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G L Wilson

Publications and source records attributed to G L Wilson.

At least 91 records · Page 5Linked to original sources
PubMed1987

Insulin and insulin-like growth factor-I stimulate a common endogenous phosphoprotein substrate (pp185) in intact neuroblastoma cells.

Mouse neuroblastoma N18 cells contain specific high affinity insulin and insulin-like growth factor-I (IGF-I) receptors. Insulin and IGF-I induce phosphorylation, in intact cells, of their respective receptor beta subunits. The insulin receptor beta subunit is represented by a 95-kDa phosphoprotein that is recognized by a specific antiserum (B10). The IGF-I receptor beta subunit is represented by two phosphoproteins of molecular mass 95 and 105 kDa. The hormone-induced phosphorylation was rapid and dose-dependent occurring on both phosphoserine and phosphotyrosine residues. In addition, both insulin and IGF-I induced phosphorylation of an endogenous protein of molecular mass 185 kDa (pp185). The rapidity and dose dependency of the phosphorylation of pp185 suggested that it may represent a common endogenous substrate for the insulin and IGF-I receptors in these neural-derived cells. Phosphorylation was primarily on phosphoserine and phosphotyrosine residues. pp185 did not absorb to wheat germ agglutinin-agarose and was not stimulated by either epidermal growth factor or platelet-derived growth factor. The finding of pp185 in these neural-related cells as well as in non-neural tissues suggests that it may represent a ubiquitous endogenous substrate for both the insulin and IGF-I receptor kinases.

Animals↗
PubMed1987

Factors affecting the infection of the D variant of encephalomyocarditis virus in the B cells of C57BL/6J mice.

The D variant of encephalomyocarditis virus is capable of infecting most inbred strains of mice. However, only certain strains are susceptible to the diabetogenic effect of this virus. In order to understand why some inbred strains do not become diabetic, the pathogenesis of infection was studied in diabetes-resistant C57BL/6J mice. It was the purpose of the investigation to ascertain whether specific host defense factors might play a crucial role in the mechanism of resistance. To determine whether perturbations of the immune response would alter the resistance of these animals, mice were treated with a high dose (1.15 mmol/kg body weight) of the T- and B-cell toxin cyclophosphamide prior to infection with the D variant. This treatment did not induce overt diabetes or glucose intolerance in the mice tested 7 days after infection. Based on this finding, it appeared likely that resistance to the D variant is conveyed by some factor other than cell-mediated immunity. A likely candidate to control this viral infection is the interferon system. To investigate this possibility, C57BL/6J mice were infected with the D variant and the concentrations of serum interferon titred at various intervals thereafter. In contrast to previous reports with diabetes susceptible mice, C57BL/6J mice were found to generate a substantial interferon response against this variant, with peak levels found in the serum at 24 h following infection. Additional studies were performed in which mice were treated with antibody to mouse interferon alpha/beta at the time of infection and again 3 days after infection with the D variant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Altered pathogenesis in encephalomyocarditis virus (D variant)-infected diabetes-susceptible and resistant strains of mice.

The D variant of encephalomyocarditis virus (EMCV-D) induces a diabetes mellitus-like disease in male SJL/J mice. Other inbred strains, while resistant to the diabetogenic effect, exhibit strikingly different responses to this virus. In these studies, infection of diabetes resistant C3H mice with the D variant produces massive acute pancreatitis with little apparent direct islet cell involvement. This exocrine tropism is not altered when C3H mice with an inherent macrophage defect are infected, and appears to be a gender-specific phenomenon, with female C3H mice resistant to this exocrine involvement. Long-term infection of both male and female C3H mice does not change their response to the virus. Castration of male C3H mice, using a protocol that has been reported to block the diabetogenic effect of this virus, does not alter the development of this acinar lesion. The B variant of EMCV does not induce acinar destruction, nor is it diabetogenic. However, preinfection with the B variant 3 days prior to infection with the D variant does protect against the development of the exocrine lesion. Coinfection with equal doses of the two variants also protects against this lesion, as does coinfection with a lower dose of B variant. Therefore, the host response that is generated against the B variant appears to be responsible for this protection from D variant exocrine destruction. Due to the short time frame, it is unlikely that this protection is the result of an antibody response. Rather, this data is more consistent with an interferon response generated against the B variant that would inhibit replication of the D variant.

