Association of the GHRd3 polymorphism with adult height and type 2 diabetes in a Saudi Arabian population from Jazan Province: A case-control study.

Objectives: This study investigated the association of the GHRd3 polymorphism with height and type-2 diabetes mellitus (T2DM) in Saudi Arabia. Methods: This case-control study included a total of 284 participants, divided into healthy controls (n = 142) and patients with T2DM (n = 142), recruited from Jazan University Hospital, southwest of Saudi Arabia in the period between January to September 2022. The GHRd3 polymorphism was genotyped using multiplex PCR. The correlation between height and genotypes was analyzed using one-way analysis of variance. The association between GHRd3 polymorphism and T2DM was assessed using logistic regression analysis. Results: The data showed a significant difference between the means of heights associated with each GHRd3 genotype, flfl, fld3, and d3d3. Logistic regression analysis showed no association between GHRd3 variants and T2DM. Conclusion: Homozygous GHRd3 polymorphism carriers, d3d3 genotype, were taller than fld3 or flfl carriers in our population. None of the GHRd3 variants were associated with T2DM. Thus, the GHRd3 polymorphism has growth-related actions with a minor contribution to T2DM. However, more studies with a larger sample size are required to confirm these findings.

Common Genetic Variants in SIRT1 Gene Promoter and Type 2 Diabetes Mellitus in Saudi Arabia.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is common in Saudi Arabia and represents a major health concern. Silent information regulator of transcription-1 (SIRT1) positively influences insulin sensitivity and might contribute to the pathogenesis of T2DM. This study aimed to investigate the frequency of two common functional single nucleotide polymorphisms (SNPs) in the promoter region of SIRT1; rs12778366 (T>C) and rs3758391 (T>C) in Saudi Arabian population and examine any association with T2DM. METHODS: A total of 445 volunteers were divided into 224 healthy controls and 221 patients previously diagnosed with T2DM. Genomic DNA was extracted from all samples and genotyped for SIRT1 rs12778366 and rs3758391 SNPs by TaqMan RT-PCR allelic discrimination assay. Logistic regression analysis was used to establish any relationship between these polymorphisms and T2DM. RESULTS: In the total study population, rs12778366 genotype frequencies were TT (89.2%), TC (10.3%), and CC (0.45%) and for the rs3758391 they were TT (16.4%), TC (44.5%), and CC (39.1%). The distribution of these genotypes, in both polymorphisms, were similar among T2DM and controls. Logistic regression analysis confirmed the lack of association between the presence of CC or CT variants and T2DM for rs12778366 and rs3758391 SNP (OR = 0.98 [CI]: 0.55 - 1.75; p = 0.999 and OR= 0.75; [CI]: 0.45 - 1.24; p = 0.313), respectively. CONCLUSIONS: This study revealed the frequency of SIRT1 rs12778366 and rs3758391 SNPs in our population and reported no association between these polymorphisms and the risk for T2DM. This finding might add to the growing body of literature exploring the genetics of T2DM.

MTNR 1B (rs10830963) Gene Polymorphism, but not MTNR 1A (rs2119882), Associated with Type 2 Diabetes Mellitus Risk in Saudi Arabia.

BACKGROUND: Disrupted circadian rhythm has been linked to the pathogenesis of type 2 diabetes mellitus (T2DM). Single nucleotide polymorphisms (SNPs) in melatonin receptors (MTNR), MTNR 1A rs2119882 (T>C) and MTNR 1B rs10830963 (C>G) may interfere with the normal function of melatonin and increase the risk of T2DM. This study investigated the prevalence of MTNR 1A rs2119882 (T>C) and MTNR 1B rs10830963 (C>G) SNPs and tested their association with T2DM in Saudi Arabian population. METHODS: A total of 459 Saudi Arabian participants from Jazan Province, Saudi Arabia, were selected and included 227 T2DM patients and 232 control subjects. DNA was extracted from all participants and genotyped for rs2119882 and rs10830963 SNPs using TaqMan technology. Genotype frequencies were determined for both SNPs, and logistic regression was fitted to test the association with T2DM. RESULTS: No association was found between MTNR 1A rs2119882 (T>C) SNP and T2DM (odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.44 - 1.08; p-value = 0.111). However, the MTNR 1B rs10830963 (C>G) SNP was significantly associated with T2DM (OR = 1.73; 95% CI = 1.18 - 2.55; p-value = 0.0065). Co-inheritance of the MTNR 1B rs10830963 G allele and MTNR 1A rs2119882 T allele further increased the risk of T2DM (OR = 2.80; 95% CI = 1.71 - 4.57; p-value < 0.0001). CONCLUSIONS: The minor G allele of the MTNR 1B rs10830963 SNP was significantly associated with T2DM in our population. This association further intensified with the presence of the T allele in MTNR 1A rs2119882 locus. This study sheds light on the importance of melatonin receptor polymorphisms as genetic candidates for the development of T2DM in Saudi Arabia.

