Unraveling the significance of PPP1R1A gene in pancreatic ß-cell function: A study in INS-1 cells and human pancreatic islets.

BACKGROUND AND AIMS: The protein phosphatase 1 regulatory inhibitor subunit 1A (PPP1R1A) has been linked with insulin secretion and diabetes mellitus. Yet, its full significance in pancreatic ß-cell function remains unclear. This study aims to elucidate the role of the PPP1R1A gene in ß-cell biology using human pancreatic islets and rat INS-1 (832/13) cells. RESULTS: Disruption of Ppp1r1a in INS-1 cells was associated with reduced insulin secretion and impaired glucose uptake; however, cell viability, ROS, apoptosis or proliferation were intact. A significant downregulation of crucial ß-cell function genes such as Ins1, Ins2, Pcsk1, Cpe, Pdx1, Mafa, Isl1, Glut2, Snap25, Vamp2, Syt5, Cacna1a, Cacna1d and Cacnb3, was observed upon Ppp1r1a disruption. Furthermore, silencing Pdx1 in INS-1 cells altered PPP1R1A expression, indicating that PPP1R1A is a target gene for PDX1. Treatment with rosiglitazone increased Ppp1r1a expression, while metformin and insulin showed no effect. RNA-seq analysis of human islets revealed high PPP1R1A expression, with α-cells showing the highest levels compared to other endocrine cells. Muscle tissues exhibited greater PPP1R1A expression than pancreatic islets, liver, or adipose tissues. Co-expression analysis revealed significant correlations between PPP1R1A and genes associated with insulin biosynthesis, exocytosis machinery, and intracellular calcium transport. Overexpression of PPP1R1A in human islets augmented insulin secretion and upregulated protein expression of Insulin, MAFA, PDX1, and GLUT1, while silencing of PPP1R1A reduced Insulin, MAFA, and GLUT1 protein levels. CONCLUSION: This study provides valuable insights into the role of PPP1R1A in regulating ß-cell function and glucose homeostasis. PPP1R1A presents a promising opportunity for future therapeutic interventions.

Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis.

Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key ß-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in ß-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons.

Hypoglycemia-associated autonomic failure (HAAF) is a well-established complication of diabetes. Although HAAF has serious outcomes such as recurrent morbidity, coma, and death, the mechanisms of HAAF and its pathological components are largely unknown. Our previous studies have revealed that hypoglycemia is associated with the upregulation of an immediate early gene - FOS. In addition, it is documented that glucose deprivation activates neuronal autophagic activities. Therefore, the present study aimed to identify the role of FOS and one of the core components of the autophagy pathway, Beclin-1 (encoded by the BECN1 gene), in the regulation of autophagic mechanisms in embryonic hypothalamic neurons in response to hypoglycemic conditions. Embryonic Mouse Hypothalamic Cell Line N39 (mHypoE-N39 or N39) was cultured in reduced concentrations of glucose (2000, 900, 500, and 200 mg/L). Gene and protein expression, as well as immunofluorescence studies on autophagy were conducted under different reduced glucose concentrations in N39 hypothalamic neurons with and without FOS and BECN1 gene knockdowns (KD). The outcomes of the present study have demonstrated a significant increase in autophagosome formation and subsequent lysosomal degradation in the hypothalamic neurons in response to reduced glucose concentrations. This hypoglycemic response appears to be lowered to a similar extent in the FOS KD and BECN1 KD cells, albeit insignificantly from the negative control, is indicative of the involvement of FOS in the autophagic response of hypothalamic neurons to hypoglycemia. Moreover, the KD cells exhibited a change in morphology and reduced cell viability compared with the control cells. Our findings suggest that reduced FOS expression could potentially be associated with impaired autophagic activities that are dependent on BECN1, which could lead to decreased or blunted hypothalamic activation in response to hypoglycemia, and this, in turn, may contribute to the development of HAAF.

Predictive factors of perinatal depression among women with gestational diabetes mellitus in the UAE: a cross-sectional clinical study.

