Future therapeutic perspectives in nonalcoholic fatty liver disease: a focus on nuclear receptors, a promising therapeutic target.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide, with an increasing incidence, secondary to the increasing incidence of obesity and diabetes, from a very young age. It is associated with metabolic and cardiovascular disorders, as components of the metabolic syndrome (MS). NAFLD is the hepatic manifestation of MS. The pathogenesis of the disease is multifactorial and complex, involving genetic, metabolic, but also environmental factors. Currently, nuclear receptors (NRs) represent a promising therapeutic target in the treatment of non-alcoholic steatohepatitis (NASH). Of these, the most studied receptor was the liver X receptor (LXR), which would have great potential in the treatment of metabolic diseases, namely hypercholesterolemia, atherosclerosis, and NAFLD. However, the therapeutic use of NRs is restricted in medical practice for two reasons: limited knowledge of the structure of the receptor and its inability to modulate certain actions in the target organs and genes. One problem is the understanding of the function and structure of the N-terminal domain which has a major transcriptional activation function (AF1).

Vasculitis and infectious risk in a patient with type 2 diabetes mellitus: A case report.

The connection between vasculitis and infection is complex. The present study described a typical situation for a patient with unbalanced type 2 diabetes and chronic complications, in which a lack of adherence to the protection and care measures ultimately led to the appearance of some of the worst consequences of the condition, namely, ulceration, gangrene and amputation. In the context of an unstable condition with significant metabolic imbalance there was an impaired response to infections in the present patient, and the amputation resulted in wound persistence and ulcer development, followed by superinfection with methicillin-resistant Staphylococcus aureus according to the antibiogram performed. In this case, an episode of vasculitis was triggered without evidence of bacteraemia. The present case report highlighted the importance of proper hygiene and good metabolic control in patients with diabetes that suffer from amputations and conditions that expose them to certain complications, including vasculitis.

The therapeutic mechanisms and beneficial effects of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease: a systematic review.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes hepatic steatosis (HS) and non-alcoholic steatohepatitis (NASH) with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD may represent the hepatic manifestation of the metabolic syndrome (MS), with a prevalence directly proportional to the prevalence of obesity and MS. The standard treatment for patients with NAFLD is lifestyle modification, which in medical practice has many limitations. To overcome them, numerous drugs with benefits in the prevention and treatment of the disease have been studied. Currently, the most used substances are vitamin E and Pioglitazone, with numerous benefits. Furthermore, new strategies and beneficial treatments are needed for the prevention of the disease, which is currently a priority in both the health and research fields. One of the most studied agents in the last decades has been ursodeoxycholic acid (UDCA), which is of great interest in the treatment of NAFLD due to its hepatoprotective effects.

Prothrombotic status in COVID­19 with diabetes mellitus (Review).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused an important social and health impact worldwide and the coronavirus disease-19 (COVID-19) has elicited devastating economy problems. The pathogenesis of SARS-CoV-2 infection is a complex mechanism and is considered to be the result of a challenging interaction, in which host and virus immune responses are the key elements. In this process, several inflammatory pathways are involved, and their initiation can have multiple consequences with a considerable impact on evolution, such as hyperinflammation and cytokine storm, thereby promoting activation of the coagulation system and fibrinolytic activity suppression. It is commonly recognized that COVID-19 severity involves multiple factors, including diabetes which increases the risk of developing different complications. This could be as a result of the low-grade inflammation as well as the innate and adaptive immune response dysfunction that is observed in patients with diabetes mellitus. In patients with diabetes, multiple metabolic disturbances which have a major impact in disturbing the balance between coagulation and fibrinolysis were discovered, thus the risk for thrombotic events is increased. Diabetes has been recognized as an important severity prognosis factor in COVID-19 cases and considering there is a significant association between diabetes and prothrombotic status, it could be responsible for the increased risk of thrombotic events with a worse prognosis.

