Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Northern-blot analysis was used to demonstrate that an increase in extracellular glucose concentration increased the content of preproinsulin mRNA 2.3-fold in the beta-cell line HIT T15. A probe for the constitutively expressed glyceraldehyde-3-phosphate dehydrogenase was used as a control. Mannoheptulose blocked this effect of glucose. A stimulatory effect on preproinsulin mRNA levels was also observed in response to mannose and to 4-methyl-2-oxopentanoate. However, galactose and arginine were ineffective. Glucagon, forskolin and dibutyryl cyclic AMP also elicited an increase in HIT-cell preproinsulin mRNA. The ability of the 5' upstream region of the preproinsulin gene to mediate the effect of glucose and other metabolites on transcription was studied by using a bacterial reporter gene technique. HIT cells were transfected with a plasmid, pOK1, containing the upstream region of the rat insulin-1 gene (-345 to +1) linked to chloramphenicol acetyltransferase (CAT). Co-transfection with a plasmid pRSV beta-gal containing beta-galactosidase driven by the Rous sarcoma virus promoter was used as a control for the efficiency of transfection; expression of CAT activity in transfected HIT cells was normalized by reference to expression of beta-galactosidase. Glucose caused a dose-dependent increase in expression of CAT activity, with a half-maximal effect at 5.5 mM and a maximum response of 4-fold. Mannoheptulose blocked this effect of glucose. Other metabolites (mannose, 4-methyl-2-oxopentanoate and leucine plus glutamine) were also able to increase insulin promoter-driven CAT expression, but galactose and arginine were ineffective. The stimulatory effect of glucose on CAT expression was not blocked by verapamil and was inhibited by increasing extracellular Ca2+ from 0.4 to 5 mM. Both dibutyryl cyclic AMP and forskolin caused an increase in insulin promoter-driven gene expression in the presence of 1 mM-glucose, but neither agent further increased the level of expression occurring in the presence of a maximally stimulating glucose concentration. The phorbol ester phorbol 12-myristate 13-acetate (PMA) also increased insulin promoter-driven CAT expression in the presence of 1 mM-, but not 11 mM-glucose. Staurosporine blocked the stimulatory effect not only of PMA but also of glucose and of dibutyryl cyclic AMP. We conclude that the 5' upstream region of the insulin gene contains sequences responsible for mediating the stimulatory effect of glucose on insulin-gene transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Control of insulin gene expression by glucose. 132 37

We investigated the kinetics of the mitochondrial respiratory chain, proton leak, and phosphorylating subsystems of liver mitochondria from mannoheptulose-treated and control rats. Mannoheptulose treatment raises glucagon and lowers insulin; it had no effect on the kinetics of the mitochondrial proton leak or phosphorylating subsystems, but the respiratory chain from succinate to oxygen was stimulated. Previous attempts to detect any stimulation of cytochrome c oxidase by glucagon are shown by flux control analysis to have used inappropriate assay conditions. To investigate the site of stimulation of the respiratory chain we measured the relationship between the thermodynamic driving force and respiration rate for the span succinate to coenzyme Q, the cytochrome bc1 complex and cytochrome c oxidase. Hormone treatment of rats altered the kinetics of electron transport from succinate to coenzyme Q in subsequently isolated mitochondria and activated succinate dehydrogenase. The kinetics of electron transport through the cytochrome bc1 complex were not affected. Effects on cytochrome c oxidase were small or nonexistent.
 ...
PMID:Stimulation of the electron transport chain in mitochondria isolated from rats treated with mannoheptulose or glucagon. 217 25

Mannoheptulose (2g/kg i.p.) increases serum glucagon and decreases serum insulin via its effect on pancreatic islet cells. These changes in endogenous hormone status had effects on rat liver mitochondria that were comparable to the effects of injecting porcine glucagon (0.5 mg/kg i.p.). Mitochondrial adenine nucleotide content was increased 38 or 39% by mannoheptulose or glucagon respectively, citrulline synthesis by 165 or 193%, pyruvate carboxylation by 113 or 135%, coupled respiration by 34 or 42%, and uncoupled respiration by 40 or 54%. We conclude that the reciprocal changes in endogenous insulin and glucagon brought about by mannoheptulose offer a useful and interesting alternative to glucagon injection for studying the effects of these pancreatic hormones on liver mitochondria.
 ...
PMID:Mitochondrial function after acute alteration of the endogenous insulin-to-glucagon ratio. 302 11

In adult rats, mannoheptulose injection causes a transient decrease in the serum insulin-to-glucagon ratio and a concomitant increase in serum glucose concentration. These effects attain a maximum 1 h after the injection and then decline toward normal. Correlated with the hormone changes is a dramatic increase in the adenine nucleotide content (ATP + ADP + AMP) of liver mitochondria, which peaks to over 50% of control values at 1 h. The increase in mitochondrial adenine nucleotides must occur by uptake from the cytosol, because the adenine nucleotide content of the whole tissue remains constant. The accumulation of adenine nucleotides by the mitochondria probably occurs over the recently characterized carboxyatractyloside-insensitive transport pathway that allows exchange of ATP-Mg for Pi. The actual mechanism by which net uptake is regulated after mannoheptulose injection has not yet been elucidated; however, changes in the Km or Vmax of the carrier and an increase in the tissue ATP/ADP ratio were eliminated as possibilities. The increase in matrix adenine nucleotide content in response to hormone changes brought about by mannoheptulose was much greater and more reproducible than what is achieved with glucagon injection. Mannoheptulose treatment may therefore be preferable as a model for further study of hormone effects on mitochondrial function.
 ...
PMID:Increased adenine nucleotides in liver mitochondria after mannoheptulose injection in vivo. 351 32

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.
 ...
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

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.
 ...
PMID:The betaHC-9 pancreatic beta-cell line preserves the characteristics of progenitor mouse islets. 892 64