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Suzanne G Laychock

Publications and source records attributed to Suzanne G Laychock.

7 recordsLinked to original sources
PubMed2006

Sphingosine 1-phosphate affects cytokine-induced apoptosis in rat pancreatic islet beta-cells.

Cytokines mediate pancreatic islet beta-cell apoptosis and necrosis, leading to loss of insulin secretory capacity and type 1 diabetes mellitus. The cytokines, IL-1beta and interferon-gamma, induced terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining of rat islet cells within 48 h by about 25-30%, indicative of apoptosis and/or necrosis. Sphingosine 1-phosphate (S1P) at nanomolar concentrations significantly reduced islet cell cytokine-induced TUNEL staining. Similar effects were observed in INS-1 cells. The dihydro analog of S1P also reduced the percentage of TUNEL stained islet and INS-1 cells, whereas the S1P receptor antagonist BML-241 blocked the protective effects. Pertussis toxin did not affect the S1P protective response. In the presence of a phospholipase C antagonist, U73122, there was significant inhibition of the S1P protective effects against apoptosis/necrosis. S1P stimulated INS-1 cell protein kinase C activity. Carbamylcholine chloride acting through muscarinic receptors also inhibited cytokine-induced TUNEL staining in pancreatic islet cells. S1P and/or dihydro-S1P also antagonized cytokine-induced increases in cytochrome c release from mitochondria and caspase-3 activity in INS-1 cells, which are indicative of cell apoptosis vs. necrosis. S1P failed to affect nitric oxide synthase activity after 48 h. Thus, the evidence suggests that S1P acting on S1P receptors coupled to G(q) mediates protective effects on islet beta-cells against cytokine-induced apoptosis.

Animals↗
PubMed2005

Sphingosine kinase activity and sphingosine-1 phosphate production in rat pancreatic islets and INS-1 cells: response to cytokines.

Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid with the potential to mobilize Ca2+, to inhibit apoptosis, and to promote mitogenesis. Sphingosine kinase (SPHK) and S1P were characterized in INS-1 insulinoma cells and isolated rat islets of Langerhans. SPHK activity increased in INS-1 cell homogenates treated with interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha), and responses were additive. IL-1beta or TNF-alpha increased islet SPHK activity within 15 min to 1 h; activity remained elevated after 8 h. SPHK2 was the predominant active isoform in INS-1 cells; little or no SPHK1 activity was detected. Cytokines increased endogenous S1P biosynthesis in 32P(i)-prelabeled INS-1 cells, and cycloheximide inhibited the response after 8 h, suggesting that protein synthesis mediated the response. There was no [32P]S1P release from cells. Compared with basal values, IL-1beta and TNF-alpha induced increases in SPHK1a mRNA levels relative to 18S ribosomal RNA in INS-1 cells within 1 h; relative SPHK2 mRNA levels were unchanged after cytokine treatment. IL-1beta, but not TNF-alpha, induced relative SPHK1a mRNA expression levels within 1 h in islets, whereas SPHK2 mRNA levels were unchanged. Thus, IL-1beta and TNF-alpha induced an early and sustained increase in SPHK activity in INS-1 cells and isolated islets, suggesting that S1P plays a role in the pathological response of pancreatic beta-cells to cytokines.

Animals↗
PubMed2003

Prolactin regulates adenylyl cyclase and insulin secretion in rat pancreatic islets.

A role for prolactin (PRL) in the regulation of adenylyl cyclase (AC), cyclic AMP (cAMP) formation and insulin secretion was studied in isolated rat pancreatic islets cultured for 4 days at 5.5 mM glucose in the absence (control) or presence of PRL (500 ng/ml). In PRL-treated islets, stimulation by glucose (8 mM), carbamylcholine chloride (CCh) and phorbol dibutyrate increased cAMP levels 40, 89, and 151%, respectively, above similarly stimulated control islets without PRL. Moreover, insulin secretion in PRL-treated islets was more than doubled in response to 8 mM glucose plus glucagon-like peptide 1 compared with control islets. PRL also increased protein kinase C (PKC) activity in cultured islets. When islets were cultured at an insulin secretion desensitizing concentration of glucose (11 mM) for 4 days, there was a decrease in forskolin-stimulated cAMP production. However, the presence of PRL with 11 mM glucose prevented the glucose-induced decrease in cAMP production. Insulin secretion in response to 17 mM glucose was also higher (P<0.02) in islets cultured with 11 mM glucose plus PRL compared with islets cultured with 11 mM glucose alone. Islet AC types -III, -V, and -VI mRNA levels increased relative to 18s rRNA following PRL treatment. In contrast, culture at 11 mM glucose decreased relative AC-III, -V and -VI mRNA levels by as much as 50%. Culture with PRL prevented the decrease in AC expression during islet culture with 11 mM glucose, and the mRNA levels remained similar to control islets cultured at 5.5 mM glucose. Thus, PRL not only increased islet AC expression and activity and insulin secretory responsiveness, but also protected islets from chronic glucose-induced inhibition of these beta-cell activation parameters.

