|
1
|
Obradovic M, Zafirovic S, Gluvic Z, Radovanovic J, Isenovic ER. Autophagy and diabetes. EXPLORATION OF MEDICINE 2023:576-588. [DOI: 10.37349/emed.2023.00162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 05/29/2023] [Indexed: 10/13/2023] [Imported: 10/13/2023] Open
Abstract
The current literature findings on autophagy’s beneficial and detrimental roles in diabetes mellitus (DM) and diabetes-related comorbidities were reviewed. The effects of oral hypoglycaemic medicines and autophagy in DM. Autophagy plays an important function in cellular homeostasis by promoting cell survival or initiating cell death in physiological settings was also assessed. Although autophagy protects insulin-target tissues, organelle failure caused by autophagy malfunction influences DM and other metabolic diseases. Endoplasmic reticulum and oxidative stress enhance autophagy levels, making it easier to regulate stress-induced intracellular changes. Evidence suggests that autophagy-caused cell death can occur when autophagy is overstimulated and constitutively activated, which might prevent or develop DM. Even though the precise role of autophagy in DM complications is uncertain, deregulation of the autophagic machinery is strongly linked to beta cell destruction and the aetiology of DM. Thus, improving autophagy dysfunction is a possible therapeutic objective in treating DM and other metabolic disorders.
Collapse
|
|
2
|
Macvanin MT, Gluvic ZM, Zaric BL, Essack M, Gao X, Isenovic ER. New biomarkers: prospect for diagnosis and monitoring of thyroid disease. Front Endocrinol (Lausanne) 2023; 14:1218320. [PMID: 37547301 PMCID: PMC10401601 DOI: 10.3389/fendo.2023.1218320] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] [Imported: 10/13/2023] Open
Abstract
After the metabolic syndrome and its components, thyroid disorders represent the most common endocrine disorders, with increasing prevalence in the last two decades. Thyroid dysfunctions are distinguished by hyperthyroidism, hypothyroidism, or inflammation (thyroiditis) of the thyroid gland, in addition to the presence of thyroid nodules that can be benign or malignant. Thyroid cancer is typically detected via an ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) and cytological examination of the specimen. This approach has significant limitations due to the small sample size and inability to characterize follicular lesions adequately. Due to the rapid advancement of high-throughput molecular biology techniques, it is now possible to identify new biomarkers for thyroid neoplasms that can supplement traditional imaging modalities in postoperative surveillance and aid in the preoperative cytology examination of indeterminate or follicular lesions. Here, we review current knowledge regarding biomarkers that have been reliable in detecting thyroid neoplasms, making them valuable tools for assessing the efficacy of surgical procedures or adjunctive treatment after surgery. We are particularly interested in providing an up-to-date and systematic review of emerging biomarkers, such as mRNA and non-coding RNAs, that can potentially detect thyroid neoplasms in clinical settings. We discuss evidence for miRNA, lncRNA and circRNA dysregulation in several thyroid neoplasms and assess their potential for use as diagnostic and prognostic biomarkers.
Collapse
|
|
3
|
Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/23/2023] [Indexed: 07/12/2023] [Imported: 10/13/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17–25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
Collapse
|
|
4
|
Lackovic MM, Macvanin MT, Obradovic MM, Gluvic ZM, Sudar-Milovanovic EM, Sipetic Grujicic SB, Isenovic ER. Impact of treatment modalities on quality of life and depression in type 2 diabetes. EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES 2023; 27:4980-4989. [PMID: 37318472 DOI: 10.26355/eurrev_202306_32615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/16/2023] [Imported: 10/13/2023]
Abstract
OBJECTIVE Type 2 diabetes mellitus (T2DM) is a chronic disease with numerous complications that increase mortality and reduce the quality of life (QoL). The current study compares QoL in T2DM patients treated with insulin to those treated with oral antihyperglycemics (OAHs), as well as the frequency and severity of depression in patients. SUBJECTS AND METHODS This prospective cross-sectional study included 200 patients with insulin or OAHs. Triglycerides, total cholesterol, low-density lipoprotein, and high-density lipoprotein cholesterol levels were measured. The Beck Depression Inventory and the SF-36 Quality of Life Questionnaire were used to assess depression symptoms and QoL in response to different treatment modalities. RESULTS Insulin-treated patients have a longer duration of illness, higher preprandial glycemic levels, lower scores in three of four dimensions of the SF-36 physical component, and a lower score in the SF-36 psychological component's emotional role dimension. Patients on insulin have milder depression symptoms than those with OAHs. Depression symptoms, according to the findings, worsen QoL and glycemic control in insulin-treated patients. CONCLUSIONS According to these findings, any treatment modality's success in T2DM patients primarily depends on psychological support and preventive measures that promote and maintain mental health.