BACKGROUND: Gestational Diabetes Mellitus (GDM) is responsible for the development of 30-50% of type 2 diabetes mellitus that predisposes later to adverse consequences among affected mothers and their offspring. Several studies have suggested that GDM increases the risk of developing perinatal depression (PND); however, factors that are involved in this association are yet to be determined. This study aims to identify factors that interrelate GDM and PND among pregnant and postnatal women in the United Arab Emirates (UAE). METHODS: A total of 186 women between 18 and 45 years old attending the obstetrics clinic during their 3rd trimester or up to 6 months postnatal were recruited between October 2021 and April 2022. Women who were known to have pre-existing diabetes mellitus (type 1 or type 2), kidney disease, liver disease, and those receiving hormonal therapy were excluded. Participants completed a structured questionnaire including sociodemographic data and the Edinburgh Postnatal Depression Scale (EPDS). Based on their EPDS scores, study participants were categorized into three groups: no depression (> 9), possible depression (9-11), and high possibility/strong positive depression (≥ 12). SPSS 26 was used for data analysis. RESULTS: Among the 186 participants, 81% (n = 151) were Emirati, 41% (n = 76) had no GDM, and 58% (n = 110) had GDM. Of the study participants, 34.4% had a high possibility of strong positive depression, 40.9% had possible depression, and only 6.5% had no depression. The association between GDM and PND was clinically and statistically insignificant, with a calculated odds ratio (OR) of 1.574 (p value = 0.204) and a 95% confidence interval (0.781-3.172). However, age, personal history of depression, and BMI were found to be strong predictors of depression among pregnant/postpartum women in the UAE. CONCLUSIONS: The study findings propose that age, personal history of depression, and obesity are strong predictors of depression during pregnancy. The strong correlation between obesity (which is a known strong predictor of GDM) and PND suggests that further studies with longitudinal designs and longer observational periods might better reveal the relationship between GDM and PND. TRIAL REGISTRATION: Retrospectively registered study by Research Ethics Committees of the University Hospital Sharjah and the University of Sharjah (Ref. No.: UHS-HERC- 025-17122019) December 17, 2019.

Cryopreservation and validation of differentiated PDGFRα-positive cells for long term usage in experimentation.

OBJECTIVE: Differentiation of immortalized Mesenchymal Stromal Cells (iMSCs) into PDGFRα-positive cells under controlled growth conditions has several vital implications in functional studies concerned with the pathogenesis of Diabetic Gastroparesis (DGP). A study published previously by our research group demonstrated the importance of these cells as a novel, in-vitro model for investigating the functional role of neuronal nitric oxide synthase. The currently available methods require fresh differentiation of PDGFRα-positive cells for each round of experimentation. This leads to longer delays, higher usage of reagents, and inconsistency in reproducibility of experiments frequently. We thus aimed to establish through validation that cryopreserving and maintaining the iMSC-derived PDGFRα-positive cells for functional investigations help us to overcome these challenges. RESULTS: We demonstrated for the first time that the differentiated PDGFRα-positive cells from iMSCs can be cryopreserved and thawed to be used as per the experimental requirements with prolonged preservation of their characteristics. We assessed the viability of differentiated PDGFRα-positive cells pre- and post-freezing with the subsequent validation of their functional features using flow cytometry, qRT-PCR, and western blotting. We have been successful in demonstrating for the first time that the cryopreservation of previously differentiated PDGFRα-positive cells can be used as a feasible and cost-effective model for experimental reproducibility in functional studies of Diabetes Gastroparesis.

Impact of COVID-19 Pandemic on Weight Change Among Adults in the UAE.

