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Identification of Transmembrane Protease Serine 2 and Forkhead Box A1 As the Potential Bisphenol A Responsive Genes in the Neonatal Male Rat Brain

Ubuka T, Moriya S, Soga T, Parhar I

Front Endocrinol (Lausanne), 2018;9:139.
PMID: 29643838 DOI: 10.3389/fendo.2018.00139

Perinatal exposure of Bisphenol A (BPA) to rodents modifies their behavior in later life. To understand how BPA modifies their neurodevelopmental process, we first searched for BPA responsive genes from androgen and estrogen receptor signaling target genes by polymerase chain reaction array in the neonatal male rat brain. We used a transgenic strain of Wistar rats carrying enhanced green fluorescent protein tagged to gonadotropin-inhibitory hormone (GnIH) promoter to investigate the possible interaction of BPA responsive genes and GnIH neurons. We found upregulation of transmembrane protease serine 2 (Tmprss2), an androgen receptor signaling target gene, and downregulation of Forkhead box A1 (Foxa1), an ER signaling target gene, in the medial amygdala of male rats that were subcutaneously administered with BPA from day 1 to 3. Tmprss2-immunoreactive (ir) cells were distributed in the olfactory bulb, cerebral cortex, hippocampus, amygdala, and hypothalamus in 3 days old but not in 1-month-old male rats. Density of Tmprss2-ir cells in the medial amygdala was increased by daily administration of BPA from day 1 to 3. Tmprss2 immunoreactivity was observed in 26.5% of GnIH neurons clustered from the ventral region of the ventromedial hypothalamic nucleus to the dorsal region of the arcuate nucleus of 3-day-old male rat hypothalamus. However, Tmprss2 mRNA expression significantly decreased in the amygdala and hypothalamus of 1-month-old male rats. Foxa1 mRNA expression was higher in the hypothalamus than the amygdala in 3 days old male rats. Intense Foxa1-ir cells were only found in the peduncular part of lateral hypothalamus of 3-day-old male rats. Density of Foxa1-ir cells in the hypothalamus was decreased by daily administration of BPA from day 1 to 3. Foxa1 mRNA expression in the hypothalamus also significantly decreased at 1 month. These results suggest that BPA disturbs the neurodevelopmental process and behavior of rats later in their life by modifying Tmprss2 and Foxa1 expressions in the brain.
Fulltext Biological Significance of Kisspeptin-Kiss 1 Receptor Signaling in the Habenula of Teleost Species

Ogawa S, Parhar IS

Front Endocrinol (Lausanne), 2018;9:222.
PMID: 29867758 DOI: 10.3389/fendo.2018.00222

Kisspeptin is a neuropeptide, encoded by kisspeptin 1 (KISS1)/Kiss1 gene, which primarily acts as the regulator of reproductive functions via its receptor, kisspeptin receptor (KissR) in vertebrates. In the brain, Kiss1 gene is mainly expressed in the hypothalamic region, but KissR gene is widely distributed throughout the brain, suggesting that kisspeptin-KissR system may be involved in not only reproductive, but also non-reproductive functions. In non-mammalian vertebrates, there are two or more kisspeptin and KissR types. The zebrafish (Danio rerio) possess two kisspeptin (Kiss1 and Kiss2) and their respective receptors [Kiss1 receptor (KissR1) and KissR2]. In the brain of zebrafish, while Kiss2 is expressed in the preoptic-hypothalamic area, Kiss1 is predominantly expressed in the habenula, an evolutionarily conserved epithalamic structure. Similarly, KissR1 is expressed only in the habenula, while KissR2 is widely distributed in the brain, suggesting that the two kisspeptin systems play specific roles in the brain. The habenular Kiss1 is involved in the modulation of the raphe nuclei and serotonin-related behaviors such as fear response in the zebrafish. This review summarizes the roles of multiple kisspeptin-KissR systems in reproductive and non-reproductive functions and neuronal mechanism, and debates the biological and evolutional significance of habenular kisspeptin-KissR systems in teleost species.
Fulltext Integrated Characterization of MicroRNA and mRNA Transcriptome in Papillary Thyroid Carcinoma

Mohamad Yusof A, Jamal R, Muhammad R, Abdullah Suhaimi SN, Mohamed Rose I, Saidin S, et al.