Animals↗
PubMed1986

Comparative interactions of streptozotocin and chlorozotocin with DNA of an insulin-secreting cell line (RINr).

Both streptozotocin and chlorozotocin, the 2-chloroethyl analogue of streptozotocin, are diabetogenic chemicals in rodents. Although these chemicals are similar structurally, they appear to act on pancreatic B cells via different mechanisms. In studies here, damage and repair of DNA after exposure of an insulin-secreting cell line to streptozotocin and chlorozotocin were assessed by nucleoid sedimentation and alkaline elution. Equitoxic concentrations of streptozotocin and chlorozotocin caused significant single-strand breakage of DNA (p less than 0.005). These lesions were repaired in a time-dependent manner, with most repair completed by 24-h post-exposure to chemicals. Additionally, chlorozotocin caused DNA-DNA and DNA-protein crosslinks in insulinoma cells. When proteinase K was included in the crosslinking assay, a substantial proportion of the chlorozotocin-associated crosslinks proved to be DNA interstrand in nature. Analysis of the amount of interstrand crosslinking in insulinoma cells after exposure to chlorozotocin for 1 h showed that formation of interstrand crosslinks was slow. Increasing amounts appeared over a 24-h period. These results suggest that the formation of irreversible DNA interstrand crosslinks may be a critical factor in cytotoxicity and diabetogenicity caused by chlorozotocin.

Alkylation↗
PubMed1986

Postreceptor myocardial metabolic defect in a rat model of non-insulin-dependent diabetes mellitus.

Hearts isolated from non-insulin-dependent diabetic rats were found to exhibit reduced rates of basal and insulin-stimulated glucose metabolism. Since tissue levels of fructose 1,6-bisphosphate are significantly reduced in the diabetic heart, it was concluded that phosphofructokinase may be inhibited. However, neither glycogen nor glucose 6-phosphate accumulated in the myocyte, indicating that the phosphofructokinase reaction was not a bottleneck diverting substrate away from glycolysis. The other major factor contributing to decreased glycolytic flux in the diabetic heart is the impairment in glucose transport. Both basal and insulin-stimulated transport of 3-O-methyl-D-glucose was 30% less in the diabetic heart. While insulin sensitivity was unaltered in the diabetic rat, insulin responsiveness was decreased, indicating that the impairment in insulin-stimulated hexose transport was caused by a post-receptor defect. The net result of these abnormalities in glucose metabolism is a significant reduction in the rate of ATP synthesis by the diabetic heart.

3-O-Methylglucose↗
PubMed1986

Mechanisms of nitrosourea-induced beta-cell damage. Alterations in DNA.

The initial step in streptozocin (STZ)-induced beta-cell toxicity has been hypothesized to be the alkylation of specific sites on DNA bases. The enzymatic removal of these lesions results in single-strand breaks that over-activate the nuclear enzyme poly(ADP-ribose) synthetase and critically deplete the cell of NAD. Our studies were performed to quantitatively evaluate the extent of DNA damage in beta-cells and correlate this damage with toxicity. Monolayer cultures of neonatal rat beta-cells were used to determine cytotoxicity and DNA damage after exposure to STZ or the aglycone N-methyl-N-nitrosourea (MNU). Toxicity in beta-cells was determined by correlating morphological alterations observed by phase-contrast microscopy with decrements in immunoreactive insulin release. The extent of DNA damage was determined by alterations in nucleoid density and quantitation of N7-methylguanine formation. Toxicity tests revealed that STZ and MNU were not toxic at equimolar concentrations. Streptozocin was toxic at 10(-3) M, whereas only mild toxicity was observed with MNU at 10(-2) M. Surprisingly, however, at equimolar concentrations the two drugs caused comparable DNA-strand breaks as evidenced by their ability to shift the nucleoid migration ratio in neutral sucrose gradients. Additionally, quantitation of N7-methylguanine formation after exposure to equimolar concentrations of the drugs demonstrated that the two alkylated DNA to the same extent. These findings suggest that factors in addition to the activation of poly(ADP-ribose) synthetase must be responsible for the toxicity seen with STZ, because MNU at a nonlethal concentration is capable of causing comparable DNA damage.