Collapse
|
|
5
|
Macvanin MT, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs. Front Endocrinol (Lausanne) 2023; 14:1124613. [PMID: 36950696 PMCID: PMC10025540 DOI: 10.3389/fendo.2023.1124613] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/16/2023] [Indexed: 03/08/2023] [Imported: 10/13/2023] Open
Abstract
Diabetes mellitus (DM) is on the rise, necessitating the development of novel therapeutic and preventive strategies to mitigate the disease's debilitating effects. Diabetic cardiomyopathy (DCMP) is among the leading causes of morbidity and mortality in diabetic patients globally. DCMP manifests as cardiomyocyte hypertrophy, apoptosis, and myocardial interstitial fibrosis before progressing to heart failure. Evidence suggests that non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), regulate diabetic cardiomyopathy-related processes such as insulin resistance, cardiomyocyte apoptosis and inflammation, emphasizing their heart-protective effects. This paper reviewed the literature data from animal and human studies on the non-trivial roles of miRNAs and lncRNAs in the context of DCMP in diabetes and demonstrated their future potential in DCMP treatment in diabetic patients.
Collapse
|
|
6
|
Macvanin MT, Gluvic Z, Zafirovic S, Gao X, Essack M, Isenovic ER. The protective role of nutritional antioxidants against oxidative stress in thyroid disorders. Front Endocrinol (Lausanne) 2023; 13:1092837. [PMID: 36686463 PMCID: PMC9846570 DOI: 10.3389/fendo.2022.1092837] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] [Imported: 10/13/2023] Open
Abstract
An imbalance between pro-oxidative and antioxidative cellular mechanisms is oxidative stress (OxS) which may be systemic or organ-specific. Although OxS is a consequence of normal body and organ physiology, severely impaired oxidative homeostasis results in DNA hydroxylation, protein denaturation, lipid peroxidation, and apoptosis, ultimately compromising cells' function and viability. The thyroid gland is an organ that exhibits both oxidative and antioxidative processes. In terms of OxS severity, the thyroid gland's response could be physiological (i.e. hormone production and secretion) or pathological (i.e. development of diseases, such as goitre, thyroid cancer, or thyroiditis). Protective nutritional antioxidants may benefit defensive antioxidative systems in resolving pro-oxidative dominance and redox imbalance, preventing or delaying chronic thyroid diseases. This review provides information on nutritional antioxidants and their protective roles against impaired redox homeostasis in various thyroid pathologies. We also review novel findings related to the connection between the thyroid gland and gut microbiome and analyze the effects of probiotics with antioxidant properties on thyroid diseases.
Collapse
|
|
7
|
Obradovic M, Sudar-Milovanovic E, Gluvic Z, Banjac K, Rizzo M, Isenovic ER. The Na +/K +-ATPase: A potential therapeutic target in cardiometabolic diseases. Front Endocrinol (Lausanne) 2023; 14:1150171. [PMID: 36926029 PMCID: PMC10011626 DOI: 10.3389/fendo.2023.1150171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 02/14/2023] [Indexed: 03/08/2023] [Imported: 10/13/2023] Open
Abstract
Cardiometabolic diseases (CMD) are a direct consequence of modern living and contribute to the development of multisystem diseases such as cardiovascular diseases and diabetes mellitus (DM). CMD has reached epidemic proportions worldwide. A sodium pump (Na+/K+-ATPase) is found in most eukaryotic cells' membrane and controls many essential cellular functions directly or indirectly. This ion transporter and its isoforms are important in the pathogenesis of some pathological processes, including CMD. The structure and function of Na+/K+-ATPase, its expression and distribution in tissues, and its interactions with known ligands such as cardiotonic steroids and other suspected endogenous regulators are discussed in this review. In addition, we reviewed recent literature data related to the involvement of Na+/K+-ATPase activity dysfunction in CMD, focusing on the Na+/K+-ATPase as a potential therapeutic target in CMD.