Front Endocrinol (Lausanne), 2018;9:158.
PMID: 29713312 DOI: 10.3389/fendo.2018.00158

The incidence rate of papillary thyroid carcinoma (PTC) has rapidly increased in the recent decades, and the microRNA (miRNA) is one of the potential biomarkers in this cancer. Despite good prognosis, certain features such as lymph node metastasis (LNM) and BRAF V600E mutation are associated with a poor outcome. More than 50% of PTC patients present with LNM and BRAF V600E is the most common mutation identified in this cancer. The molecular mechanisms underlying these features are yet to be elucidated. This study aims to elucidate miRNA-genes interaction networks in PTC with or without LNM and to determine the association of BRAF V600E mutation with miRNAs and genes expression profiles. Next generation sequencing was performed to characterize miRNA and gene expression profiles in 20 fresh frozen tumor and the normal adjacent tissues of PTC with LNM positive (PTC LNM-P) and PTC without LNM (PTC LNN). BRAF V600E was genotyped using Sanger sequencing. Bioinformatics integration and pathway analysis were performed to determine the regulatory networks involved. Based on network analysis, we then investigated the association between miRNA and gene biomarkers, and pathway enrichment analysis was performed to study the role of candidate biomarkers. We identified 138 and 43 significantly deregulated miRNAs (adjusted p value
Fulltext Initial Potassium Replacement in Diabetic Ketoacidosis: The Unnoticed Area of Gap

Usman A

Front Endocrinol (Lausanne), 2018;9:109.
PMID: 29619008 DOI: 10.3389/fendo.2018.00109
Fulltext Can Brain Natriuretic Peptides and Osteoprotegerin Serve As Biochemical Markers for the Detection of Aortic Pathology in Children and Adolescents with Turner Syndrome?

Mavinkurve M, O'Gorman CS

Front Endocrinol (Lausanne), 2017;8:142.
PMID: 28725213 DOI: 10.3389/fendo.2017.00142

Turner syndrome (TS) is a chromosomal disorder that affects 1:2,000 females. It results from either the complete or partial loss of the X chromosome as well as other aberrations. Clinical features of TS include short stature, delayed puberty, and congenital cardiac malformations. TS children also have an increased prevalence of cardiometabolic risk factors, which predisposes them to complications like coronary artery disease, cerebrovascular-related deaths, and aortic dissection. Early cardiac imaging, such as echocardiography and cardiac magnetic resonance imaging, are recommended to detect underlying aortic pathology. However, these modalities are limited by cost, accessibility, and are operator dependent. In view of these shortcomings, alternative methods, like vascular biomarkers, are currently being explored. There are only a few studies that have examined the relationship between B-type natriuretic peptide (BNP), N-terminal pro BNP (NT pro-BNP), and osteoprotegerin (OPG) and aortic disease in TS, and thus the data are only in proof-of-concept stages. Further meticulous longitudinal studies are required before BNP, NT pro-BNP, and OPG are used as vascular biomarkers for the detection of aortic disease in childhood and adolescent TS.
Fulltext Self-care and self-management among adolescent T2DM patients: a review

Eva JJ, Kassab YW, Neoh CF, Ming LC, Wong YY, Abdul Hameed M, et al.

Front Endocrinol (Lausanne), 2018;9:489.
PMID: 30459707 DOI: 10.3389/fendo.2018.00489

