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Biomedical subjects

Liam J Murphy

Publications and source records attributed to Liam J Murphy.

34 records · Page 2Linked to original sources
PubMed2004

Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse.

OBJECTIVE: To examine gender differences and hormonal regulation of resistin, adiponectin, and leptin. RESEARCH METHODS AND PROCEDURES: Plasma levels were measured, and mRNA expression in perigonadal fat was quantified by RNase protection assays. RESULTS: Plasma resistin declined with age despite an increase in adiposity in both genders. In male mice, plasma leptin increased, whereas adiponectin levels were constant. In females, both adiponectin and leptin levels increased with age. Resistin mRNA levels were significantly higher in female than male mice at all ages, whereas leptin and adiponectin mRNA levels were similar in fat from 6-week-old male and female mice, and sexual dimorphism was apparent only in the older mice, with higher levels apparent in females. Castration did not abolish gender differences in plasma levels or resistin, adiponectin, or leptin mRNAs. Castration of male mice did not significantly change adipokine mRNA levels or plasma levels of resistin or leptin; however, adiponectin was significantly increased. Dihydrotestosterone treatment had no effect on adipokine mRNA expression or resistin and adiponectin levels but increased leptin levels. In contrast, ovariectomy significantly increased resistin mRNA abundance and decreased leptin and adiponectin mRNAs. Plasma leptin levels were also increased by ovariectomy, whereas resistin and adiponectin levels were unchanged. Estrogen replacement significantly reduced resistin mRNA and increased leptin and adiponectin mRNA levels but had no effect on plasma adipokine levels. DISCUSSION: The gender differences in adipokine mRNA expression and plasma levels were not ablated by castration and seem to be dependent on other factors in addition to gonadal steroids.

Adiponectin↗
PubMed2004

Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome.

BACKGROUND: Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established. DESIGN: We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary-dependent CS were re-examined at least 9 months after curative surgery. RESULTS: CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA-R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5.05 +/- 0.56 vs. 2.91 +/- 0.39 micro g/l, P = 0.015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low-density lipoprotein (LDL) cholesterol, glucose and HOMA-R. A reduction in both resistin and adiponectin was also observed but the differences between pre- and post-treatment levels did not achieve statistical significance. CONCLUSION: Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.

Adiponectin↗
PubMed2004

The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance.

BACKGROUND: Growth hormone deficiency (GHD) in adult life has been associated with increased central adiposity, decreased insulin sensitivity, dyslipidaemia and increased risk of cardiovascular disease. The effects of GH replacement on adiponectin and resistin, adipokines which have a role in modulating insulin sensitivity have not been previously reported. AIM: To examine the effects of GH replacement on adipokine levels and insulin resistance in GHD patients. DESIGN: Seventeen adult GHD patients were examined at baseline and after 1 year of treatment with recombinant human GH (mean dose 0.31 mg/day, range 0.13-0.67 mg/day). RESULTS: GH replacement significantly increased IGF-I levels. The mean IGF-I SD score increased from -1.98 at baseline to 0.76 at study end. GH replacement was associated with a significant reduction in percentage body fat (34.11 +/- 1.33 vs. 30.65 +/- 1.27%, P < 0.0005) and a significant increase in lean body mass (63.57 +/- 1.24 vs. 66.96 +/- 1.18%, P < 0.0004), before and after treatment, respectively. Surprisingly, there was no effect of GH replacement on the plasma levels of leptin, resistin or adiponectin or on plasma lipid profile. Insulin sensitivity did not deteriorate during GH replacement despite the known 'anti-insulin' effect of GH. Fasting glucose, insulin and insulin resistance as calculated using the homeostasis model assessment insulin resistance index (HOMA-R) were unchanged by GH treatment. CONCLUSION: These data demonstrate GH replacement in adult subjects with GHD is effective in changing body composition and restoring IGF-I levels over a 12-month period; however, in our study, these changes were not accompanied by changes in adipokine levels or beneficial effects on plasma lipids or insulin resistance.

Adiponectin↗
PubMed2003

Interaction of insulin-like growth factor binding protein-3 with latent transforming growth factor-beta binding protein-1.

Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the replication and promotes apoptosis in various cell lines in an IGF-independent manner. We utilized a yeast two-hybrid system to identify binding partners for IGFBP-3 in a mouse embryo cDNA library. A partial cDNA encoding mouse latent transforming growth factor beta (TGF-beta) binding protein-1 (LTBP-1) was identified. This cDNA encoded a mouse LTBP-1 mRNA fragment corresponding to amino acid residues 1160-1712. Analysis of C-terminal deleted mutants indicated that the IGFBP-3 interacting domain resides in the 552 residue C-terminal fragment encoding amino acids 831-1383. The interaction of IGFBP-3 with recombinant human LTBP-1 immobilized on nitrocellulose was also demonstrated. Neither binding of IGF-1 to IGFBP-3 nor binding of latency associated protein (LAP) with LTBP-1 inhibited the interaction of IGFBP-3 with LTBP-1. Furthermore the large latent complex, 125I-TGF-beta/LAP/LTBP-1 was able to bind to immobilized IGFBP-3. These data demonstrate that IGFBP-3 can bind to LTBP-1 and provide a potential mechanism whereby IGFBP-3 can interact with the TGF-beta system.