Collapse
|
|
8
|
Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 2023; 14:1142644. [PMID: 36843588 PMCID: PMC9947133 DOI: 10.3389/fendo.2023.1142644] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] [Imported: 10/13/2023] Open
Abstract
INTRODUCTION Cardiovascular (CV) disorders are steadily increasing, making them the world's most prevalent health issue. New research highlights the importance of insulin-like growth factor 1 (IGF-1) for maintaining CV health. METHODS We searched PubMed and MEDLINE for English and non-English articles with English abstracts published between 1957 (when the first report on IGF-1 identification was published) and 2022. The top search terms were: IGF-1, cardiovascular disease, IGF-1 receptors, IGF-1 and microRNAs, therapeutic interventions with IGF-1, IGF-1 and diabetes, IGF-1 and cardiovascular disease. The search retrieved original peer-reviewed articles, which were further analyzed, focusing on the role of IGF-1 in pathophysiological conditions. We specifically focused on including the most recent findings published in the past five years. RESULTS IGF-1, an anabolic growth factor, regulates cell division, proliferation, and survival. In addition to its well-known growth-promoting and metabolic effects, there is mounting evidence that IGF-1 plays a specialized role in the complex activities that underpin CV function. IGF-1 promotes cardiac development and improves cardiac output, stroke volume, contractility, and ejection fraction. Furthermore, IGF-1 mediates many growth hormones (GH) actions. IGF-1 stimulates contractility and tissue remodeling in humans to improve heart function after myocardial infarction. IGF-1 also improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. These findings point to the intriguing medicinal potential of IGF-1. Human studies associate low serum levels of free or total IGF-1 with an increased risk of CV and cerebrovascular illness. Extensive human trials are being conducted to investigate the therapeutic efficacy and outcomes of IGF-1-related therapy. DISCUSSION We anticipate the development of novel IGF-1-related therapy with minimal side effects. This review discusses recent findings on the role of IGF-1 in the cardiovascular (CVD) system, including both normal and pathological conditions. We also discuss progress in therapeutic interventions aimed at targeting the IGF axis and provide insights into the epigenetic regulation of IGF-1 mediated by microRNAs.
Collapse
|
|
9
|
Mitrovic B, Gluvic Z, Klisic A, Obradovic M, Macut D, Tomasevic R, Isenovic E. A non-invasive method for estimating the severity of liver steatosis and the risk of fibrosis in non-obese type 2 diabetes patients with NAFLD. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2022; 18:480-487. [PMID: 37152882 PMCID: PMC10162827 DOI: 10.4183/aeb.2022.480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] [Imported: 10/13/2023]
Abstract
Context Prognostic considerations include assessing the risk of liver fibrosis in people with non-alcoholic fatty liver disease (NAFLD). Objectives This study evaluates the use of hematologic and metabolic parameters regarding liver steatosis and fibrosis scores (FLI and Fib-4) in non-obese type 2 diabetes mellitus (t2DM) patients with NAFLD. Methods Subjects underwent abdominal ultrasound examinations, and FLI and Fib-4 scores were calculated to evaluate liver steatosis and the risk of liver fibrosis non-invasively: 61 non-obese NAFLD subjects with t2DM were included in the cohort study and were divided into 2 groups depending on the t2DM treatment regimen. Results Fib-4 and WBC count demonstrated a significant inverse correlation (OR = 0.509, p = 0.007). WBC count had an R2 of 0.237, indicating that this marker could account for up to 23.7% of a variation in Fib-4. Fib-4 and FFA had positive correlation which did not achieve statistically significant prediction (OR=7.122, p=0.062). Additionally, a significant prediction of HbA1c (OR=1.536, p=0.016) and haemoglobin (OR=1.071, p=0.020) for FLI was revealed. Conclusion HbA1c and other haematological and metabolic parameters, such as haemoglobin and WBC, may be another non-invasive tool for determining whether non-obese NAFLD patients with t2DM are at risk of developing liver steatosis and fibrosis.