Uncontrolled hyperglycaemia can lead to macro- and microvascular complications. Adolescents with T2DM develop similar complications as in adults, including cardiovascular disease, stroke, myocardial infarction, renal insufficiency, and chronic renal failure. Although regular medical follow-up is essential to avoid long-term complications, patients with diabetes mellitus need to perform holistic self-care activities such as opting for a healthy diet, physical activity, self-monitoring, and proper medication. To the best of our knowledge, only a limited number of studies have focused on self-care activities and self-management, including self-care practices, supportive networks, and self-care education programs in adolescent with T2DM. Some of the studies focused on the appreciation of self-care in adolescents with T2DM. This review aimed to analyse self-care and self-management among adolescents with T2DM, and discuss the impact of self-care and self-management on glycaemic control. The difficulties faced by adolescents in self-managing their disease are also highlighted. Such information is essential for healthcare providers in promoting self-care practices among adolescents with T2DM. A thorough search of the literature was performed using three databases: Medline, Google Scholar, and Scopus. The articles focused on self-care and self-management of adolescents patients with T2DM aged between 12 and 19 years old were included. Findings from this review reveal that healthy food adaptation, adequate physical activity, proper medication practices, and regular glucose monitoring are the most common self-care practices. Parental involvement and clinician encouragement also contribute toward the practice of self-care and self-management among the adolescents with T2DM. In conclusion, independent self-management regimens and supportive networks for appropriate administration are vital factors to enhance clinical outcomes of adolescents with T2DM.
Fulltext Antidiabetic, Antihyperlipidemic, Antioxidant, Anti-inflammatory Activities of Ethanolic Seed Extract of Annona reticulata L. in Streptozotocin Induced Diabetic Rats

Wen W, Lin Y, Ti Z

Front Endocrinol (Lausanne), 2019;10:716.
PMID: 31708869 DOI: 10.3389/fendo.2019.00716

Annona reticulata L. (Bullock's heart) is a pantropic tree commonly known as custard apple, which is used therapeutically for a variety of maladies. The present research was carried out to evaluate the possible protective effects of Annona reticulata L. (A. reticulata) ethanolic seed extract on an experimentally induced type 2 diabetes rat model. Male Albino Wistar rats were randomly divided into five groups with six animals in each group viz., control rats in group I, diabetic rats in group II, diabetic rats with 50 and 100 mg/kg/bw of ethanolic seed extract of A. reticulata in groups III and IV, respectively, and diabetic rats with metformin in group V. Treatment was given for 42 consecutive days through oral route by oro-gastric gavage. Administration of A. reticulata seed extract to diabetes rats significantly restored the alterations in the levels of body weight, food and water intake, fasting blood glucose (FBG), insulin levels, insulin sensitivity, HbA1c, HOMA-IR, islet area and insulin positive cells. Furthermore, A. reticulata significantly decreased the levels of triglycerides, cholesterol, LDL, and significantly increased the HDL in diabetic rats. A. reticulata effectively ameliorated the enzymatic (ALT, AST, ALP, GGT) and modification of histopathological changes in diabetic rats. The serum levels of the BUN, creatinine levels, uric acid, urine volume, and urinary protein were significantly declined with a significant elevation in CCr in diabetic rats treated with A. reticulata. MDA and NO levels were significantly reduced with an enhancement in SOD, CAT, and GPx antioxidant enzyme activities in the kidney, liver, and pancreas of diabetic rats treated with A. reticulata. Diabetic rats treated with A. reticulata have shown up-regulation in mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1), Heme oxygenase-1 (HO-1) and protein expression level of Nrf2 with diminution in Keap1 mRNA expression level in pancreas, kidney, and liver. From the outcome of the current results, it can be inferred that seed extract of A. reticulata exhibits a protective effect in diabetic rats through its anti-diabetic, anti-hyperlipidemic, antioxidant and anti-inflammatory effects and could be considered as a promising treatment therapy in the treatment of diabetes mellitus.
Fulltext Prevalence and Histopathological Characteristics of KCNJ5 Mutant Aldosterone-Producing Adenomas in a Multi-Ethnic Malaysian Cohort

Mohideen SK, Mustangin M, Kamaruddin NA, Muhammad R, Jamal ARA, Sukor N, et al.