Alkylation↗
PubMed1985

Behavioral cohabitation: increasing satisfaction among nonmarried dyads?

The present study reports upon a standard behavior therapy treatment package applied to three clinically referred cohabitating couples. Multidimensional assessment measures included reports by self, partner, and external observers of couples' interactions. Moreover, a multiple-baseline design across couples was employed as a means of evaluating treatment efficacy. Therapy involved the weekly administration of bibliotherapy and exercise material, with therapist contact purposely minimized. An analysis of results indicates modest treatment success with considerable between-subject variability. These findings are discussed with regard to gender differences, ceiling effects, and utilization of standardized therapy packages. Recommendations are made for future behavioral cohabitation research.

Adult↗
PubMed1985

Development of a cardiomyopathy in a model of noninsulin-dependent diabetes.

Wistar rats were injected with streptozotocin (SZ) at 3 days of age. This maneuver produced a marked glucose intolerance, as determined by intraperitoneal glucose tolerance tests, but plasma fasting and nonfasting glucose values remained at or near normal throughout the 12-mo study period. Hearts obtained from these glucose-intolerant rats exhibited a progressive cardiomyopathy that consisted of both contractile and metabolic abnormalities. Contractile abnormalities were characterized by reductions in aortic output, ventricular pressure, and cardiac work. Associated with these mechanical defects was a decrease in glucose utilization. These abnormalities were not ameliorated by acute exposure to insulin or changes in the work load of the heart. These results demonstrate that, in the rat, a progressive cardiomyopathy results from persistent glucose intolerance in the absence of fasting hyperglycemia. This cardiomyopathy is reminiscent of that described in human noninsulin-dependent diabetes.

Animals↗
PubMed1985

Somatostatin-like material is present in flowering plants.

Extracts of spinach contain somatostatin (SRIF)-related material (6-80 pg/g wet wt). The SRIF-related material, when purified on HPLC, was recovered as two major mol wt forms; one that eluted with a retention time similar to that of synthetic SRIF-28 and reacted in both N- and C-terminal-specific immunoassays, and a second peak that eluted with a retention time similar to that of SRIF-14 and reacted only in the C-terminal immunoassays. The purified material was active in a sensitive bioassay, and the bioactivity was neutralized in the presence of anti-SRIF antiserum. Since we have previously described the presence of similar material in bacteria, we also tested extracts of the flowering plant Lemna gibba G3, which was grown under sterile conditions. The Lemna extracts also had SRIF-related material (3.0 pg/g wet wt). Since plants are probably derived evolutionarily from unicellular organisms, the presence of SRIF-like material in higher plants gives support for the hypothesis that vertebrate-type peptide hormones have early evolutionary origins.

Animals↗
PubMed1985

Chlorozocin. A diabetogenic analogue of streptozocin with dissimilar mechanisms of action on pancreatic beta cells.

Chlorozotocin (chlorozocin, CLZ), the 2-chloroethyl analogue of streptozocin (STZ), was evaluated in three species of rodents. The drug is currently being used in phase II chemotherapeutic trials in man, and appears to be effective in the treatment of certain tumors. In our studies, hyperglycemia was induced in hamsters as early as 2 days after a single intraperitoneal (i.p.) injection of 30-60 mg/kg and was most striking at 4 days. Greater concentrations of CLZ (greater than or equal to 50 mg/kg) were required to produce hyperglycemia in CD-1 mice. Degranulation and necrosis of beta cells developed in hamsters and mice, whereas alpha and acinar cells of the pancreas revealed no morphologic changes. Hyperglycemia was not induced in rats at any concentration tested; however, animals showed abnormal carbohydrate tolerance after administration of 100 mg/kg CLZ (LD50 dosage). The nature of damage by CLZ to beta cells was investigated both in vivo and in vitro. Pretreatment of hamsters with nicotinamide (500 mg/kg, i.p.) failed to alter the extent of CLZ-induced beta cell injury and associated hyperglycemia, but decreased the amount of beta cell necrosis and hyperglycemia in animals receiving STZ. The nonmetabolizable sugar, 3-O-methylglucose (3-O-MG), and 3-aminobenzamide, an inhibitor of the nuclear enzyme, polyADPribose synthetase, prevented STZ-associated damage to beta cells in islet cell cultures, but only 3-O-MG reduced CLZ-induced toxicity. Thus, in comparison to STZ, CLZ appears to be a diabetogenic agent with different species specificity and alternative mechanisms of cytotoxicity. The glucose moiety of both drugs appears critical in the induction of beta cell damage.