Comprehensive Analysis of Global Research on Erectile Dysfunction from 2002 to 2021: A Scientometric Approach.

Background: Erectile dysfunction (ED) is a multifaceted yet prevalent male-related sexual dysfunction that manifests as a change in any of the erectile response components, including relational, psychological, and biological. We aimed to use bibliometric analyses to determine how ED research has progressed and define the future trends necessary to contribute to scholarly literature. Methods: Two tools, VOSviewer and MS Excel, were used, and the study was conducted in May 2022. A total of 16,114 records were selected for in-depth analyses. We examined the most eminent authors, highly cited papers within journals, and the institutions that have provided the greatest number of articles regarding ED, and demonstrated that ED research has increased over the last two decades. Results: The total number of research documents published between 1971 and 2021 was 16,114, with a growth rate of 5%. Montorsi, Maggi, and Mulhall shared the top spot in the number of publications (n = 164). The Journal of Sexual Medicine has the most papers (N = 1839), followed by the International Journal of Impotence Research (N = 780), the Journal of Urology (N = 557), and Urology (N = 489). Conclusion: The study revealed increased ED research in the past two decades, with notable authors and sources identified. The top three countries contributing to ED are the UK, Italy, and the USA. Recommendations include interdisciplinary collaboration, novel therapeutic approaches, addressing psychological and relational factors, conducting longitudinal studies, and publishing in reputable journals. Implementing these can advance understanding, improve treatment options, and enhance ED management.

Diabetes mellitus research in Saudi Arabia: A bibliometric study (2010-2021).

Diabetes Mellitus (DM) causes global exhaustion, consumes economic resources, and has several risk factors. The bibliometric studies re-evaluate the research efforts on this illness using mathematical and statistical tools to indicate current research and future trends. This study examines KSA's DM research during 2010-2021. Data were acquired from Scopus and analyzed using VOSviewer and MS Excel. Several characteristics were examined to measure the quantity and quality of KSA-related DM articles. In total, 1,919 journal and conference papers were published. DM research included researchers from multidisciplinary sectors. Thirty-seven percent of them have ten or more scientific publications. Al-Daghri, N.M. (King Saud University) leads the pack. In total, 757 (39.44%) research projects got funding from 159 sources within and outside KSA. Memish, Z.A. is the most cited author. The Saudi Medical Journal has the most citations (1214). Al-Daghri, N.M. (KSU) collaborates the most. One hundred forty-one nations aided KSA's diabetes research. Egypt's High Institute of Public Health has the most scientific collaboration with KSA. Authors' and all Keywords analyses indicated a rich knowledge structure. Diabetes Care Journal has the most cocitations with 2,220 and a total link strength of 19,283, followed by The New England Journal of Medicine. The study results will be helpful to stakeholders to understand better the trends and performance of diabetes-related regional research, which will be beneficial.

The NLRP3 inflammasome rs35829419 C>A polymorphism is associated with type 2 diabetes mellitus in Saudi Arabia.

OBJECTIVES: To investigate the frequency of NLRP3 gene rs35829419 C>A single-nucleotide polymorphism (SNP) in a Saudi Arabian population from Jazan (Southwest Saudi Arabia) and test its potential association with type 2 diabetes mellitus (T2DM). METHODS: This case-control study included 546 volunteers (271 patients with T2DM and 275 healthy controls) recruited from outpatient clinics at Jazan University Hospital and King Fahad Central Hospital in Jazan, Saudi Arabia, between December 2021 and July 2022. Genomic DNA was extracted from all samples and genotyped for the NLRP3 rs35829419 C>A SNP using TaqMan technology. The association between the NLRP3 rs35829419 polymorphism and T2DM was examined using logistic regression analysis. RESULTS: Overall genotype distributions were 90.5% (CC), 9.3% (CA), and 0.2% (AA). The heterozygous CA genotype was more frequent in T2DM group (12.2%) compared to the control group (6.5%) and logistic regression analysis showed a statically significant association with T2DM risk under codominant (CA versus CC; odds ratio [OR]=1.99; 95% confidence interval [CI]= [1.11-3.61]; p=0.0270), and dominant (CA+AA versus CC; OR=2.05; CI=[1.16-3.75]; p=0.019) models of inheritance. CONCLUSION: This study revealed the frequency of NLRP3 rs35829419 C>A polymorphism in our population and showed a direct correlation between having the minor allele for A and having a higher risk of developing T2DM. This study highlights the significance of NLRP3 rs35829419 C>A polymorphism in the pathophysiology of T2DM.