Background: The COVID-19 pandemic which started in November 2019 and since then has led to multiple lockdowns aimed towards controlling the pandemic, these lockdowns contributed to major changes in individuals' lifestyles including eating patterns and restriction of physical activity due to continues house confinement. Such changes have significantly contributed to weight change, with increasing rates of obesity in the UAE, COVID-19 have posed a major concern to the country's obesity levels. Aim: To measure the prevalence and investigate the views related to weight change among adults in the UAE during the COVID-19 pandemic. Methods: A cross-sectional study was conducted through a self-administered online questionnaire distributed using social media platforms between February 15th and March 14th, 2021. The sample size was 439 adults in the UAE (18-59 years), collected by volunteer sampling. Analysis was done using SPSS with a significance of 5.0%. Exclusion criteria included pregnancy and bariatric surgeries history. Results: 51.1% of participants gained weight, 36.2% lost weight and 12.7% maintained their weight. Meal consumption frequency and weight gain were correlated. Consuming fast food resulted in 65.7% of participants gaining weight. 66.2% of people who lost weight during the COVID-19 pandemic did exercise. Stress management and sleeping patterns were not contributing factors to the weight change. 64.4% of the participants who were not satisfied with their weight and believed that they need to make changes in their lifestyle received no guidance from professional personnel to reach their desired weight. Conclusion: In this study, the majority of participants have witnessed an increase in weight. UAE health authorities must provide guidance and support to the population via structured nutritional programs and lifestyle awareness campaigns.

The Role of Lifestyle Interventions in the Prevention and Treatment of Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy-related endocrinopathies, affecting up to 25% of pregnancies globally. GDM increases the risk of perinatal and delivery complications, and the chance of developing type 2 diabetes mellitus and its complications, including cardiovascular diseases. This elevated risk is then passed on to the next generation, creating a cycle of metabolic dysfunction across generations. For many years, GDM preventive measures have had inconsistent results, but recent systematic reviews and meta-analyses have identified promising new preventative routes. This review aims to summarize the evidence investigating the efficacy of lifestyle treatments for the prevention of GDM and to summarize the effects of two lifestyle interventions, including physical activity and dietary interventions. Based on the present research, future studies should be conducted to investigate whether initiating lifestyle interventions during the preconception period is more beneficial in preventing GDM. In addition, research targeting pregnancy should be designed with a personalized approach. Therefore, studies should customize intervention approaches depending on the presence of modifiable and non-modifiable risk factors at the individual level.

Investigating the Association between Diabetic Neuropathy and Vitamin D in Emirati Patients with Type 2 Diabetes Mellitus.

(1) Background: Vitamin D deficiency is a common public health problem in the United Arab Emirates (UAE) and globally, and interestingly, improvements in diabetic neuropathy after taking Vitamin D supplementation for a short time have been reported. Despite living in a country that is sunny all year round, hypovitaminosis D, indicated by an obvious low serum vitamin D level, has been recurrently noted in the UAE, as well as in the surrounding Arabian Gulf countries. This problem is receiving much attention and attracting clinical and academic interest. Therefore, the main objective of the present study is to identify the association, if any, between vitamin D deficiency and the development of diabetic neuropathy in the UAE population with T2DM. (2) Methods: a total of 600 Emirati patients (male and female) with T2DM, aged between 20 and 80, were recruited from University Hospital Sharjah (UHS). The medical records of the patients were reviewed and analyzed. (3) Results: The results of the present study showed that among the 600 patients, 50% were affected with diabetic neuropathy. Vitamin D level in patients with neuropathy were estimated to be around 20 ng/mL (IQR 14-25), and vitamin D levels were significantly higher (33 ng/mL (IQR 20-42)) among patients without neuropathy, with p < 0.001. Another important finding was that patients without neuropathy had a better vitamin D status, with only 19% being deficient and 18% having insufficient vitamin D levels, compared to patients with neuropathy, where 39% were deficient (vitamin D < 20 ng/mL) and 44% had insufficient vitamin D levels (20-30 ng/mL). (4) Conclusion: The findings of the present study show that the prevalence of vitamin D deficiency (low serum 25-hydroxy vitamin D 25-OHD level) is significantly high in diabetic neuropathy in Emirati patients with T2DM.

Effects of Varying Glucose Concentrations on ACE2's Hypothalamic Expression and Its Potential Relation to COVID-19-Associated Neurological Dysfunction.