Front Endocrinol (Lausanne), 2019;10:666.
PMID: 31636604 DOI: 10.3389/fendo.2019.00666

Studies on excised adrenals from primary aldosteronism patients have found that somatic mutations in KCNJ5 frequently cause excess aldosterone production in the culprit aldosterone-producing adenoma (APA). KCNJ5 mutant APAs were reported to be peculiarly overrepresented among young females and in Oriental cohorts, compared to their older male, or Caucasian counterparts. These larger APAs were also reported to have similarities with the zona fasciculata (ZF) in the adrenal both from the steroid production profile and the morphology of the cell. We therefore aimed to corroborate these findings by characterizing the APAs from a multi-ethnic Malaysian cohort. The prevalence of KCNJ5 mutations was estimated through targeted DNA sequencing of KCNJ5 in 54 APAs. Confirmation of APA sample acquisition was performed by CYP11B2 immunohistochemistry (IHC) staining. The ZF steroid production profile was based on the ZF enzyme CYP17A1 IHC staining, and ZF cell morphology was based on a high cytoplasm to nucleus ratio. Seventeen (31.5%) APAs studied, harbored a KCNJ5 mutation. No female over-representation was seen in this cohort though females were found to have a higher expression of CYP11B2 than males (p = 0.009; Mann-Whitney U test). Age at adrenalectomy correlated negatively with the percentage of ZF-like cells in the APA (p = 0.01; Spearman's rho) but not with the KCNJ5 genotype. KCNJ5 mutant APAs had a high percentage of ZF-like cells (and high CYP17A1 expression) but so did the wild-type APAs. In summary, prevalence of KCNJ5 mutant APAs in this cohort was similar to other Caucasian cohorts, however, over-representation of females did not occur, which is similar to some studies in Oriental cohorts.
Fulltext Evolution of Structural and Functional Diversity of Spexin in Mammalian and Non-mammalian Vertebrate Species

Lim CH, Lee MYM, Soga T, Parhar I

Front Endocrinol (Lausanne), 2019;10:379.
PMID: 31275244 DOI: 10.3389/fendo.2019.00379

Spexin (SPX) is a novel neuropeptide, which was first identified in the human genome using bioinformatics. Since then, orthologs of human SPX have been identified in mammalian and non-mammalian vertebrates. The mature sequence of SPX, NWTPQAMLYLKGAQ, is evolutionally conserved across vertebrate species, with some variations in teleost species where Ala at position 13 is substituted by Thr. In mammals, the gene structure of SPX comprises six exons and five introns, however, variation exists within non-mammalian species, goldfish and zebrafish having five exons while grouper has six exons. Phylogenetic and synteny analysis, reveal that SPX is grouped together with two neuropeptides, kisspeptin (KISS) and galanin (GAL) as a family of peptides with a common evolutionary ancestor. A paralog of SPX, termed SPX2 has been identified in non-mammalians but not in the mammalian genome. Ligand-receptor interaction study also shows that SPX acts as a ligand for GAL receptor 2 (2a and 2b in non-mammalian vertebrates) and 3. SPX acts as a neuromodulator with multiple central and peripheral physiological roles in the regulation of insulin release, fat metabolism, feeding behavior, and reproduction. Collectively, this review provides a comprehensive overview of the evolutionary diversity as well as molecular and physiological roles of SPX in mammalian and non-mammalian vertebrate species.
Fulltext The Role of GnIH in Biological Rhythms and Social Behaviors

Teo CH, Phon B, Parhar I

Front Endocrinol (Lausanne), 2021;12:728862.
PMID: 34566893 DOI: 10.3389/fendo.2021.728862

Gonadotropin-inhibitory hormone (GnIH) was first discovered in the Japanese quail, and peptides with a C-terminal LPXRFamide sequence, the signature protein structure defining GnIH orthologs, are well conserved across vertebrate species, including fish, reptiles, amphibians, avians, and mammals. In the mammalian brain, three RFamide-related proteins (RFRP-1, RFRP-2, RFRP-3 = GnIH) have been identified as orthologs to the avian GnIH. GnIH is found primarily in the hypothalamus of all vertebrate species, while its receptors are distributed throughout the brain including the hypothalamus and the pituitary. The primary role of GnIH as an inhibitor of gonadotropin-releasing hormone (GnRH) and pituitary gonadotropin release is well conserved in mammalian and non-mammalian species. Circadian rhythmicity of GnIH, regulated by light and seasons, can influence reproductive activity, mating behavior, aggressive behavior, and feeding behavior. There is a potential link between circadian rhythms of GnIH, anxiety-like behavior, sleep, stress, and infertility. Therefore, in this review, we highlight the functions of GnIH in biological rhythms, social behaviors, and reproductive and non-reproductive activities across a variety of mammalian and non-mammalian vertebrate species.
Fulltext Intersections in Neuropsychiatric and Metabolic Disorders: Possible Role of TRPA1 Channels

Sodhi RK, Singh R, Bansal Y, Bishnoi M, Parhar I, Kuhad A, et al.