Frequency of the rs2015 (T>G) and rs2241703 (G>A) polymorphisms in the miRNA-SIRT2 gene in type 2 diabetes mellitus in Saudi Arabia.

OBJECTIVES: To investigate the prevalence of rs2015 (T>G) and rs2241703 (G>A) polymorphisms in the miRNA-SIRT2 gene in Saudi Arabia and their possible associations with type 2 diabetes mellitus (T2DM). METHODS: Blood samples were collected from 428 participants from Jazan University Hospital, Jazan, Saudi Arabia between September 2021 and June 2022 and subjected to TaqMan single-nucleotide polymorphisms (SNP) genotyping assay for rs241703 (G>A) and rs2015 (G>T). Genotype frequencies were determined in control (n=217). RESULTS: The A allele of rs2241703 was undetected in our population, and all samples carried the GG genotype. The rs2015 SNP frequency was 29.4% for GG, 45.6% for GT, and 24% for TT. However, logistic regression analysis of the dominant inheritance model showed no association between the T allele and T2DM calculated odds ratio [OR]=0.80, 95% confidence interval=0.53 to 1.20, p=0.301). CONCLUSION: Although rs2241703 SNP of Sirtuins 2 is not present, rs2015 SNP is highly prevalent in Saudi Arabia, but no direct link was identified with T2DM.

The Association of UCP2-866 G/A Genotype with Autoimmune Hypothyroidism in the Southwestern Saudi Arabia Population.

Introduction: Autoimmune hypothyroidism (AHT) is a widespread disease that disproportionately affects women over men. It is characterized by the presence of autoantibodies that lead to the dysfunction of the thyroid gland. The exact cause of this process is unknown; however, some factors, such as genetic factors, may be to blame. The uncoupling protein 2 (UCP2) gene encodes uncoupling protein 2, which has been linked to several pathogeneses; however, the link between UCP2-866 G/A polymorphism and AHT has yet to be investigated. Thus, we investigate the potential relationship between UCP2-866 G/A polymorphism and AHT. Methods: A total of 158 subjects participated in this study, they were either control or AHT patient, and genotyping was performed using a polymerase chain reaction. Results: The frequencies of UCP2-866 G/G, G/A, and A/A in the control subject were 34%, 51%, and 15%, respectively, whereas these frequencies in the AHT were 43%, 46%, and 10%. Conclusion: The study concludes a significant relationship between UCP2-866 G/A polymorphism and AHT, with a carrier subject of the -866 A allele being 3 times more likely to suffer from AHT than wild-type carriers in the study population.

Potential Roles of Anti-Inflammatory Plant-Derived Bioactive Compounds Targeting Inflammation in Microvascular Complications of Diabetes.

Diabetes mellitus (DM) is a group of metabolic disorders, the characteristics of which include chronic hyperglycemia owing to defects in insulin function, insulin secretion, or both. Inflammation plays a crucial role in DM pathogenesis and innate immunity in the development of microvascular complications of diabetes. In addition, hyperglycemia and DM mediate a proinflammatory microenvironment that can result in various microvascular complications, including diabetic nephropathy (DNP), diabetic neuropathy (DN), and diabetic retinopathy (DR). DNP is a major cause of end-stage renal disease. DNP can lead to albuminuria, decreased filtration, mesangium expansion, thickening of the basement membrane, and eventually renal failure. Furthermore, inflammatory cells can accumulate in the interstitium and glomeruli to deteriorate DNP. DN is another most prevalent microvascular complication of DM and the main cause of high mortality, disability, and a poor quality of life. DNs have a wide range of clinical manifestations because of the types of fiber dysfunctions and complex structures of the peripheral nervous system. DR is also a microvascular and multifactorial disease, as well as a major cause of visual impairment globally. Pathogenesis of DR is yet to be fully revealed, however, numerous studies have already confirmed the role of inflammation in the onset and advancement of DR. Despite evidence, and better knowledge regarding the pathogenesis of these microvascular complications of diabetes, there is still a deficiency of effective therapies. Bioactive compounds are mainly derived from plants, and these molecules have promising therapeutic potential. In this review, evidence and molecular mechanisms regarding the role of inflammation in various microvascular complications of diabetes including DNP, DN, and DR, have been summarized. The therapeutic potential of several bioactive compounds derived from plants in the treatment of these microvascular complications of diabetes has also been discussed.

