Phospholipid metabolism in pancreatic islets

Conclusions The secretion of insulin can be elicited by a wide spectrum of stimuli including nutrients, hormones and neurotransmitters as well as a large number of pharmacological agents such as tumor-promoters and sulphonylureas. The diversity of these secretagogues suggests that islets may be activated through a number of distinct biochemical mechanisms. The work discussed in this review suggests that certain of the above-mentioned secretagogues, especially nutrient and neurotransmitter stimuli, may induce insulin secretion by a mechanism involving enhanced metabolism of inositol-containing lipids. The way in which this process is coupled to secretion is not known, although several possibilities exist. The hydrolysis of phosphoinositides and release of inositol phosphates may result, respectively in altered calcium permeability of the plasma membrane and mobilization of calcium from intracellular sources. The accompanying production of diacylglycerol might also influence membrane permeability and fluidity and also lead to activation of protein kinase C. Diacylglycerol can be phosphorylated to form phosphatidic acid which may play a role as an endogenous ionophore. Finally, inositol lipid breakdown could lead, through diacylglycerol and/or phosphatidic intermediates, to the liberation of arachidonic acid and subsequent conversion to active metabolites of the cyclo-oxygenase and lipoxygenase pathways. Thus, enhanced phospholipid metabolism in islets could, theoretically, result in the generation of a range of intracellular signals which mediate or modulate insulin secretion during stimulation by certain types of secretagogues. Continued investigation is clearly neccessary in order to elucidate the mechanisms by which such secretagogues provoke increased phospholipid metabolism and to understand the role(s) of this process in the regulation of islet function.     

1Alpha,25-dihydroxyvitamin D3 inhibits hepatic chromosomal aberrations, DNA strand breaks and specific DNA adducts during rat hepatocarcinogenesis

The possible promoting effect of streptozotocin (STZ; 65 mg/kg body weight, intraperitoneal)-induced diabetes during 2-acetylaminofluorene (2-AAF; 0.04% in basal diet)-initiated hepatocarcinogenesis and modulatory effect of 1α,25-dihydroxyvitamin D₃ (VD₃; 0.3 μg/0.1 ml in propylene glycol, per os) were investigated by monitoring chromosomal aberrations (CAs), DNA strand breaks and specific DNA adducts in rat liver. VD₃ treatment (twice a week) was started 4 weeks before the 2-AAF regimen and continued throughout the study. Aberrant metaphase chromosomes were counted from the regenerating hepatocytes 15, 30 or 45 weeks after STZ injection, while DNA strand break and adduct assays were performed 45 days post-STZ treatment. Dietary exposure to 2-AAF elicited a substantial increase in CAs and elevated the extent of DNA strand breaks and formation of N-(deoxyguanosin-8-yl)-2-aminofluorene. A promoting effect of STZ was evident from CAs coupled with DNA strand break analysis. VD₃ treatment substantially reducted 2-AAF+STZ-induced CAs as well as DNA strand breaks and adducts. Thus, VD₃ appears to be effective in suppressing liver-specific early chromosomal as well as DNA damage during the process of rat hepatocarcinogenesis initiated with 2-AAF and promoted by STZ contributing to its promise as a cancer chemotherapeutic agent. Received 27 April 2001; accepted 22 May 2001     

L-arginine and pancreatic islet blood flow in anesthetized rats

The aim of the present study was to see if L-arginine, which induces insulin release and is a precursor of the endothelial-derived relaxing factor nitric oxide, affects whole pancreatic and/or islet blood flow. For this purpose, anesthetized male Sprague-Dawley rats were injected intravenously with either saline or L-arginine (25, 100 or 250 mg/kg body weight). All doses of arginine caused a slight increase in blood glucose concentration, while the highest dose (250 mg/kg body weight) also increased insulin concentration. However, no changes in either mean arterial blood pressure, whole pancreatic or islet blood flow could be discerned with any of the doses of arginine used. It is concluded that insulin release is not necessarily associated with an increased islet blood perfusion.     

A convulsant, 3-mercaptopropionic acid,decreases the level of GABA and GAD in rat pancreatic islets and brain

To investigate the properties of the gamma-aminobutyric acid (GABA) synthesizing enzyme, glutamate decarboxylase (GAD), in the brain and the pancreatic islets of the rat, GABA concentration in the brain and the pancreatic islets was measured after intraperitoneal administration of 3-mercaptopropionic acid (3-MP) at 25 mg/kg. 60 min after the administration of 3-MP, GABA concentration in the hypothalamus, the superior colliculus and the hippocampus of the brain decreased by 20–30% and in the pancreatic islets by 35%. The concentration in the pancreatic acini did not change. Western blotting showed that GAD activity in the pancreatic islets decreased after administration of 3-MP compared to the control. The activity of GAD in the pancreatic islets as well as brain can be modified by a convulsant, in this case 3-MP. These results suggest the properties of GAD may be similar in the pancreatic islets and brain.     

The search for the right partner: Homologous pairing and DNA strand exchange proteins in eukaryotes

Finding the right partner is a central problem in homologous recombination. Common to all models for general recombination is a homologous pairing and DNA strand exchange step. In prokaryotes this process has mainly been studied with the RecA protein ofEscherichia coli. Two approaches have been used to find homologous pairing and DNA strand exchange proteins in eukaryotes. A biochemical approach has resulted in numerous proteins from various organisms. Almost all of these proteins are biochemically fundamentally different from RecA. The in vivo role of these proteins is largely not understood. A molecular-genetical approach has identified structural homologs to theE. coli RecA protein in the yeastSaccharomyces cerevisiae and subsequently in other organisms including other fungi, mammals, birds, and plants. The biochemistry of the eukaryotic RecA homologs is largely unsolved. For the fungal RecA homologs (S. cerevisiae RAD51, RAD55, RAD57, DMC1; Schizosaccharomyces pombe rad51; Neurospora crassa mei3) a role in homologous recombination and recombinational repair is evident. Besides recombination, homologous pairing proteins might be involved in other cellular processes like chromosome pairing or gene inactivation.     

Phenytoin-induced DNA synthesis and inositol 1,4,5-triphosphate formation in L-929 fibroblasts

Summary Culture of L-929 fibroblasts in the presence of phenytoin (2.5–5.0 g/ml) increased DNA synthesis, as indicated by increased [³H]thymidine uptake, while a higher dose (20 g/ml) inhibited DNA synthesis. In like manner, a low dose of phenytoin (5.0 g/ml) was effective in increasing inositol 1,4,5-trisphosphate formation while a higher dose (10 g/ml) tended to inhibit this activity. These data suggest that the formation of inositol phosphate second messengers may play a role in phenytoin-induced fibroblast proliferation and connective tissue growth.