Front Endocrinol (Lausanne), 2021;12:771575.
PMID: 34912298 DOI: 10.3389/fendo.2021.771575

Neuropsychiatric disorders (NPDs) are a huge burden to the patient, their family, and society. NPDs have been greatly associated with cardio-metabolic comorbidities such as obesity, type-2 diabetes mellitus, dysglycaemia, insulin resistance, dyslipidemia, atherosclerosis, and other cardiovascular disorders. Antipsychotics, which are frontline drugs in the treatment of schizophrenia and off-label use in other NPDs, also add to this burden by causing severe metabolic perturbations. Despite decades of research, the mechanism deciphering the link between neuropsychiatric and metabolic disorders is still unclear. In recent years, transient receptor potential Ankyrin 1 (TRPA1) channel has emerged as a potential therapeutic target for modulators. TRPA1 agonists/antagonists have shown efficacy in both neuropsychiatric disorders and appetite regulation and thus provide a crucial link between both. TRPA1 channels are activated by compounds such as cinnamaldehyde, allyl isothiocyanate, allicin and methyl syringate, which are present naturally in food items such as cinnamon, wasabi, mustard, garlic, etc. As these are present in many daily food items, it could also improve patient compliance and reduce the patients' monetary burden. In this review, we have tried to present evidence of the possible involvement of TRPA1 channels in neuropsychiatric and metabolic disorders and a possible hint towards using TRPA1 modulators to target appetite, lipid metabolism, glucose and insulin homeostasis and inflammation associated with NPDs.
Fulltext Is Misdiagnosis of Type 1 Diabetes Mellitus in Malaysian Children a Common Phenomenon?

Mavinkurve M, Jalaludin MY, Chan EWL, Noordin M, Samingan N, Leong A, et al.

Front Endocrinol (Lausanne), 2021;12:606018.
PMID: 33763028 DOI: 10.3389/fendo.2021.606018

Background: Children with Type 1 diabetes (T1DM) commonly present in diabetic ketoacidosis (DKA) at initial diagnosis. This is likely due to several factors, one of which includes the propensity for T1DM to be misdiagnosed. The prevalence of misdiagnosis has been reported in non-Asian children with T1DM but not in Asian cohorts.
Aim: To report the rate of misdiagnosis and its associated risk factors in Malaysian children and adolescents with T1DM.
Methods: A retrospective analysis of children with T1DM below 18 years of age over a 10 year period was conducted.
Results: The cohort included 119 children (53.8% female) with a mean age 8.1 SD ± 3.9 years. 38.7% of cases were misdiagnosed, of which respiratory illnesses were the most common (37.0%) misdiagnosis. The rate of misdiagnosis remained the same over the 10 year period. Among the variables examined, younger age at presentation, DKA at presentation, healthcare professional (HCP) contact and admission to the intensive care unit were significantly different between the misdiagnosed and correctly diagnosed groups (p <0.05).
Conclusion: Misdiagnosis of T1DM occurs more frequently in Malaysian children <5 years of age. Misdiagnosed cases are at a higher risk of presenting in DKA with increased risk of ICU admission and more likely to have had prior HCP contact. Awareness of T1DM amongst healthcare professionals is crucial for early identification, prevention of DKA and reducing rates of misdiagnosis.
Fulltext A Combination of Glucagon-Like Peptide-1 Receptor Agonist and Dietary Intervention Could Be a Promising Approach for Obesity Treatment