Animals↗
PubMed2003

Perturbations in adiponectin, leptin and resistin levels in acromegaly: lack of correlation with insulin resistance.

BACKGROUND: Insulin resistance, impaired glucose tolerance and type 2 diabetes are common in acromegalic subjects. The mechanism underlying this insulin resistance is unclear. DESIGN: We investigated the levels of the adipocytokines, resistin, adiponectin and leptin in a group of 18 acromegalic subjects and 18 control subjects matched for age, gender and body mass index. RESULTS: Here we demonstrate for the first time significant elevation in adiponectin levels in acromegalic subjects compared to control subjects 12.5 +/- 1.2 vs. 8.97 +/- 1.1 mg/l, P = 0.029. The resistin levels were similar in acromegalic subjects and controls; 20.65 +/- 2.99 vs. 19.03 +/- 4.72 micro g/l. No evidence of a correlation between adiponectin and insulin resistance as calculated from HOMA-R was found. No correlation was observed either between adiponectin or resistin levels and GH levels, total IGF-I or free IGF-I levels. Leptin levels were significantly reduced in acromegalic subjects, 8.22 +/- 2.26 vs. 18.3 +/- 4.1 micro g/l, P = 0.004. In control subjects, significant correlations between leptin levels and HOMA-R and between resistin levels and HOMA-R were observed. These relationships were not apparent in acromegalic subjects. CONCLUSION: From these data we conclude that changes in resistin and adiponectin levels are unlikely to account for the insulin resistance of acromegaly.

Acromegaly↗
PubMed2003

Changes in adipokine expression during food deprivation in the mouse and the relationship to fasting-induced insulin resistance.

We investigated the changes in insulin resistance and adipose tissue expression of the adipokines resistin, adiponectin, and leptin and the transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) during 48 h of food deprivation. Insulin sensitivity (SI) declined, whereas glucose effectiveness (SG) increased. Plasma adiponectin levels declined in the first 8 h and remained constant thereafter. There was no correlation between either SI or SG and adiponectin protein or mRNA levels. PPAR-gamma mRNA abundance remained constant, whereas leptin and resistin mRNAs and plasma leptin declined and RXR-alpha mRNA abundance increased in both white and brown fat. Leptin mRNA abundance was closely correlated with SI (R2 = 0.91 and 0.87 for white and brown fat, respectively). Resistin mRNA abundance correlated inversely with SG (R2 = 0.99 and 0.84 for white and brown fat, respectively). These data indicate that changes in the expression of leptin are more closely correlated with the insulin resistance of fasting than with changes in other adipokines or RXR-alpha and PPAR-gamma expression.

Adiponectin↗
PubMed2003

Phosphorylation of insulin-like growth factor (IGF) binding protein-3 by breast cancer cell membranes enhances IGF-I binding.

Cross-linking of nonglycosylated biotinylated IGF binding protein (IGFBP)-3 to T-47D cell membranes identifies complexes with Mr of 32, 50, 70, and 100 kDa. Nonbiotinylated glycosylated IGFBP-3 competed for binding to each of these sites. The 32-kDa band approximated the size of intact nonglycosylated IGFBP-3, but its abundance was enhanced by cross-linking, and it had a more acidic isoelectric point on isoelectric focusing, suggesting that it had undergone phosphorylation. Immobilized IGFBP-3 was phosphorylated in the presence of (32)P-gamma ATP by both T-47D cell membranes and by intact cells treated with phenylarsine oxide to inhibit internalization. MCF-7 and COS-1 cells were also able to bind and phosphorylated IGFBP-3. IGF-I inhibited both IGFBP-3 binding to membranes and phosphorylation. However, incubation of T-47D cells with IGFBP-3 enhanced binding of (125)I-IGF-I to the cell monolayer indicating that membrane bound IGFBP-3 was able to bind IGF-I. Immobilized IGFBP-3 when phosphorylated by T-47D membranes bound significantly more (125)I-IGF-I than nonphosphorylated IGFBP-3. Treatment with alkaline phosphatase significantly reduced (125)I-IGF-I binding to phosphorylated immobilized IGFBP-3 and also reduced (125)I-IGF-I to T-47D cell monolayers preincubated with IGFBP-3. Phosphorylation of IGFBP-3 by T-47D membranes was partially blocked by inhibitors of both protein kinase A and C. These data demonstrate that binding of IGFBP-3 to breast cancer membranes is accompanied by phosphorylation at the plasma membrane and that both processes are inhibited by IGF-I. However, once phosphorylated the ability of IGFBP-3 to bind IGF-I is enhanced, resulting in increased association of the IGF-I with the cell membrane.

