes, the time of alloxan administration. Since glucose administration can protect animals from alloxan, the possibility that alcohol-induced hyperglycemia protected mice from alloxan was investigated. Mannoheptulose, an antagonist of glucose action at the pancreatic beta-cell, when given 24 minutes after n-butanol and 6 minutes before alloxan, eliminated the alcohol-induced protection. Fasted mice did not exhibit n-butanol-induced hyperglycemia at 30 minutes and alloxan given at that time produced diabetes. No protection was observed in fed animals when n-butanol was given 5 minutes before alloxan. The high serum levels of butanol and normal serum glucose which were observed at 5 minutes after alcohol administration indicated that the lack of protection was not due to a lack of circulating alcohol but resulted from an absence of hyperglycemia. The results indicate that pretreatment with n-butanol protects mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan administration.
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PMID:Mechanism of protection from alloxan diabetes provided by n-butanol. 32 64

The ability of sugars to protect the beta cell from alloxan diabetes is highly stereospecific. The alpha anomer, which is present in equilibrium in both glucose and 3-O-methyl glucose (3-OMG) at approximately 34 per cent, provides greater protection than the beta anomer. The greater protection of the alpha anomer of glucose is present fifteen seconds between its administration and alloxan, but there is no difference in protection following a thirty-second interval. The nonmetabolized analogue, 3-OMG, provides even greater protection than glucose, and this higher affinity is expressed both by the lower dose necessary to provide protection, as well as by the higher dose of mannoheptulose needed to remove thr protection. Mannoheptulose not only removes the protection provided by exogenous glucose but sensitizes the beta cell to the toxic effects of alloxan in the fasting state, probably by inhibiting the protection provided by endogenous glucose. Mannoheptulose is able to remove glucose protection before, with, or after the administration of glucose prior to alloxan injection. Finally, the protective effect of both glucose and 3-OMG is time-related, and the protection not only is due to absolute concentration but also appears to be affected by a changing concentration.
Diabetes 1975 May
PMID:Studies of alloxan toxicity on the beta cell. 109 83

We demonstrated previously that the conversion rate of proinsulin to insulin in pancreatic islets progressively increased after prolonged prior exposure to glucose (11 mM) and that this effect could be blocked by cycloheximide. This study was designed to characterize further the time course and regulation of the proinsulin conversion process. The effects of prior exposure to glucose on proinsulin conversion were dose dependent (Km, approximately 7 mM glucose) and time dependent, taking approximately 3 h to reach the maximum rate. Glucose added at or after the subsequent [3H]leucine pulse was ineffective. Mannoheptulose, added during a 3-h exposure with glucose (11 mM), prevented glucose-induced activation of the proinsulin conversion process. L-Leucine (20 mM) was as effective as 11 mM glucose in activating conversion, whereas 2-alpha-ketoisocaproic acid (20 mM) or phorbol ester (50 nM) had little effect. Activation of proinsulin conversion by a 24-h exposure to glucose (11 mM) was reversed by a subsequent 3-h prior exposure to cycloheximide. alpha-Amanitin, an inhibitor of mRNA synthesis, did not influence the glucose-induced activation of proinsulin conversion when present during a 3-h exposure to glucose; however, it completely inhibited glucose-stimulated conversion when present during 24 h exposure. Results suggest that activation of the proinsulin conversion process is regulated by glucose metabolism rather than the glucose molecule per se and that other, but not all, secretagogues are effective. Conversion may require prior synthesis of a pool of converting enzyme(s) or other regulatory proteins whose turnover is relatively rapid (approximately 33 h) and whose mRNA is more stable (to 24 h).
Diabetes 1988 Oct
PMID:Glucose-regulated proinsulin processing in isolated islets from rat pancreas. 304 72