Human Growth Hormone Fragment 176-191 Peptide Enhances the Toxicity of Doxorubicin-Loaded Chitosan Nanoparticles Against MCF-7 Breast Cancer Cells.

Introduction: Numerous drugs with potent toxicity against cancer cells are available for treating malignancies, but therapeutic efficacies are limited due to their inefficient tumor targeting and deleterious effects on non-cancerous tissue. Therefore, two improvements are mandatory for improved chemotherapy 1) novel delivery techniques that can target cancer cells to deliver anticancer drugs and 2) methods to specifically enhance drug efficacy within tumors. The loading of inert drug carriers with anticancer agents and peptides which are able to bind (target) tumor-related proteins to enhance tumor drug accumulation and local cytotoxicity is a most promising approach. Objective: To evaluate the anticancer efficacy of Chitosan nanoparticles loaded with human growth hormone hGH fragment 176-191 peptide plus the clinical chemotherapeutic doxorubicin in comparison with Chitosan loaded with doxorubicin alone. Methods: Two sets of in silico experiments were performed using molecular docking simulations to determine the influence of hGH fragment 176-191 peptide on the anticancer efficacy of doxorubicin 1) the binding affinities of hGH fragment 176-191 peptide to the breast cancer receptors, 2) the effects of hGH fragment 176-191 peptide binding on doxorubicin binding to these same receptors. Further, the influence of hGH fragment 176-191 peptide on the anticancer efficacy of doxorubicin was validated using viability assay in Human MCF-7 breast cancer cells. Results: In silico analysis suggested that addition of the hGH fragment to doxorubicin-loaded Chitosan nanoparticles can enhance doxorubicin binding to multiple breast cancer protein targets, while photon correlation spectroscopy revealed that the synthesized dual-loaded Chitosan nanoparticles possess clinically favorable particle size, polydispersity index, as well as zeta potential. Conclusion: These dual-loaded Chitosan nanoparticles demonstrated greater anti-proliferative activity against a breast cancer cell line (MCF-7) than doxorubicin-loaded Chitosan. This dual-loading strategy may enhance the anticancer potency of doxorubicin and reduce the clinical side effects associated with non-target tissue exposure.

Rasch and Confirmatory Factor Analyses of the Arabic Version of the Diabetes Self-Management Scale (DSMS): An Intercultural Approach.

The current study was designed to validate the Arabic version of the Diabetes Self-Management Scale (DSMS) using Rasch and confirmatory factor analyses. This included person and item fit, separation, and reliability; rating scale functionality to evidence substantive validity; unidimensional structure to evidence structural validity; and item technical quality to evidence content validity. The study was conducted between September 2021 and March 2022. Utilizing AMOS-based confirmatory factor analysis (CFA), the study also assured the dimensionality of the DSMS. The participants were 103 diabetic patients in Saudi Arabia with a mean age of 44.72 years (standard deviation = 17.35). The analysis was performed using a trichotomous rating scale, and only one item exhibited a misfit (DSMS14). The item difficulty range was -1.0 to +1.0 logits, while the person's ability range was -3.0 to +3.0 logits. The first construct proved one Rasch dimension, which was explained and further analyzed using AMOS-CFA for the one-factor model. The DSMS was shown to be beneficial as a screening instrument for patient-reported diabetes self-management, despite several flaws that need to be addressed to improve the scale further.

Association between Angiotensin-Converting Enzyme- Insertion/Deletion Polymorphism and Diabetes Mellitus-2 in Saudi Population.