Alkaline Phosphatase↗
PubMed2003

Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice.

UNLABELLED: IGF-I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP-3 indicates that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. INTRODUCTION: Low serum insulin-like growth factor I (IGF-I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF-I is largely bound to IGF-binding protein-3 (IGFBP-3), which can inhibit IGF-I action and enhance delivery of IGF-I to tissues. Its role in bone biology is unclear. METHODS: Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP-3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. RESULTS: Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild-type (Wt) mice, and the mitogenic response to IGF-I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP-3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP-3 Tg mice but were significantly reduced in PGKBP-3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP-3 Tg mice compared with Wt mice. CONCLUSIONS: These data show that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.

Amino Acids↗
PubMed2003

Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance.

OBJECTIVE: Adipose tIssue regulates insulin sensitivity via the circulating adipocytokines, leptin, resistin and adiponectin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. METHODS: We examined plasma levels of resistin, adiponectin and leptin in 17 lean subjects with a mean body mass index (BMI) of approximately 23 and 34 non-diabetic obese individuals with a mean BMI approximately 33. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. RESULTS: Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 35.4+/-6.5 (s.e.) vs 15.4+/-2.9 microg/L, P<0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P<0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly lower in obese compared with lean subjects, P<0.005, and higher in women, P<0.001, but showed no significant correlation with HOMA-R. Leptin levels were significantly higher in obese subjects and women and correlated with HOMA-R and resistin. DISCUSSION: In this small group of patients we demonstrated that insulin resistance correlated most strongly with leptin levels. A significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for adiponectin, the correlation with insulin resistance did not achieve statistical significance.

Adiponectin↗
PubMed2003

Sildenafil citrate for treatment of erectile dysfunction in men with type 1 diabetes: results of a randomized controlled trial.

OBJECTIVE: In the 5-10% of diabetic men with type 1 diabetes, erectile dysfunction (ED) may be a particularly common and unwanted complication. This is the first study focusing exclusively on the effects of sildenafil in men with type 1 diabetes and ED. RESEARCH DESIGN AND METHODS: A total of 188 patients were entered into a double-blind, placebo-controlled, parallel-group, flexible-dose study and were randomized to receive sildenafil (25-100 mg; n = 95) or placebo (n = 93) for 12 weeks. Efficacy was evaluated using questions three (Q3; achieving an erection) and four (Q4; maintaining an erection) from the International Index of Erectile Function (IIEF), a global efficacy question (GEQ; "Did treatment improve your erections?"), and a patient event log of sexual activity. RESULTS: Improvements in mean scores from baseline to end-of-treatment for IIEF Q3 (35.7 vs. 19.9%) and Q4 (68.4 vs. 26.5%) were significant in patients receiving sildenafil compared with those receiving placebo (P = 0.0001). Moreover, the percent of improved erections (GEQ, 66.6 vs. 28.6%) and successful intercourse attempts (63 vs. 33%) was significantly increased with sildenafil compared with placebo. Improvements in sexual function were seen irrespective of the degree of ED severity. Adverse events were generally mild to moderate in severity, with headache (20 vs. 8%), flushing (18 vs. 3%), and dyspepsia (8 vs. 1%) reported more often in the sildenafil than in placebo-treated patients. CONCLUSIONS: Treatment with sildenafil for ED was effective, resulting in an increased percentage of successful attempts at intercourse, and was well tolerated among men with type 1 diabetes.

Adult↗
PubMed2002

Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice.

Glucose homeostasis was examined in male transgenic (Tg) mice that overexpressed the human insulin-like growth factor (IGF)-binding protein (IGFBP)-3 cDNA, driven by either the cytomegalovirus (CMV) or the phosphoglycerate kinase (PGK) promoter. The Tg mice of both lineages demonstrated increased serum levels of human (h) IGFBP-3 and total IGF-I compared with wild-type (Wt) mice. Fasting blood glucose levels were significantly elevated in 8-wk-old CMV-binding protein (CMVBP)-3- and PGK binding protein (PGKBP)-3-Tg mice compared with Wt mice: 6.35 +/- 0.22 and 5.22 +/- 0.39 vs. 3.99 +/- 0.26 mmol/l, respectively. Plasma insulin was significantly elevated only in CMVBP-3-Tg mice. The responses to a glucose challenge were significantly increased in both Tg strains: area under the glucose curve = 1,824 +/- 65 and 1,910 +/- 115 vs. 1,590 +/- 67 mmol. l(-1). min for CMVBP-3, PGKBP-3, and Wt mice, respectively. The hypoglycemic effects of insulin and IGF-I were significantly attenuated in Tg mice compared with Wt mice. There were no differences in adipose tissue resistin, retinoid X receptor-alpha, or peroxisome proliferator-activated receptor-gamma mRNA levels between Tg and Wt mice. Uptake of 2-deoxyglucose was reduced in muscle and adipose tissue from Tg mice compared with Wt mice. These data demonstrate that overexpression of hIGFBP-3 results in fasting hyperglycemia, impaired glucose tolerance, and insulin resistance.