Collapse
|
|
10
|
Gluvic ZM, Zafirovic SS, Obradovic MM, Sudar-Milovanovic EM, Rizzo M, Isenovic ER. Hypothyroidism and Risk of Cardiovascular Disease. Curr Pharm Des 2022; 28:2065-2072. [PMID: 35726428 DOI: 10.2174/1381612828666220620160516] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/12/2022] [Indexed: 11/22/2022] [Imported: 10/13/2023]
Abstract
Thyroid hormones (TH) have a significant impact on cellular oxidative metabolism. Besides that, they maintain vascular homeostasis by positive effects on endothelial and vascular smooth muscle cells. Subclinical (SCH) and clinical (CH) hypothyroidism influences target organs by changing their morphology and function and impaired blood and oxygen supply induced by accelerated atherosclerosis. The increased risk of acceleration and extension of atherosclerosis in patients with SCH and CH could be explained by dyslipidemia, diastolic hypertension, increased arterial stiffness, endothelial dysfunction, and altered blood coagulation. Instability of atherosclerotic plaque in hypothyroidism could cause excessive activity of the elements of innate immunity, which are characterized by: the significant presence of macrophages in atherosclerotic plaques, increased nuclear factor kappa B (NFkB) expression, and elevated levels of tumor necrosis factor α (TNF-α) and matrix metalloproteinase (MMP) 9, with reduced interstitial collagen, which all together creates inflammation milieu resulted in plaque rupture. Optimal substitution by levothyroxine (LT4) restores biochemical euthyroidism. In postmenopausal women and elderly patients with hypothyroidism and associated vascular comorbidity, excessive LT4 substitution could lead to atrial rhythm disorders and osteoporosis. Therefore, it is of interest to maintain thyroid-stimulating hormone (TSH) levels in the reference range, thus eliminating the deleterious effects of lower or higher TSH levels on the cardiovascular system. This review summarizes the recent literature on subclinical and clinical hypothyroidism and atherosclerotic cardiovascular disease and discusses the effects of LT4 replacement therapy on restoring biochemical euthyroidism and atherosclerosis processes.
Collapse
|
|
11
|
Mitrovic B, Gluvic ZM, Obradovic M, Radunovic M, Rizzo M, Banach M, Isenovic ER. Non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes mellitus: where do we stand today? Arch Med Sci 2022; 19:884-894. [PMID: 37560721 PMCID: PMC10408022 DOI: 10.5114/aoms/150639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 06/02/2022] [Indexed: 08/11/2023] [Imported: 10/13/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), metabolic syndrome (MetS), and type 2 diabetes (T2DM) are metabolic disorders that belong to a highly prevalent disease cluster with a significant impact on public health worldwide. MetS is a complex condition characterized by metabolism perturbations that include glucose intolerance, insulin resistance, dyslipidaemia, associated pro-inflammatory state, and arterial hypertension. Because the components of MetS commonly co-occur, the management of these disorders cannot be considered separate issues. Thus NAFLD, recognized as a hepatic manifestation of MetS, is frequently associated with T2DM. This review analyses the underlying connections between these diseases and the risks associated with their co-occurrence. The effective management of NAFLD associated with MetS and T2DM involves an early diagnosis and optimal treatment of each condition leading to improvement in glycaemic and lipid regulation, liver steatosis, and arterial hypertension. The net effect of such treatment is the prevention of atherosclerotic cardiovascular diseases and liver fibrosis.
Collapse
|
|
12
|
Role of C-Reactive Protein in Diabetic Inflammation. Mediators Inflamm 2022; 2022:3706508. [PMID: 35620114 PMCID: PMC9129992 DOI: 10.1155/2022/3706508] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/20/2022] [Accepted: 04/29/2022] [Indexed: 01/08/2023] [Imported: 10/13/2023] Open
Abstract
Even though type 2 diabetes mellitus (T2DM) represents a worldwide chronic health issue that affects about 462 million people, specific underlying determinants of insulin resistance (IR) and impaired insulin secretion are still unknown. There is growing evidence that chronic subclinical inflammation is a triggering factor in the origin of T2DM. Increased C-reactive protein (CRP) levels have been linked to excess body weight since adipocytes produce tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are pivotal factors for CRP stimulation. Furthermore, it is known that hepatocytes produce relatively low rates of CRP in physiological conditions compared to T2DM patients, in which elevated levels of inflammatory markers are reported, including CRP. CRP also participates in endothelial dysfunction, the production of vasodilators, and vascular remodeling, and increased CRP level is closely associated with vascular system pathology and metabolic syndrome. In addition, insulin-based therapies may alter CRP levels in T2DM. Therefore, determining and clarifying the underlying CRP mechanism of T2DM is imperative for novel preventive and diagnostic procedures. Overall, CRP is one of the possible targets for T2DM progression and understanding the connection between insulin and inflammation may be helpful in clinical treatment and prevention approaches.