3-O-Methylglucose↗
PubMed1985

Therapeutic and diabetogenic potential of two newly synthesized nitrosoureido sugars.

Two newly synthesized nitrosoureido sugars have been evaluated for their antitumor activity and diabetogenic potential in a number of in vitro and in vivo preclinical tumor model systems. 2-Amino-2-deoxy-N'-methyl-N'-nitrosoureido-1,3,4,6-tetra-O-acetyl-alpha- D- mannopyranose (MAZ), a lipophilic mannosamine derivative, and ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-alph a- D-glucofuranoside (EDOMEN or CGP 6'809), were both found to inhibit L1210 leukemia cell growth in vitro by 50% at approximately 5.0 X 10(-5) M. At these concentrations, little effect was noted immediately on L1210 cell radiolabeled precursor incorporation; however, at higher concentrations, EDOMEN inhibited [3H]leucine and [3H]mannose incorporation, while MAZ specifically decreased L1210 cell [3H]thymidine and [3H]leucine incorporation. Inhibition of Lewis lung carcinoma and B16 melanoma cell growth by 50% in vitro was achieved at higher concentrations of these agents (10(-4) to 10(-3) M). Since the currently available nitrosoureido sugars, streptozotocin and chlorozotocin, have been observed by us to be diabetogenic, EDOMEN and MAZ were evaluated for their specific toxicity to rat pancreatic beta-cells in vitro. Cytotoxicity in beta-cell cultures was monitored both by phase-contrast microscopy and the release of insulin into the culture medium. beta-Cells were found to be 10-fold more sensitive to the toxic effects of MAZ than were pancreatic fibroblasts. EDOMEN, on the other hand, did not damage beta-cells preferentially and therefore was not considered diabetogenic. Both MAZ and EDOMEN had moderate activity as antileukemic agents in mice. At 50 mg/kg/day i.p. for 5 days, MAZ increased the life span of female DBA/2J mice with L1210 leukemia by over 50%. Similarly, doses of EDOMEN at 125 to 250 mg/kg/day i.p. for 5 days increased L1210 leukemic life span by nearly 60%. At these doses, no effect of MAZ was observed on primary Lewis lung carcinoma growth or life span of tumor-bearing C57BL/6 mice. EDOMEN, however, increased life span in Lewis lung carcinoma mice by up to 33% and caused an apparent antimetastatic effect. These studies indicate that EDOMEN may have enhanced value as a cancer chemotherapeutic agent due to its therapeutic effectiveness, lack of diabetogenic potential, and other favorable formulation properties (water solubility) as compared with other clinically available nitrosoureas.

Animals↗
PubMed1984

Effects of streptozotocin on a clonal isolate of rat insulinoma cells.

Cytotoxic effects and DNA damage caused by streptozotocin, a potent beta-cell toxin and an important chemotherapeutic agent, in an insulin-secreting clonal isolate of a rat insulinoma cell line were evaluated. Cytotoxicity was monitored by phase-contrast microscopy and measurement of insulin release into the culture medium. DNA damage and repair were assessed by changes in nucleoid sedimentation rates. The insulinoma cells were resistant to streptozotocin toxicity as compared to normal rat beta-cells. They were also resistant to the stimulatory effects of glucose on insulin release. However, streptozotocin did cause DNA damage that was both dose- and time-dependent. Comparative analysis of streptozotocin-induced DNA damage and that produced by the aglycone N-methyl-N-nitrosourea revealed greater damage with the latter. Thus, streptozotocin, like N-methyl-N-nitrosourea, may enter these cells by passive diffusion rather than selective transport. DNA repair studies indicate that the nicks caused by streptozotocin are sealed and that the DNA is again supercoiled by 14 h. Therefore, overt toxicity may be avoided by a decreased drug uptake compared to normal beta-cells and efficient repair mechanisms. These studies suggest that an active glucose-sensing mechanism is necessary to enhance streptozotocin cytotoxicity in both normal and neoplastic beta-cells.