The coronavirus disease 2019 (COVID-19) pandemic has negatively impacted millions of lives, despite several vaccine interventions and strict precautionary measures. The main causative organism of this disease is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which infects the host via two key players: the angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2). Some reports revealed that patients with glycemic dysregulation could have increased susceptibility to developing COVID-19 and its related neurological complications. However, no previous studies have looked at the involvement of these key molecules within the hypothalamus, which is the central regulator of glucose in the brain. By exposing embryonic mouse hypothalamic neurons to varying glucose concentrations, we aimed to investigate the expression of ACE2 and TMPRSS2 using quantitative real time polymerase chain reaction and western blotting. A significant and time-dependent increase and decrease was observed on the viability of hypothalamic neurons with increasing and decreasing glucose concentrations, respectively (p < 0.01 and p < 0.001, respectively). Under the same increasing and decreasing glucose conditions, the expression of hypothalamic ACE2 also revealed a significant and time-dependent increase (p < 0.01). These findings suggest that SARS-CoV-2 invades the hypothalamic circuitry. In addition, it highlights the importance of strict glycemic control for COVID-19 in diabetic patients.

Identification of novel differentially expressed genes in type 1 diabetes mellitus complications using transcriptomic profiling of UAE patients: a multicenter study.

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder that mainly affects children and young adults. It is associated with debilitating and long-life complications. Therefore, understanding the factors that lead to the onset and development of these complications is crucial. To our knowledge this is the first study that attempts to identify the common differentially expressed genes (DEGs) in T1DM complications using whole transcriptomic profiling in United Arab Emirates (UAE) patients. The present multicenter study was conducted in different hospitals in UAE including University Hospital Sharjah, Dubai Hospital and Rashid Hospital. A total of fifty-eight Emirati participants aged above 18 years and with a BMI < 25 kg/m2 were recruited and forty-five of these participants had a confirmed diagnosis of T1DM. Five groups of complications associated with the latter were identified including hyperlipidemia, neuropathy, ketoacidosis, hypothyroidism and polycystic ovary syndrome (PCOS). A comprehensive whole transcriptomic analysis using NGS was conducted. The outcomes of the study revealed the common DEGs between T1DM without complications and T1DM with different complications. The results revealed seven common candidate DEGs, SPINK9, TRDN, PVRL4, MYO3A, PDLIM1, KIAA1614 and GRP were upregulated in T1DM complications with significant increase in expression of SPINK9 (Fold change: 5.28, 3.79, 5.20, 3.79, 5.20) and MYO3A (Fold change: 4.14, 6.11, 2.60, 4.33, 4.49) in hyperlipidemia, neuropathy, ketoacidosis, hypothyroidism and PCOS, respectively. In addition, functional pathways of ion transport, mineral absorption and cytosolic calcium concentration were involved in regulation of candidate upregulated genes related to neuropathy, ketoacidosis and PCOS, respectively. The findings of this study represent a novel reference warranting further studies to shed light on the causative genetic factors that are involved in the onset and development of T1DM complications.

Neural control of pancreatic peptide hormone secretion.

Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.

Inflammatory Biomarkers Levels in T2DM Emirati Patients with Diabetic Neuropathy.

INTRODUCTION: Previous studies have suggested the involvement of chronic low-grade inflammation in the pathogenesis of diabetic neuropathy (DNP). However, none of these studies have examined the levels of monocyte chemoattractant protein-1 (MCP-1) in type 2 diabetes mellitus (T2DM) patients with confirmed diagnosis of neuropathy. Therefore, the present study aims to investigate the levels of MCP-1 along with IL-6, IL-8 and TGF-ß in patients with T2DM and confirmed neuropathy and identify correlations, if any, between MCP-1 and other parameters. METHODS: A single center cross-sectional clinical study was conducted at University Hospital Sharjah (UHS) and University of Sharjah. One hundred and two patients with T2DM were recruited from diabetes clinics at UHS and were stratified into different groups based on diagnosis of DNP and other parameters. Several analyses were conducted to evaluate and compare the levels of MCP-1, IL-6, IL-8, and TGF-ß across these groups of patients and identify correlations, if any, between MCP-1 and other variables. RESULTS: A significant increase was found in the levels of MCP-1 in T2DM patients with DNP compared to the patients without DNP (p=0.002, p-adj=0.007). Further analysis has shown that levels of IL-8 (p=0.008) and TGF-ß (p=0.06) were increased and decreased, respectively, in patients with DNP compared to patients without DNP. Moreover, strong correlations were found between MCP-1, IL-8 and TGF-ß levels. CONCLUSION: The key finding of the present study is the significant elevation in levels of MCP-1 in T2DM patients with DNP compared to the patients without DNP and IL-8 and TGF-ß were strong predictors of MCP-1 increased levels.