OBJECTIVES: The association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the development of type 2 diabetes mellitus (T2DM) has been debated vigorously but still remains controversial. Therefore, the current study was designed to determine the possible association between ACE I/D polymorphism and T2DM and hypertension (HTN) in a population of Saudi Arabian participants. METHODS: A total of 143 individuals were recruited for the study, consisting of 74 controls and 69 patients with T2DM. Genotyping was performed via polymerase chain reaction. RESULTS: The genotype frequencies for DD, ID and II in controls were 52.7%, 39.2% and 8.1%, whereas in T2D patients it was 52.2%, 40.6% and 7.2% respectively. The DD frequency was highest out of the three genotypes in both the controls and the T2DM patients. CONCLUSION: There was no significant difference found in the genotype and allele frequencies between cases and controls, suggesting that insertion/deletion polymorphism in the ACE gene may not be associated with an increased susceptibility to type 2 diabetes in our study population.

Frequency of UCP2 45-bp Ins/Del polymorphism in Saudi population from Jazan area and its association with autoimmune hypothyroidism UCP2 45-bp Ins/Del frequency in hypothyroidism.

OBJECTIVES: Autoimmune hypothyroidism (AHT) is a common endocrine disorder. Although the exact cause of AHT is not yet understood, genetic factors may play a major role. Uncoupling protein 2 (UCP2) is a member of mitochondrial protein family involved in the regulation of cellular metabolism. An important functional polymorphism in the UCP2 gene, 45-bp insertion/deletion (ins/del) polymorphism, has been linked to certain clinical conditions. However, an association between the 45-bp ins/del polymorphism and AHT has not yet been established. METHODS: In this study, about 259 blood samples were collected from, patients with AHT and age-matched healthy control subjects. DNA was extracted for UCP2 45-bp ins/del polymorphisms genotyping, using a standard polymerase chain reaction technique. The distribution of different genotypes was determined in both groups and possible association with AHT was also assessed by logistic regression analysis using the Del/Del variant as a reference genotype. RESULTS: The frequency of the UCP2 45-bp ins/del polymorphism in the total study population was 49.04%, 40.15%, and 10.81% for Del/Del, Ins/Del, and Ins/Ins genotypes, respectively. The logistic regression analysis showed crude odds ratios (ORs), respectively, with their 95% confidence intervals (CIs) and P-values in codominant (Del/Ins) (OR = 1.53, CI = 0.89-2.60, P = 0.17), codominant (Ins/Ins) (OR = 0.75, CI = 0.34-1.74, P = 0.53), dominant (OR = 1.30, CI = 0.79-2.16, P = 0.37), and recessive (OR = 0.62, CI = 0.29-1.36, P = 0.30) inheritance models tested, where none of which were statistically significant. CONCLUSION: Our data revealed the distribution of the UCP2 45-bp ins/del polymorphisms in Jazan area and confirmed the lack of association between these genetic variants and the development of AHT.

The Deletion Polymorphism in Exon 8 of Uncoupling Protein 2 is Associated with Severe Obesity in a Saudi Arabian Case-control Study.

CONTEXT: Obesity is a major health concern in Saudi Arabia. Uncoupling protein 2 (UCP2) seems to play a major role in the regulation of human metabolism; therefore, genetic polymorphisms in the UCP2 gene might contribute to obesity. AIM: This study aims to establish whether 45-blood pressure (BP) insertion (I)/deletion (D) polymorphisms in UCP2 are associated with moderate and/or severe obesity in a Saudi Arabian population. SETTINGS AND DESIGN: Case-control study design. MATERIALS AND METHODS: The study enrolled 151 male and female subjects originating from the eastern province of Saudi Arabia, and assigned each to a "nonobese," "moderately obese," or "severely obese" group. Genomic DNA was extracted from all subjects and screened for UCP2 I/D polymorphisms using a standard polymerase chain response protocol. STATISTICAL ANALYSIS USED: Analysis of variance, Chi-squared tests, and logistic regression analysis. RESULTS: The frequencies of the UCP2 45-BP I/D genotypes D/D, I/D, and I/I within the analyzed population were 58.3%, 36.4%, and 5.3%, respectively. The D/D genotype was highly prevalent within the severely obese group (82.9%) compared to the nonobese (46.2%) and moderately obese (53.3%) groups. Using a dominance model, the conducted logistic regression analysis showed a strong association between the deletion allele and severe obesity (Odds ratio = 0.18, 95% confidence interval: 0.07-0.44, P = 0.0004). CONCLUSIONS: The present study reported that the frequency of UCP2 45-BP I/D polymorphisms in a population originating from eastern Saudi Arabia and identified a strong association between the D/D genotype and severe obesity.