Collapse
|
|
13
|
Tomasević R, Gluvić Z, Mijač D, Sokić-Milutinović A, Lukić S, Milosavljević T. Anemia as a Problem: GEH Approach. Dig Dis 2022; 40:133-141. [PMID: 33866318 DOI: 10.1159/000516480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 04/12/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. SUMMARY Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist's perspective, the clinical spectrum of anemia is vast because many different digestive tract diseases lead to bleeding. Key Messages: The gastroenterological approach in solving anemia's problem requires an optimal strategy, consideration of the accompanying clinical signs, and the fastest possible diagnosis. Although patients with symptoms of anemia are often referred to gastroenterologists, the diagnostic approach requires further improvement in everyday clinical practice.
Collapse
|
|
14
|
Popovic B, Radovanovic Spurnic A, Velickovic J, Plavsic A, Jecmenica-Lukic M, Glisic T, Ilic D, Jeremic D, Vratonjic J, Samardzic V, Gluvic Z, Adzic-Vukicevic T. Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing's Syndrome: A Case Report and Review of Literature. Front Endocrinol (Lausanne) 2022; 13:889928. [PMID: 35813652 PMCID: PMC9257249 DOI: 10.3389/fendo.2022.889928] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022] [Imported: 10/13/2023] Open
Abstract
INTRODUCTION Patients with Cushing's syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging. CASE REPORT A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient's condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient's condition quickly stabilized with no direct side effects of a given treatment. CONCLUSION Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.
Collapse
|
|
15
|
Mitrovic B, Gluvic Z, Macut D, Obradovic M, Sudar-Milovanovic E, Soskic S, Stajic D, Isenovic ER. Effects of Metformin-Single Therapy on the Level of Inflammatory Markers in Serum of Non-Obese T2DM Patients with NAFLD. Endocr Metab Immune Disord Drug Targets 2022; 22:117-124. [PMID: 33632113 DOI: 10.2174/1871530321666210225110140] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/21/2021] [Accepted: 02/01/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. METHODS All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests), serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide) and FLI/- FIB-4 were calculated. RESULTS FLI score and ultrasound NAFLD grades were found to correlate (p<0.05). We observed a significant correlation between the levels of ferritin and C-reactive protein (CRP) (p<0.05), and the FLI (p<0.05). Body weight (BW) (p<0.05), waist circumference (WC) (p<0.05), the levels of HbA1c (p<0.05), transferrin (p<0.05), insulin (p<0.05), and FLI score (p<0.05) significantly differed between groups as defined by the severity of NAFLD. CONCLUSION This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.
Collapse
|
|
16
|
Sudar-Milovanovic E, Gluvic Z, Obradovic M, Zaric B, Isenovic ER. Tryptophan Metabolism in Atherosclerosis and Diabetes. Curr Med Chem 2022; 29:99-113. [PMID: 34269660 DOI: 10.2174/0929867328666210714153649] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/07/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023]
Abstract
The essential amino acid tryptophan (Trp) undergoes catabolism through several pathways, producing biologically active metabolites that significantly impact physiological processes. The metabolic pathway responsible for the majority of Trp catabolism is the kynurenine synthesis pathway (KP). Serotonin and melatonin are among the most essential Trp pathways degradation products. It has emerged that a strong relationship exists between alterations in Trp metabolism and the onset and progression of atherosclerosis and diabetes. Atherosclerosis is a chronic inflammatory disease of the small and medium arteries wall caused by maladaptive local immune responses, which underpins several cardiovascular diseases (CVD). Systemic low-grade immune-mediated inflammation is implicated in atherosclerosis where pro-inflammatory cytokines, such as interferon-γ (IFN-γ), play a significant role. IFN-γ upregulates the enzyme indoleamine 2,3-dioxygenase (IDO), decreasing serum levels of the Trp and increasing metabolite levels of kynurenine. Increased IDO expression and activity could accelerate the atherosclerosis process. Therefore, activated IDO inhibition could offer possible treatment options regarding atherosclerosis management. Diabetes is a chronic metabolic disease characterized by hyperglycemia that, over time, leads to severe damage to the heart, blood vessels, eyes, kidneys, and peripheral nerves. Trp serum levels and lower activity of IDO were higher in future type 2 diabetes (T2DM) patients. This article reviews recent findings on the link between mammalian Trp metabolism and its role in atherosclerosis and diabetes and outlines the intervention strategies.