To investigate how the D-cell recognizes the glucose stimulus, the hormone response to (1) glucose, (2) the trioses glyceraldehyde and dihydroxyacetone, (3) the metabolic blocker, mannoheptulose, and (4) the low- or nonmetabolized sugars galactose, fructose, or ribose were studied using the isolated dog pancreas. We found (1) a sigmoidal relationship between extracellular glucose concentrations and the somatostatin release. The threshold concentration was around 5 mM and the largest increase in somatostatin release occurs between 5 and 10 mM of glucose. (2) Glyceraldehyde at concentrations ranging between 1.25 and 5 mM stimulated the release of somatostatin, whereas the higher concentrations of 10 and 20 mM were suppressive. Dihydroxyacetone (11 mM), also initiated somatostatin release in the absence of glucose. Both of the trioses stimulated B- and inhibited A-cell secretion. (3) Mannoheptulose (5 mM) attenuated somatostatin and insulin secretion to 8.3 mM glucose, while it augmented glucagon output. In contrast, mannoheptulose (5 mM) did not affect D-, A-, or B-cell responses to glyceraldehyde (5 mM) in the absence of glucose. (4) The somatostatin, insulin, and glucagon release remained unchanged when 8.3 mM of either galactose, fructose, or ribose was added. The results suggest that the initiation of glucose-mediated D- as well as A- and B-cell responses depends on the metabolism of the sugar.
Diabetes 1981 Mar
PMID:Pancreatic D-cell recognition of D-glucose: studies with D-glucose, D-glyceraldehyde, dihydroxyacetone, D-mannoheptulose, D-fructose, D-galactose, and D-ribose. 611 Jun

Dimethylthiourea (DMTU, 4.0 mmol/kg) injected into mice 30 min prior to alloxan injection markedly protected mice against the diabetogenic actions of 75 mg/kg alloxan. At 30 min after the above dose of DMTU alone (no alloxan), there was a marked rise in blood glucose. Mannoheptulose, an antagonist of glucose action at pancreatic beta-cells, when given 24 min after DMTU and 6 min before alloxan, eliminated the DMTU-induced protection. The protection was also removed in the fasted mice in which DMTU did not cause hyperglycemia. These results indicate that DMTU protected mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan injection.
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PMID:Involvement of blood glucose in the dimethylthiourea-induced protection against alloxan-induced diabetes. 786 63

Diethyldithiocarbamate (DEDC, 0.25-2.00 mmol/kg) injected into mice at 0.5 hr prior to alloxan administration dose-dependently protected the mice against the diabetogenic actions of 75 mg/kg alloxan. Disulfiram (DS, 0.50-2.00 mmol/kg), a corresponding disulfide form, also exhibited similar protection. The maximum effect of DEDC was found by dosing at 0.5 hr prior to alloxan, and the effect afforded by DEDC pretreatment persisted up to 3 hr, whereas the effect of DS was exhibited when the compound was given 0.5 hr prior to alloxan. Of the metabolites of DEDC, diethylamine and carbon disulfide had no effect. At 0.5 hr after injection, DEDC alone had a potent increasing ability on blood glucose in a dose-dependent manner, but DS was less potent. Mannoheptulose, an antagonist of glucose action at pancreatic beta-cells, when given 24 min after DEDC and 6 min before alloxan, eliminated the DEDC-induced protection. Fasted mice did not exhibit hyperglycemia at 0.5 hr after DEDC injection, and alloxan given at that time produced diabetes. These findings indicate that DEDC itself protected mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan administration. The anti-diabetogenic action of low doses of DS and DEDC, in animals lacking hyperglycemia at the time of alloxan injection, is likely based on a mechanism other than one involving hyperglycemia.
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PMID:Protection against alloxan-induced diabetes by diethyldithiocarbamate and disulfiram in mice. 802 15

Glucokinase has exclusively high control strength on glucose usage in the pancreatic beta-cell. However, glucokinase also has extraordinarily high control strength on insulin secretion, which is linked to the phosphate potential, [ATP]/([ADP][Pi]) (F.M. Matschinsky, Y.Liang, P. Kesavan, L. Wang, P. Froguel, G. Velho, D. Cohen, M.A. Permutt, Y. Tanizawa, T.L. Jetton, K. Niswender, and M.A. Magnuson. J. Clin. Invest. 92: 2092-2098, 1993). We propose that the ATP produced via the tricarboxylic acid cycle is approximately constant, irrespective of the glucose level. Furthermore, the component of ATP production that is derived from glycolysis and glycolytically derived NADH, which is shuttled into the mitochondria, is a critical signal controlling the ionic events leading to insulin secretion, as suggested previously (M. J. MacDonald. Diabetes 39: 1461-1466, 1990 and I.D. Dukes, M.S. McIntyre, R.J. Mertz, L.H. Philipson, M.W. Roe, B. Spencer, and J.F. Worley III. J. Biol. Chem. 269: 10979-10982, 1994). To test this hypothesis, glucose usage, oxidation, and insulin secretion were measured in cultured rat islets over a wide range of concentrations of glucose and mannoheptulose, an inhibitor of glucokinase. These data were fit to a mathematical model that predicts that glucokinase will govern the rate of glucose usage and ATP production and will also have a strong, but not complete, control over the rate of glucose oxidation, the phosphate potential, and insulin release. Mannoheptulose caused an inhibition of all three fluxes. The estimates of the mechanistic parameters of the model [maximal velocity (Vmax) and Michaelis constant for glucokinase, Vmax for hexokinase and glucose transport, and the inhibition constant of mannoheptulose to glucokinase] were similar to those obtained in vitro. Thus the data are consistent with a model in which the primary importance of glycolysis in transducing the glucose signal into changes of the phosphate potential imparts to glucokinase a high control strength on glucose-induced insulin secretion.
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PMID:Effect of a glucokinase inhibitor on energy production and insulin release in pancreatic islets. 884 58