Adenylyl Cyclases↗
PubMed2003

Role of nerve growth factor in the regulation of parotid cell differentiation induced by rat serum.

The present study was undertaken to examine the factors that regulate rat serum (RS)- and nerve growth factor (NGF)-induced differentiation in a rat parotid acinar cell line. RS elicited extracellular signal-regulated kinase (ERK1/ERK2) activation within 5min, while cyclic AMP (cAMP) levels transiently rose after 6hr. RS also elicited a rise in amylase mRNA levels within 30min, which preceded the rise in amylase protein levels. A possible role for NGF was suggested by the findings that parotid cells express both TrkA and p75 receptors. The immunoreactivity of these NGF receptors was reduced during exposure to RS. Following prolonged incubation in RS when ERK activity subsided to near basal levels, NGF restored ERK1/ERK2 activity to the elevated level initially observed in RS. NGF was ineffective when cells were incubated in fetal bovine serum. NGF, when incubated in combination with the cAMP-generating neuropeptides, calcitonin gene-related peptide and vasoactive intestinal peptide, markedly enhanced the cellular amylase content produced by RS. We conclude that parotid cell differentiation arises from an activation of cell surface receptors by humoral factors in combination with NGF and cAMP-generating neuropeptides.

Amylases↗
PubMed2003

Neonatal nutrition: metabolic programming of pancreatic islets and obesity.

Obese individuals are more likely to suffer from diseases termed the "metabolic syndrome," which includes type 2 diabetes. It is now recognized that early life dietary experiences play an important role in the etiology of such diseases. In this context, the consequences of a high carbohydrate (HC) dietary intervention in neonatal rats is being studied in our laboratory. Artificial rearing of 4-day-old rat pups on a HC milk formula up to Day 24 results in the immediate onset of hyperinsulinemia, which persists throughout the period of dietary intervention. Several adaptations at the biochemical, cellular, and molecular levels in the islets of these HC rats support the onset and persistence of the hyperinsulinemic condition during this period. Some of these adaptations include a distinct leftward shift in the insulin secretory capacity, increased hexokinase activity, increased gene expression of preproinsulin and related transcription factors and specific kinases in 12-day-old HC islets, and alterations in the number and size of islets. These adaptations are programmed and expressed in adulthood thereby sustain the hyperinsulinemic condition in the postweaning period and form the basis for adult-onset obesity. HC females spontaneously transmit the HC phenotype (chronic hyperinsulinemia and adult-onset obesity) to their progeny. Collectively, our results indicate that even a mere switch in the nature of the source of calories (from fat rich in rat milk to carbohydrate rich in the HC milk formula) during critical phases of early development in the rat results in metabolic programming of islet functions leading to chronic hyperinsulinemia (throughout life) and adult-onset obesity. This metabolic programming, once established, forms a vicious cycle because HC female rats spontaneously transmit the HC phenotype to their progeny. The results from our laboratory in the context of metabolic programming due to neonatal nutritional experiences are discussed in this review.

Animals↗
PubMed2003

Endothelial differentiation gene receptors in pancreatic islets and INS-1 cells.

The endothelial differentiation gene (EDG) receptors are a class of G protein-coupled receptors. EDG-1, -3, -5, -6, and -8 bind the bioactive lipid sphingosine-1-phosphate (SPP) as the primary signaling ligand. EDG-2, -4, and -7 bind the ligand lysophosphatidic acid. EDG-1, -2, -3, -5, -6, and -7, but not -8, mRNAs were expressed in isolated rat pancreatic islets, whereas INS-1 insulinoma cells expressed only EDG-1, -2, -3, and -5 mRNAs. EDG-4 mRNA was expressed in mouse islets. EDG-1 mRNA but not EDG-3 mRNA was rapidly induced relative to 18S rRNA after stimulation of isolated islets with phorbol 12-myristate 13-acetate (PMA) or cholecystokinin-8S for 2 h. The protein kinase C inhibitor GF 109203X blocked the EDG-1 induction by PMA. Similarly, in islets stimulated for 2 h with 17 mmol/l glucose, the relative EDG-1 mRNA levels increased almost twofold compared with levels in control islets at 5.5 mmol/l glucose. In contrast, after 11 mmol/l glucose stimulation for 7 days, the relative levels of rat islet EDG-1 mRNA were significantly reduced to 54% below that of islets cultured at 5.5 mmol/l glucose. There was no change in relative EDG-3 mRNA levels. Stimulation of EDG receptors in islets and INS-1 cells with SPP inhibited glucagon-like peptide 1 (GLP-1)-stimulated cAMP production and insulin secretion in a concentration-dependent manner. Pertussis toxin antagonized the SPP effects on insulin release. Thus, EDG receptors are expressed in pancreatic islet beta-cells and G(i) seems to mediate the inhibition by SPP of adenylyl cyclase and cAMP formation and inhibition of the stimulation of insulin secretion by GLP-1.

Animals↗