Collapse
|
|
17
|
Gluvic Z, Tomasevic R, Bojovic K, Obradovic M, Isenovic ER. Non-alcoholic fatty liver disease: a multidisciplinary clinical practice approach—the institutional adaptation to existing Clinical Practice Guidelines. EMERGENCY AND CRITICAL CARE MEDICINE 2021; 2:12-22. [DOI: 10.1097/ec9.0000000000000016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] [Imported: 10/13/2023]
Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most frequently encountered chronic liver diseases in everyday clinical practice. It is considered the hepatic manifestation of metabolic syndrome. Today, liver biopsy is still the gold standard for NAFLD confirmation and assessing NAFLD's possible progression to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Because of the high prevalence of NAFLD and potential associated risks of invasive diagnostic procedures, it is of great interest to recruit the patients for liver biopsy. However, as the presence of liver fibrosis determines the further clinical course, liver biopsy is expectedly reserved for those with increased fibrosis risk. The quality of liver biopsy recruitment and patient monitoring could be significantly improved by using non-invasive tools to assess liver fibrosis presence and interactive collaboration between general practitioners, gastroenterologists, and endocrinologists. As a result, the quality of liver biopsy recruitment and patients monitoring could be significantly improved. Here, we proposed clinical practice guidelines that could be implemented for everyday clinical practice in NAFLD patients.
Collapse
|
|
18
|
Gluvic Z, Obradovic M, Stewart AJ, Essack M, Pitt SJ, Samardzic V, Soskic S, Gojobori T, Isenovic ER. Levothyroxine Treatment and the Risk of Cardiac Arrhythmias - Focus on the Patient Submitted to Thyroid Surgery. Front Endocrinol (Lausanne) 2021; 12:758043. [PMID: 34803920 PMCID: PMC8600254 DOI: 10.3389/fendo.2021.758043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/11/2021] [Indexed: 02/05/2023] Open
Abstract
Levothyroxine (LT4) is used to treat frequently encountered endocrinopathies such as thyroid diseases. It is regularly used in clinical (overt) hypothyroidism cases and subclinical (latent) hypothyroidism cases in the last decade. Suppressive LT4 therapy is also part of the medical regimen used to manage thyroid malignancies after a thyroidectomy. LT4 treatment possesses dual effects: substituting new-onset thyroid hormone deficiency and suppressing the local and distant malignancy spreading in cancer. It is the practice to administer LT4 in less-than-high suppressive doses for growth control of thyroid nodules and goiter, even in patients with preserved thyroid function. Despite its approved safety for clinical use, LT4 can sometimes induce side-effects, more often recorded with patients under treatment with LT4 suppressive doses than in unintentionally LT4-overdosed patients. Cardiac arrhythmias and the deterioration of osteoporosis are the most frequently documented side-effects of LT4 therapy. It also lowers the threshold for the onset or aggravation of cardiac arrhythmias for patients with pre-existing heart diseases. To improve the quality of life in LT4-substituted patients, clinicians often prescribe higher doses of LT4 to reach low normal TSH levels to achieve cellular euthyroidism. In such circumstances, the risk of cardiac arrhythmias, particularly atrial fibrillation, increases, and the combined use of LT4 and triiodothyronine further complicates such risk. This review summarizes the relevant available data related to LT4 suppressive treatment and the associated risk of cardiac arrhythmia.