Lee CY

Front Endocrinol (Lausanne), 2021;12:748477.
PMID: 34616367 DOI: 10.3389/fendo.2021.748477
Fulltext Social Isolation Modulates CLOCK Protein and Beta-Catenin Expression Pattern in Gonadotropin-Inhibitory Hormone Neurons in Male Rats

Teo CH, Soga T, Parhar IS

Front Endocrinol (Lausanne), 2017;8:225.
PMID: 28936198 DOI: 10.3389/fendo.2017.00225

Postweaning social isolation reduces the amplitude of the daily variation of CLOCK protein in the brain and induces lower reproductive activity. Gonadotropin-inhibitory hormone (GnIH) acts as an inhibitor in the reproductive system and has been linked to stress. Social isolation has been shown to lower neuronal activity of GnIH-expressing neurons in the dorsomedial hypothalamus (DMH). The exact mechanism by which social isolation may affect GnIH is still unclear. We investigated the impact of social isolation on regulatory cellular mechanisms in GnIH neurons. We examined via immunohistochemistry the expression of CLOCK protein at four different times throughout the day in GnIH cells tagged with enhanced fluorescent green protein (EGFP-GnIH) in 9-week-old adult male rats that have been raised for 6 weeks under postweaning social isolation and compared them with group-raised control rats of the same age. We also studied the expression of β-catenin-which has been shown to be affected by circadian proteins such as Bmal1-in EGFP-GnIH neurons to determine whether it could play a role in linking CLOCK in GnIH neurons. We found that social isolation modifies the pattern of CLOCK expression in GnIH neurons in the DMH. Socially isolated rats displayed greater CLOCK expression in the dark phase, while control rats displayed increased CLOCK expression in the light phase. Furthermore, β-catenin expression pattern in GnIH cells was disrupted by social isolation. This suggests that social isolation triggers changes in CLOCK and GnIH expression, which may be associated with an increase in nuclear β-catenin during the dark phase.
Fulltext A Journey through the Gonadotropin-Inhibitory Hormone System of Fish

Muñoz-Cueto JA, Paullada-Salmerón JA, Aliaga-Guerrero M, Cowan ME, Parhar IS, Ubuka T

Front Endocrinol (Lausanne), 2017;8:285.
PMID: 29163357 DOI: 10.3389/fendo.2017.00285

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that belongs to the RFamide peptide family and was first identified in the quail brain. From the discovery of avian GnIH, orthologous GnIH peptides have been reported in a variety of vertebrates, including mammals, amphibians, teleosts and agnathans, but also in protochordates. It has been clearly established that GnIH suppresses reproduction in avian and mammalian species through its inhibitory actions on brain GnRH and pituitary gonadotropins. In addition, GnIH also appears to be involved in the regulation of feeding, growth, stress response, heart function and social behavior. These actions are mediated via G protein-coupled GnIH receptors (GnIH-Rs), of which two different subtypes, GPR147 and GPR74, have been described to date. With around 30,000 species, fish represent more than one-half of the total number of recognized living vertebrate species. In addition to this impressive biological diversity, fish are relevant because they include model species with scientific and clinical interest as well as many exploited species with economic importance. In spite of this, the study of GnIH and its physiological effects on reproduction and other physiological processes has only been approached in a few fish species, and results obtained are in some cases conflicting. In this review, we summarize the information available in the literature on GnIH sequences identified in fish, the distribution of GnIH and GnIH-Rs in central and peripheral tissues, the physiological actions of GnIH on the reproductive brain-pituitary-gonadal axis, as well as other reported effects of this neuropeptide, and existing knowledge on the regulatory mechanisms of GnIH in fish.
Fulltext Editorial: The Roles of GnIH in Reproductive Function and Behavior

Ubuka T, Parhar I, Kriegsfeld LJ, Tsutsui K

Front Endocrinol (Lausanne), 2018;9:19.
PMID: 29445358 DOI: 10.3389/fendo.2018.00019
Fulltext Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic-Pituitary-Gonadal Axis

Ubuka T, Parhar I

Front Endocrinol (Lausanne), 2017;8:377.
PMID: 29375482 DOI: 10.3389/fendo.2017.00377

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic-pituitary-gonadal (HPG) axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH) release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.
Fulltext Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm

Palihaderu PADS, Mendis BILM, Premarathne JMKJK, Dias WKRR, Yeap SK, Ho WY, et al.