COVID-19 and Neurological Impairment: Hypothalamic Circuits and Beyond.

In December 2019, a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, the capital of Hubei, China. The virus infection, coronavirus disease 2019 (COVID-19), represents a global concern, as almost all countries around the world are affected. Clinical reports have confirmed several neurological manifestations in COVID-19 patients such as headaches, vomiting, and nausea, indicating the involvement of the central nervous system (CNS) and peripheral nervous system (PNS). Neuroinvasion of coronaviruses is not a new phenomenon, as it has been demonstrated by previous autopsies of severe acute respiratory syndrome coronavirus (SARS-CoV) patients who experienced similar neurologic symptoms. The hypothalamus is a complex structure that is composed of many nuclei and diverse neuronal cell groups. It is characterized by intricate intrahypothalamic circuits that orchestrate a finely tuned communication within the CNS and with the PNS. Hypothalamic circuits are critical for maintaining homeostatic challenges including immune responses to viral infections. The present article reviews the possible routes and mechanisms of neuroinvasion of SARS-CoV-2, with a specific focus on the role of the hypothalamic circuits in mediating the neurological symptoms noted during COVID-19 infection.

Differentiated PDGFRα-Positive Cells: A Novel In-Vitro Model for Functional Studies of Neuronal Nitric Oxide Synthase.

It is evident that depletion of interstitial cells and dysfunction of nitric oxide (NO) pathways are key players in development of several gastrointestinal (GI) motility disorders such as diabetic gastroparesis (DGP). One of the main limitations of DGP research is the lack of isolation methods that are specific to interstitial cells, and therefore conducting functional studies is not feasible. The present study aims (i) to differentiate telomerase transformed mesenchymal stromal cells (iMSCs) into platelet-derived growth factor receptor-α-positive cells (PDGFRα-positive cells) using connective tissue growth factor (CTGF) and L-ascorbic acids; (ii) to investigate the effects of NO donor and inhibitor on the survival rate of differentiated PDGFRα-positive cells; and (iii) to evaluate the impact of increased glucose concentrations, mimicking diabetic hyperglycemia, on the gene expression of neuronal nitric oxide synthase (nNOS). A fibroblastic differentiation-induction medium supplemented with connective tissue growth factor was used to differentiate iMSCs into PDGFRα-positive cells. The medium was changed every day for 21 days to maintain the biological activity of the growth factors. Gene and protein expression, scanning electron and confocal microscopy, and flow cytometry analysis of several markers were conducted to confirm the differentiation process. Methyl tetrazolium cell viability, nitrite measurement assays, and immunostaining were used to investigate the effects of NO on PDGFRα-positive cells. The present study, for the first time, demonstrated the differentiation of iMSCs into PDGFRα-positive cells. The outcomes of the functional studies showed that SNAP (NO donor) increased the survival rate of differentiated PDGFRα-positive cells whereas LNNA (NO inhibitor) attenuated these effects. Further experimentations revealed that hyperglycemia produced a significant increase in expression of nNOS in PDGFRα-positive cells. Differentiation of iMSCs into PDGFRα-positive cells is a novel model to conduct functional studies and to investigate the involvement of NO pathways. This will help in identifying new therapeutic targets for treatment of DGP.

Identification of Common Pathogenetic Processes between Schizophrenia and Diabetes Mellitus by Systems Biology Analysis.