Frequency of the exon 3-deleted/full-length growth hormone receptor polymorphism in Saudi Arabian population.

OBJECTIVES: To investigate the frequency of the growth hormone receptor (GHR)-d3 polymorphism in a random sample of Saudi Arabian population from Jazan province, and test the effects of the polymorphism on some anthropometric factors. METHODS: This cross-sectional population-based study was conducted during the period from January to April 2017 at the College of Applied Medical Sciences, Jazan University, Southwestern Saudi Arabia. A total of 230 healthy adult male and female volunteers were randomly recruited. Genomic DNA was extracted from the whole blood, and the GHR exon 3 locus was genotyped using multiplex polymerase chain reaction. RESULTS: The distributions of the GHR genotypes were as follows: fl/fl (39.1%), fl/d3 (44.8%), and d3/d3 (16.1%). No statistically significant differences were found between fl/fl, fl/d3, or d3/d3 GHR genotypes in terms of weight (p=0.90), height (p=0.12), or body mass index (BMI) (p=0.83) values. CONCLUSION: No correlations were found between the GHR-d3 polymorphism and weight, height, or BMI.

Lack of association between the insulin receptor substrates-1 Gly972Arg polymorphism and type-2 diabetes mellitus among Saudis from Eastern Saudi Arabia.

OBJECTIVES: To investigate the association between  the insulin receptor substrate-1 (IRS1) Gly972Arg polymorphism and type-2 diabetes mellitus (T2DM) among Saudis from Eastern Saudi Arabia.  METHODS: This study was conducted between May and December 2014 at King Fahad Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia. In a case-control study design, a total of 143 subjects (age range: 35-73 years) comprising 74 healthy controls and 69 patients with T2DM were examined. Blood samples were collected from subjects and subjected to genomic DNA extraction and chemical analysis. The IRS1 Gly972Arg polymorphism was then genotyped using the standard polymerase chain reaction-restriction fragment length polymorphism technique.  RESULTS: Eight out of 74 (10.8%) of the control group carried at least one copy of the mutated allele. The frequency (8.7%) of the IRS1 variant was also found in the diabetic group. Logistic regression analysis showed an adjusted odds ratio of 1.04, 95% confidence interval 0.28 - 3.95, and a p-value of 0.94.   CONCLUSION: We failed to find any association between the IRS1 Gly972Arg polymorphism and T2DM.

Acute one-cigarette smoking decreases ghrelin hormone in saliva: a pilot study.

Cigarette smoking is commonly associated with weight loss and mechanisms for these weight changes are still elusive. Ghrelin is a peptide hormone that works in a neuroendocrine fashion to stimulate hunger and the desire for food intake. Ghrelin is also secreted in saliva, probably to enhance food taste. In the current study, we tested the direct impact of acute cigarette smoking on total ghrelin found in saliva. Methods. Blood and saliva samples were collected from 30 healthy nonsmoker male volunteers before and after one-cigarette smoke. Total ghrelin in serum and saliva was measured by ELISA based method. Results. Data showed a statistically significant reduction in salivary ghrelin after smoking (P < 0.0001). In serum, total ghrelin levels were not affected before and after smoking (P = 0.1362). Additionally, positive correlation was observed between serum and salivary ghrelin before smoking (r = 0.4143 and P = 0.0158); however, this correlation was lost after smoking (r = 0.1147 and P = 0.5461). Conclusion. Acute one-cigarette smoking can negatively affect ghrelin levels in saliva that might contribute to the dull food taste in smokers.

Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling.

We have investigated the interaction between GH (growth hormone) and GHR (GH receptor). We previously demonstrated that a truncated GHR that possesses a transmembrane domain but no cytoplasmic domain blocks receptor signalling. Based on this observation we investigated the impact of tethering the receptor's extracellular domain to the cell surface using a native lipid GPI (glycosylphosphatidylinositol) anchor. We also investigated the effect of tethering GH, the ligand itself, to the cell surface and demonstrated that tethering either the ecGHR (extracellular domain of GHR) or the ligand itself to the cell membrane via a GPI anchor greatly attenuates signalling. To elucidate the mechanism for this antagonist activity, we used confocal microscopy to examine the fluorescently modified ligand and receptor. GH-GPI was expressed on the cell surface and formed inactive receptor complexes that failed to internalize and blocked receptor activation. In conclusion, contrary to expectation, tethering an agonist to the cell surface can generate an inactive hormone receptor complex that fails to internalize.