Front Endocrinol (Lausanne), 2022;13:1028846.
PMID: 36479211 DOI: 10.3389/fendo.2022.1028846

The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.
Fulltext Triglyceride to high-density lipoprotein cholesterol ratio is an independent predictor of liver fibrosis among pediatrics non-alcoholic fatty liver disease

Ting YW, Jalaludin MY, Zaini AA, Mohamed R

Front Endocrinol (Lausanne), 2022;13:1071350.
PMID: 36589844 DOI: 10.3389/fendo.2022.1071350

BACKGROUND: Insulin resistance (IR), one of the key components of the metabolic syndrome, is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the relationship between surrogate markers of IR and the severity of NAFLD among overweight or obese children.
METHODOLOGY: A total of 56 consecutive children aged 6 to 18 years old were recruited from the pediatric obesity and type 2 diabetes mellitus (T2DM) clinic in University Malaya Medical Centre (UMMC) from 2016 to 2019. Data on anthropometric measurements, clinical components of metabolic syndrome and fasting serum insulin were collected. Triglyceride to high-density lipoprotein cholesterol ratio (TG: HDL-C), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Single Point Insulin Sensitivity Estimator (SPISE) were calculated. Transient elastography was performed with hepatic steatosis and liver fibrosis assessed by controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively.
RESULTS: A total of 44 children (78.6%) had liver steatosis and 35.7% had presence of significant liver fibrosis (stage F≥2). Majority (89.3%) are obese and 24 children (42.9%) were diagnosed with metabolic syndrome. Higher number of children with T2DM and significant liver fibrosis were associated with higher tertiles of TG: HDL-C ratio (p<0.05). Top tertile of TG: HDL-C ratio was an independent predictor of liver fibrosis (OR=8.14, 95%CI: 1.24-53.36, p=0.029). ROC analysis showed that the area under the curve (AUC) of HOMA-IR (0.77) and TG: HDL-C ratio (0.71) were greater than that of metabolic syndrome (0.70), T2DM (0.62) and SPISE (0.22). The optimal cut-off values of HOMA-IR and TG: HDL-C ratio for detecting liver fibrosis among children with NAFLD are 5.20 and 1.58, respectively.
CONCLUSION: Children with NAFLD and higher TG: HDL-C ratio are more likely to have liver fibrosis. TG: HDL-C ratio is a promising tool to risk stratify those with NAFLD who are at risk of developing advanced liver disease.
Fulltext Diverse nanocomposites as a potential dressing for diabetic wound healing

Renuka RR, Julius A, Yoganandham ST, Umapathy D, Ramadoss R, Samrot AV, et al.

Front Endocrinol (Lausanne), 2022;13:1074568.
PMID: 36714604 DOI: 10.3389/fendo.2022.1074568

Wound healing is a programmed process of continuous events which is impaired in the case of diabetic patients. This impaired process of healing in diabetics leads to amputation, longer hospitalisation, immobilisation, low self-esteem, and mortality in some patients. This problem has paved the way for several innovative strategies like the use of nanotechnology for the treatment of wounds in diabetic patients. The use of biomaterials, nanomaterials have advanced approaches in tissue engineering by designing multi-functional nanocomposite scaffolds. Stimuli-responsive scaffolds that interact with the wound microenvironment and controlled release of bioactive molecules have helped in overcoming barriers in healing. The use of different types of nanocomposite scaffolds for faster healing of diabetic wounds is constantly being studied. Nanocomposites have helped in addressing specific issues with respect to healing and improving angiogenesis. Method: A literature search was followed to retrieve the articles on strategies for wound healing in diabetes across several databases like PubMed, EMBASE, Scopus and Cochrane database. The search was performed in May 2022 by two researchers independently. They keywords used were "diabetic wounds, nanotechnology, nanocomposites, nanoparticles, chronic diabetic wounds, diabetic foot ulcer, hydrogel". Exclusion criteria included insulin resistance, burn wound, dressing material.

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