Schizophrenia (SCZ) is a psychiatric disorder characterized by both positive symptoms (i.e., psychosis) and negative symptoms (such as apathy, anhedonia, and poverty of speech). Epidemiological data show a high likelihood of early onset of type 2 diabetes mellitus (T2DM) in SCZ patients. However, the molecular processes that could explain the epidemiological association between SCZ and T2DM have not yet been characterized. Therefore, in the present study, we aimed to identify underlying common molecular pathogenetic processes and pathways between SCZ and T2DM. To this aim, we analyzed peripheral blood mononuclear cell (PBMC) transcriptomic data from SCZ and T2DM patients, and we detected 28 differentially expressed genes (DEGs) commonly modulated between SCZ and T2DM. Inflammatory-associated processes and membrane trafficking pathways as common biological processes were found to be in common between SCZ and T2DM. Analysis of the putative transcription factors involved in the regulation of the DEGs revealed that STAT1 (Signal Transducer and Activator of Transcription 1), RELA (v-rel reticuloendotheliosis viral oncogene homolog A (avian)), NFKB1 (Nuclear Factor Kappa B Subunit 1), and ERG (ETS-related gene) are involved in the expression of common DEGs in SCZ and T2DM. In conclusion, we provide core molecular signatures and pathways that are shared between SCZ and T2DM, which may contribute to the epidemiological association between them.

Differential Expression of Inflammatory Markers in Hypoglycemia Unawareness Associated with Type 1 Diabetes: A Case Report.

The recurrence of hypoglycemic episodes leads to attenuation of the normal counter-regulatory mechanisms that are controlled by the hypothalamus, which results in hypoglycemia unawareness (HU). In this case report, we described for the first time the differential expression of TNF-α, IL-1ß, IL-6, and IFN-γ in a blood sample that was taken from a 27-year-old patient with type 1 diabetes mellitus (T1DM) who was diagnosed with HU. The anti-diabetic regimen is currently based on insulin injection, but the patient is planning to start the use of an insulin pump to have better control of glucose levels. Our results showed a trend toward an increase in the expression of IL-1ß, IL-6, and IFN-γ in T1DM patient with HU. However, the mRNA level of TNF-α showed a significant decrease. These observations suggest that systemic inflammation could be an underlying cause of HU.

Identification of Novel Hypothalamic MicroRNAs as Promising Therapeutics for SARS-CoV-2 by Regulating ACE2 and TMPRSS2 Expression: An In Silico Analysis.

BACKGROUND: Neuroinvasion of severe acute respiratory syndrome coronavirus (SARS-CoV) is well documented and, given the similarities between this virus and SARS-CoV-2, it seems that the neurological impairment that is associated with coronavirus disease 2019 (COVID-19) is due to SARS-CoV-2 neuroinvasion. Hypothalamic circuits are exposed to the entry of the virus via the olfactory bulb and interact centrally with crucial respiratory nuclei. Hypothalamic microRNAs are considered as potential biomarkers and modulators for various diseases and future therapeutic targets. The present study aims to investigate the microRNAs that regulate the expression of hypothalamic angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential elements for SARS-CoV-2 cell entry. METHODS: To determine potential hypothalamic miRNAs that can directly bind to ACE2 and TMPRSS2, multiple target bioinformatics prediction algorithms were used, including miRBase, Target scan, and miRWalk2.029. RESULTS: Our in silico analysis has revealed that, although there are over 5000 hypothalamic miRNAs, around 31 miRNAs and 29 miRNAs have shown binding sites and strong binding capacity against ACE2 and TMPRSS2, respectively. CONCLUSION: These novel potential hypothalamic miRNAs can be used to identify new therapeutic targets to treat neurological symptoms in COVID-19 patients via regulation of ACE2 and TMPRSS2 expression.

Nitric oxide interacts with cholinoceptors to modulate insulin secretion by pancreatic ß cells.