betaHC-9 is a pancreatic beta-cell line that is derived from the hyperplastic islets of transgenic mice that express the simian virus 40 tumor antigen gene in the islets. This cell secretes insulin in response to glucose in a concentration-dependent manner. Maximal and half-maximal concentrations were approximately 20 and approximately 10 mmol/l, respectively, with a maximal fractional release that averaged 3.7% of the total cellular insulin content per 60 min. The cellular insulin content was 3-9% of the content of mouse islet cells. Under perifusion conditions, high glucose concentrations induced a sharp first phase that lasted approximately 10 min and a succeeding second phase of sustained release, as exhibited by mouse islets. The cells did not show a rising second phase as seen with rat islets. This biphasic response was obtained without the need for activators of protein kinase A such as forskolin or 3-isobutyl-1-methylxanthine. The dose-dependency and the phasic response to glucose were essentially invariable up to passage 38 but thereafter declined. The cells respond to various well-known stimulators of insulin secretion, including leucine and arginine; to modulators such as carbachol, glucagon-like peptide I, and pituitary adenylyl cyclase activating polypeptide; and to the inhibitors norepinephrine, somatostatin, and galanin. The pharmacological agents glibenclamide, 12-O-tetradecanoylphorbol-13-acetate, and KCl stimulate and forskolin potentiates insulin release. Mannoheptulose, 2-deoxyglucose, and nitrendipine inhibit glucose-stimulated insulin release from the cells. The intracellular Ca2+ concentration was raised by high glucose and by glibenclamide. In conclusion, this cell line preserves the fundamental characteristics of the progenitor normal mouse islets very well. Although several cell lines have been reported to have glucose-responsive insulin secretion, few demonstrate clear biphasic secretion as this cell line displays. In this context, this cell line should serve as a potent tool for studying the mechanisms of insulin secretion, especially the important phasic secretion.
Diabetes 1996 Dec
PMID:The betaHC-9 pancreatic beta-cell line preserves the characteristics of progenitor mouse islets. 892 64

Mastoparan, a tetradecapeptide component of wasp venom, activates heterotrimeric G-proteins and stimulates exocytosis in several cell types, including the pancreatic beta-cell. In this study, its effects on insulin secretion were assessed in both rat and human pancreatic islets, along with the ability of glucose and alpha-ketoisocaproate (alpha-KIC) to augment mastoparan-stimulated release. In Ca2+-free Krebs-Ringer bicarbonate buffer containing 2.8 mmol/l glucose, 20 micromol/l mastoparan stimulated insulin secretion 12- and 14-fold in rat and human islets, respectively. The inactive analog mastoparan-17 had no effect on release. Under the same Ca2+-free conditions, 11.1 mmol/l glucose had no effect on insulin release alone, but augmented mastoparan-stimulated release by 74% in both rat and human islets. Stimulation of release by mastoparan and augmentation of release by glucose were unaffected by treatment with pertussis toxin. The effect of cellular GTP depletion on the mastoparan stimulation of release and augmentation by alpha-KIC was studied by culturing rat islets in the presence of 25 microg/ml mycophenolic acid for 20 h. In the control islets, alpha-KIC augmented mastoparan-stimulated insulin release by 80%. In the GTP-depleted rat islets, mastoparan-stimulated insulin release was not changed, while the augmentation by alpha-KIC was eliminated. Mannoheptulose completely blocked the augmentation by glucose. In conclusion, mastoparan stimulates insulin release by activation of a signal transduction pathway that can be augmented by nutrients such as glucose and alpha-KIC. Nutrient augmentation of this pathway is heavily dependent on GTP.
Diabetes 1998 Jul
PMID:Glucose augmentation of mastoparan-stimulated insulin secretion in rat and human pancreatic islets. 964 28