Collapse
|
|
19
|
Samardzic V, Banjac K, Obradovic M, Gluvic Z, R Isenovic E. Could the level of nitrite/nitrate contribute to malignant thyroid nodule diagnostics? Med Hypotheses 2021; 150:110569. [PMID: 33799155 DOI: 10.1016/j.mehy.2021.110569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/17/2021] [Accepted: 03/09/2021] [Indexed: 02/05/2023]
Abstract
Thyroid nodules are among highly prevalent thyroid diseases. To make a distinction between benign and malignant thyroid nodules are of cumbersome significance for each endocrinologist. There is no unique and completely accurate diagnostic test, method, or even biomarker that points to a malignant thyroid nodule. Many studies in modern thyroidology are conducted to determine the usefulness of individual biomarkers, which could help clinicians detect thyroid nodules' potential malignant nature. One interesting biomarker with a promising diagnostic potential for the thyroid gland pathological conditions is nitric oxide (NO). Inducible nitric oxide synthase expression is increased in thyroiditis cases and even more in thyroid carcinoma cases, directly connected with increased NO levels in both pathological conditions. We hypothesize that the basal levels of nitrite/nitrate in serum and biopsy washout could indicate nodules' malignant nature.
Collapse
|
|
20
|
Resanović I, Zarić B, Radovanović J, Sudar-Milovanović E, Gluvić Z, Jevremović D, Isenović ER. Hyperbaric Oxygen Therapy and Vascular Complications in Diabetes Mellitus. Angiology 2020; 71:876-885. [PMID: 32638622 DOI: 10.1177/0003319720936925] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Vascular complications in patients with diabetes mellitus (DM) are common. Since impaired oxygen balance in plasma plays an important role in the pathogenesis of chronic DM-associated complications, the administration of hyperbaric oxygen therapy (HBOT) has been recommended to influence development of vascular complications. Hyperbaric oxygen therapy involves inhalation of 100% oxygen under elevated pressure from 1.6 to 2.8 absolute atmospheres in hyperbaric chambers. Hyperbaric oxygen therapy increases plasma oxygen solubility, contributing to better oxygen diffusion to distant tissues and preservation of the viability of tissues reversibly damaged by atherosclerosis-induced ischemia, along with microcirculation restoration. Hyperbaric oxygen therapy exerts antiatherogenic, antioxidant, and cardioprotective effects by altering the level and composition of plasma fatty acids and also by promoting signal transduction through membranes, which are impaired by hyperglycemia and hypoxia. In addition, HBOT affects molecules involved in the regulation of nitric oxide synthesis and in that way exerts anti-inflammatory and angiogenic effects in patients with DM. In this review, we explore the recent literature related to the effects of HBOT on DM-related vascular complications.
Collapse
|
|
21
|
Zaric BL, Radovanovic JN, Gluvic Z, Stewart AJ, Essack M, Motwalli O, Gojobori T, Isenovic ER. Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes. Front Immunol 2020; 11:551758. [PMID: 33117340 PMCID: PMC7549398 DOI: 10.3389/fimmu.2020.551758] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.
Collapse
|
|
22
|
Gluvic ZM, Obradovic MM, Sudar-Milovanovic EM, Zafirovic SS, Radak DJ, Essack MM, Bajic VB, Takashi G, Isenovic ER. Regulation of nitric oxide production in hypothyroidism. Biomed Pharmacother 2020; 124:109881. [PMID: 31986413 DOI: 10.1016/j.biopha.2020.109881] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/25/2019] [Accepted: 01/06/2020] [Indexed: 02/08/2023] Open
Abstract
Hypothyroidism is a common endocrine disorder that predominantly occurs in females. It is associated with an increased risk of cardiovascular diseases (CVD), but the molecular mechanism is not known. Disturbance in lipid metabolism, the regulation of oxidative stress, and inflammation characterize the progression of subclinical hypothyroidism. The initiation and progression of endothelial dysfunction also exhibit these changes, which is the initial step in developing CVD. Animal and human studies highlight the critical role of nitric oxide (NO) as a reliable biomarker for cardiovascular risk in subclinical and clinical hypothyroidism. In this review, we summarize the recent literature findings associated with NO production by the thyroid hormones in both physiological and pathophysiological conditions. We also discuss the levothyroxine treatment effect on serum NO levels in hypothyroid patients.