Adenoma, Islet Cell↗
PubMed1984

Mechanisms of streptozotocin- and alloxan-induced damage in rat B cells.

In studies to evaluate possible inhibitors of the B-cell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,1-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan- and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effective scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Alloxan↗
PubMed1984

Paradoxical procedures and single-case methodology: review and recommendations.

Recently, paradoxical techniques have been increasingly employed by behavior therapists. The present paper: summarizes case study paradoxical investigations, reviews paradoxical procedures evaluated via intrasubject replication designs, and offers suggestions for continued use of single-case methodology in paradoxical research. Five major design strategies (reversal, time-series, multiple-baseline, simultaneous treatment and changing criterion) are discussed and examples provided within each area. Specific recommendations are made for a further merging of single-case experimental designs and paradoxical therapies.

Agoraphobia↗
PubMed1984

Effect of tolbutamide on myocardial metabolism and mechanical performance of the diabetic rat.

Exposure of the isolated, glucose-perfused rat heart to buffer containing 0.4 mM tolbutamide resulted in significant changes in both energy metabolism and myocardial contractility. In the nondiabetic, tolbutamide mediated only small increases in mechanical function at low atrial filling pressure, but this effect increased with increasing preload. By contrast, the stimulation of mechanical function resulting from exposure of the diabetic heart to tolbutamide was independent of preload. As a result, the tolbutamide-mediated, positive inotropic effect in the diabetic heart was greater at lower, but not higher, preload values than the effect in the nondiabetic. Moreover, the changes in energy metabolism initiated by tolbutamide were considerably larger in the diabetic. The most prominent effect was the mobilization of glycogen by tolbutamide in the diabetic, which was considerably greater than that observed in the nondiabetic. The drug also enhanced glucose utilization. The net effect of sulfonylurea exposure was to shift from preferential use of fatty acids as an energy source for contraction to use of glucose. Since the most prominent effect of the drug in the diabetic was the stimulation of glycogenolysis, it is concluded that tolbutamide can dramatically alter the metabolism of a tissue without acting through insulin.

Animals↗
PubMed1983

Streptozotocin-induced diabetes produces alterations in adenylate cyclase in rat cerebrum, cerebral microvessels and retina.

Eight weeks following streptozotocin-induced diabetes mellitus in rats, the sensitivity of adenylate cyclase to dopamine (DA) and norepinephrine (NE) was reduced in homogenates of retina. Furthermore, the activation of adenylate cyclase in cerebral microvessels (capillaries) by NE, 5'-guanylyl imidodiphosphate (alone or with NE) and forskolin was reduced in diabetic rats versus appropriate controls. In diabetic rats enzyme sensitivity to only NE was attenuated in homogenates of cerebral cortex and cortical piaarachnoid. No differences between controls and diabetics were noted with respect to guanylate cyclase or cyclic AMP phosphodiesterases. The damage observed in retina and microvessels may play an important pathogenic role in diabetes-induced blindness and stroke.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Effect of interferon on encephalomyocarditis virus infection of cultured mouse pancreatic B cells.

The M variant of encephalomyocarditis virus (EMC) produces a disease similar to human insulin-dependent diabetes mellitus in some but not all strains of mice. This diabetogenic M variant was found to induce fivefold more interferon than non-diabetogenic strains of EMC in cultures of mouse L 929 fibroblasts. When interferon induced by the M variant was added to monolayers of B cells from both diabetes-'susceptible' CD-1 mice and 'resistant' C57 bl/6 mice before EMC infection, B cell damage and virus replication were delayed. In addition, viral production in B cell cultures from C57 bl/6 mice was reduced five- to tenfold. A similar effect was not found when cultures from CD-1 mice were treated with interferon. Thus, interferon might play an important role in modulating the severity of the initial infection of B cells.

Animals↗