Animals↗
PubMed2002

Insights from insulin-like growth factor binding protein transgenic mice.

The existence of abundant high affinity binding proteins for the IGFs, the IGF binding proteins (IGFBPs), was first demonstrated more than 40 yr ago in the very early days of somatomedin research. With the development of molecular techniques and transgenic and knockout mouse models, the nature, complexity, and redundancy of the IGFBPs have now started to be elucidated. Indeed the functional role of the circulating IGFs and the originally proposed endocrine somatomedin hypothesis have recently been questioned. The limited reports to date indicate that IGFBP knockout mice have few phenotypic manifestations. In contrast, overexpression of IGFBPs in transgenic mice is associated with manifestations that provide some insight into the physiological role of the binding proteins. The predominant effect of generalized or tissue-specific overexpression of the IGFBPs has been growth inhibition as would be anticipated from inhibition of the actions of IGF-I and -II. In addition, impaired glucose homeostasis and reduced fecundity have been observed in both IGFBP-1- and IGFBP-3-overexpressing transgenic mice. This review examines the data reported to date for transgenic mouse models that overexpress IGFBPs. In addition, data from transgenic mice that overexpress the acid-labile subunit, an important component of the ternary complex, have also been reviewed.

Animals↗
PubMedDate not supplied

The Prohibitins: emerging roles in diverse functions.

The prohibitins, Phb1 and Phb2 are highly conserved proteins in eukaryotic cells that are present in multiple cellular compartments. Initial investigations focused on the role of Phb1 as an inhibitor of cell proliferation hence the original name prohibitin. However both proteins appear to have a diverse range of functions and recent evidence suggests that the prohibitins have very similar but as yet only partially understood functions. In addition to their role as chaperone proteins in the mitochondria, and their ability to target to lipid rafts, their is now compelling evidence that both prohibitins are localized in the nucleus and can modulate transcriptional activity by interacting with various transcription factors, including the steroid hormone receptors, either directly or indirectly. In addition Phb1 and Phb2 are present in the circulation and can be internalized when added to cultured cells suggesting that the circulating prohibitins may have some regulatory role. This review presents some of the recent developments in prohibitin research and focuses on the similarities in the structure and function of these interesting proteins.

Amino Acid Sequence↗
PubMedDate not supplied

Variations in parametrial white adipose tissue mass during the mouse estrous cycle: relationship with the expression of peroxisome proliferator-activated receptor-gamma and retinoic acid receptor-alpha.

Estrogen and progestin participate in the regulation of adipose tissue metabolism, and peroxisome proliferator-activated receptor-gamma (PPARgamma) and retinoic acid receptor-alpha (RXRalpha) are absolutely required for adipose tissue development. The present study is to investigate the changes in parametrial fat mass and expression of PPARgamma and RXRalpha during estrous cycle in mice. Parametrial white adipose tissues (WAT), inter-scapula brown adipose tissues, and uteri from female mice were weighed. Blood samples were collected for the measurement of 17 beta-estradiol and progesterone levels. An RNase protection assay and Western blot analysis were used to compare the expression of PPARgamma and RXRalpha in adipose tissue. The mass of parametrial WAT in diestrus was significantly higher compared with estrus. However, there is no significant difference on the mass of brown adipose tissues during estrous cycle. The expression of PPARgamma in WAT in diestrus was significantly higher than that in estrus. The expression of RXRalpha during estrous cycle was unchanged in both white and brown adipose tissues. In conclusion, the variation in parametrial WAT mass during the mouse estrous cycle correlates with changes in the expression of PPARgamma in WAT.

Adipose Tissue, Brown↗
PubMedDate not supplied

The role of the insulin-like growth factors and their binding proteins in glucose homeostasis.

The insulin like growth factors (IGF-I and -II) are structurally and functionally related to insulin. While insulin is a key regulator of glucose homeostasis over the short term, emerging evidence suggests that the IGFs are involved in the longer term glucose homeostasis, possibly by modulating insulin sensitivity. Unlike insulin, the IGFs are present in most biological fluids as complexes with high affinity binding proteins, the insulin-like growth factor binding proteins (IGFBPs). The IGFBPs regulate the bioavailability of the IGFs. Of the six IGFBPs identified there is evidence from studies in transgenic mice that both IGFBP-1 and IGFBP-3 may have a role in glucose regulation.

Animals↗