Collapse
|
|
23
|
Gluvic Z, Obradovic M, Lackovic M, Samardzic V, Tica Jevtic J, Essack M, Bajic VB, Isenovic ER. HbA1C as a marker of retrograde glycaemic control in diabetes patient with co-existed beta-thalassaemia: A case report and a literature review. J Clin Pharm Ther 2020; 45:379-383. [PMID: 31736110 PMCID: PMC7384187 DOI: 10.1111/jcpt.13073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/03/2019] [Accepted: 10/22/2019] [Indexed: 02/05/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE The HbA1C marker used in assessing diabetes control quality is not sufficient in diabetes patients with thalassaemia. CASE DESCRIPTION A male diabetic patient with thalassaemia was hospitalized due to distal neuropathic pain, right toe trophic ulcer, unacceptable five-point glycaemic profile and recommended HbA1C value. After simultaneously initiated insulin therapy and management of ulcer by hyperbaric oxygen, the patient showed improved glycaemic control and ulcer healing, which led to the patient's discharge. WHAT IS NEW AND CONCLUSION In thalassaemia and haemoglobinopathies, due to discrepancies in the five-point glycaemic profile and HbA1C values, it is necessary to measure HbA1C with a different method or to determine HbA1C and fructosamine simultaneously.
Collapse
|
|
24
|
Resanović I, Gluvić Z, Zarić B, Sudar-Milovanović E, Vučić V, Arsić A, Nedić O, Šunderić M, Gligorijević N, Milačić D, Isenović ER. Effect of Hyperbaric Oxygen Therapy on Fatty Acid Composition and Insulin-like Growth Factor Binding Protein 1 in Adult Type 1 Diabetes Mellitus Patients: A Pilot Study. Can J Diabetes 2020; 44:22-29. [PMID: 31311728 DOI: 10.1016/j.jcjd.2019.04.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/05/2019] [Accepted: 04/30/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Metabolic changes in type 1 diabetes mellitus (T1DM) impair vasodilation, and this leads to tissue hypoxia and microvascular pathology. Hyperbaric oxygen therapy (HBOT) can significantly improve the outcome of ischemic conditions in T1DM patients and reduce vascular complications. The aim of our study was to assess the effects of HBOT on plasma fatty acid (FA) composition, and expression of insulin-like growth factor binding protein 1 (IGFBP-1) in T1DM patients. METHODS Our study included 24 adult T1DM patients diagnosed with peripheral vascular complications. The patients were exposed to 10 sessions of 100% oxygen inhalation at 2.4 atmosphere absolute for 1 hour. Blood samples were collected at admission and after HBOT for measurement of metabolic parameters, FA composition and IGFBP-1. Measurement of plasma FA composition was determined by gas chromatography. Expression of IGFBP-1 in the serum was estimated by Western blot analysis. RESULTS HBOT decreased blood levels of total cholesterol (p<0.05), triglycerides (p<0.05) and low-density lipoprotein (p<0.05). HBOT increased plasma levels of individual FAs: palmitic acid (p<0.05), palmitoleic acid (p<0.05), docosapentaenoic acid (p<0.05) and docosahexaenoic acid (p<0.01), and decreased levels of stearic acid (p<0.05), alpha linolenic acid (p<0.05) and linoleic acid (p<0.01). Expression of IGFBP-1 (p<0.01) was increased, whereas the level of insulin (p<0.001) was decreased in the serum after HBOT. CONCLUSIONS Our results indicate that HBOT exerts beneficial effects in T1DM patients by improving the lipid profile and altering FA composition.
Collapse
|
|
25
|
Dugalic P, Djuranovic S, Pavlovic-Markovic A, Dugalic V, Tomasevic R, Gluvic Z, Obradovic M, Bajic V, Isenovic ER. Proton Pump Inhibitors and Radiofrequency Ablation for Treatment of Barrett's Esophagus. Mini Rev Med Chem 2020; 20:975-987. [PMID: 31644405 DOI: 10.2174/1389557519666191015203636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/04/2019] [Accepted: 06/25/2019] [Indexed: 02/07/2023]
Abstract
Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux in the distal oesophagus, and this may cause the development of reflux esophagitis and Barrett's oesophagus (BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and High-Grade Dysplastic (HGD) BE, with the expected increase in malignancy transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution white-light endoscopy, followed by uniform endoscopy findings description (Prague classification) with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE includes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of resection and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and prevention of its transfer to EAC.
Collapse
|