Dysfunction of the pancreatic ß cells leads to several chronic disorders including diabetes mellitus. Several mediators and mechanisms are known to be involved in the regulation of ß cell secretory function. In this study, we propose that cytokine-induced nitric oxide (NO) production interacts with cholinergic mechanisms to modulate insulin secretion from pancreatic ß cells. Using a rat insulinoma cell line INS-1, we demonstrated that ß cell viability decreases significantly in the presence of SNAP (NO donor) in a concentration- and time-dependent manner. Cell viability was also found to be decreased in the presence of a combined treatment of SNAP with SMN (muscarinic receptor antagonist). We then investigated the impact of these findings on insulin secretion and found a significant reduction in glucose uptake by INS-1 cells in the presence of SNAP and SMN as compared with control. Nitric oxide synthase 3 gene expression was found to be significantly reduced in response to combined treatment with SNAP and SMN suggesting an interaction between the cholinergic and nitrergic systems. The analysis of gene and protein expression further pin-pointed the involvement of M3 muscarinic receptors in the cholinergic pathway. Upon treatment with cytokines, reduced cell viability was observed in the presence of TNF-α and IFN-γ. A significant reduction in insulin secretion was also noted after treatment with TNF-α and IFN-γ and IL1-ß. The findings of the present study have shown for the first time that the inhibition of the excitatory effects of cholinergic pathways on glucose-induced insulin secretion may cause ß cell injury and dysfunction of insulin secretion in response to cytokine-induced NO production.

Growth of Diabetes Research in United Arab Emirates: Current and Future Perspectives.

BACKGROUND: Diabetes mellitus (DM) is one of the most prevalent metabolic diseases in the UAE. During the last two decades, the United Arab Emirates (UAE) has experienced tremendous development in all fields including DM research. The present study sheds light on the growth in DM research in UAE and represents a guide for DM researchers to create more focused future directions in DM research. OBJECTIVES: The main objective of the present study is to investigate and document the changes that occurred in DM research in the UAE over the last two decades. METHODS: Several research databases were reviewed and all the articles that involved any form of DM research within the UAE were selected. Inclusion criteria were: (i) Research studies related to DM and conducted by institutions based in UAE (ii) Research studies related to DM and conducted in the population of UAE and (iii) Research articles related to DM and the authors (principal investigators or co-investigators) are from UAE. RESULTS: Between the years of 1996 and 2000, there was an average of 6.4 articles about DM being published per year. This pattern changed dramatically between years 2011 to 2015 where an average of 22.8 articles were being published. In addition, a significant increase was noticed in the year 2015 with 42 articles published per year. It was also found that 46.8% articles involved clinical study, 12.1% were basic research, 17.5% cross-sectional studies, 8.91% reviews, 8.2% were cohort and all the other types of research represented about 5.58%. CONCLUSION: Significant progress has been noticed in DM research in the UAE during the last two decades. Based on the findings of the present study, more focus should be given to the case reports and clinical trials.

Potential role of hypothalamic microRNAs in regulation of FOS and FTO expression in response to hypoglycemia.

Hypoglycemia-associated autonomic failure (HAAF) is a serious complication of diabetes which is associated with the absence of physiological homeostatic counter-regulatory mechanisms that are controlled by the hypothalamus and sympathetic nervous system. Identification of biomarkers for early detection of HAAF requires an advanced understanding of molecular signature of hypoglycemia which is yet to be identified. The outcomes of the present study have shown that the viability and the apoptotic rate of the hypothalamic neurons (mHypoE-N39) were decreased significantly due to hypoglycemia in a dose-dependent fashion (p < 0.05). Although there are more than 1000 miRNAs differentially expressed in hypothalamus, only twelve miRNAs (miR-7a, miR-7b, miR-9, miR-29b, miR-29c, miR-30a, miR-30b, miR-30c, miR-101b-3p, miR-181a-5p, miR-378-3p and miR-873-5p) were correlated to two main hypothalamic regulatory proteins, FOS and FTO. Expression of these proteins was very sensitive to hypoglycemia. We demonstrated that hypoglycemia modulates the expression of hypothalamic miRNAs that are related to FOS and FTO.