A Study of Biomarkers Associated with Metabolic Dysfunction-Associated Fatty Liver Disease in Patients with Type 2 Diabetes.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term that no longer excludes patients that consume alcohol or present other liver diseases, unlike nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the role of different biomarkers as predictors of MAFLD in patients with type 2 diabetes mellitus (T2DM). In this regard, a cross-sectional, non-interventional study was conducted over a period of 8 months in patients with T2DM. Liver steatosis displayed by abdominal ultrasound certified the MAFLD diagnosis. A percentage of 49.5% of the studied patients presented MAFLD. Through logistic regression adjusted for gender, age, T2DM duration, lipid-lowering therapy, smoking status, nutritional status, we demonstrated that elevated triglycerides (TG) levels, high non-high-density-lipoprotein (HDL)-cholesterol-to-HDL-cholesterol (non-HDL/HDL) ratio, high atherogenic index of plasma (AIP), and increased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) had predictive value for MAFLD in patients with T2DM. Furthermore, we calculated the optimal cut-off values for these biomarkers (184 mg/dL for TG, 0.615 for AIP, 3.9 for the non-HDL/HDL ratio, and 2.01 for HOMA-IR) which can predict the presence of MAFLD in patients with T2DM. To our knowledge, this is the first study to assess the predictive value of the non-HDL/HDL ratio for MAFLD in patients with T2DM.

Associations of Chronic Diabetes Complications and Cardiovascular Risk with the Risk of Obstructive Sleep Apnea in Patients with Type 2 Diabetes.

Background: Type 2 diabetes mellitus (T2DM) is associated with increased mortality and morbidity, including cardiovascular diseases and obstructive sleep apnea (OSA). The aim of this study was to assess the associations between cardiovascular risk, chronic diabetes complications and the risk of OSA in adult patients with T2DM. Methods: The study included 529 patients with T2DM in whom moderate-to-severe OSA risk was assessed using the STOP-Bang questionnaire, dividing the subjects into two groups: group 1: STOP-Bang score <5, and group 2: STOP-Bang score ≥5, respectively. In all the subjects, cardiovascular risk was assessed using the UKPDS risk engine. Statistical analysis was performed using SPSS 26.0, the results being statistically significant if p value was <0.05. Results: 59% of the subjects scored ≥5 on the STOP-Bang questionnaire. We recorded statistically significant differences between the two groups regarding diabetes duration, HbA1c, HOMA-IR, albuminuria, as well as cardiovascular risk at 10 years for both coronary heart disease (CHD) and stroke (p < 0.05). Furthermore, through logistic regression, adjusting for confounding factors, we demonstrated that the STOP-Bang score ≥ 5 is a risk factor for 10-year fatal and nonfatal CHD risk. Conclusions: It is extremely important to screen and diagnose OSA in patients with T2DM, in order to improve the primary and secondary prevention of cardiovascular events in these patients.

Analysis of Risk Factors for the Development of Gestational Diabetes Mellitus in a Group of Romanian Patients.

Introduction: Gestational diabetes mellitus (GDM) is caused by numerous risk factors, the most common being old age, obesity, family history of diabetes mellitus, GDM, history of fetal macrosomia, history of polycystic ovary syndrome or treatment with particular drugs, multiple births, and certain races. The study proposed to analyze the risk factors causing GDM. Method: In the study, we included 97 pregnant women to whom there was an OGTT performed between weeks 24th and 28th of pregnancy, divided into two groups, with GDM and without GDM. The statistical analysis was performed with SPSS 26.0, the tests being statistically significant if p value < 0.05. Results: The favoring risk factors for the onset of GDM were analyzed, with statistically significant differences between the GDM group and the group without GDM related to the delivery age (32.39 ± 4.66 years old vs. 28.61 ± 4.71 years old), history of fetal macrosomia (13.7% vs. 0%), presence of GDM during previous pregnancies (7.8% vs. 0%), HBP before pregnancy (9.8% vs. 0%), gestational HBP (17.6% vs. 0%), glycemia value at first medical visit (79.37 ± 9.34 mg/dl vs. 71.39 ± 9.16 mg/dl), and weight gain during pregnancy (14.61 ± 4.47 kg vs. 12.48 ± 5.87 kg). Conclusions: Identifying the risk factors for the GDM onset has a special importance, implying an early implementation of interventional measures in order to avoid the onset of GDM and associated maternal and fetal complications.

Triglyceride and Glucose Index as a Screening Tool for Nonalcoholic Liver Disease in Patients with Metabolic Syndrome.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is regarded as a component of metabolic syndrome, which involves insulin resistance (IR) as the primary physiopathological event. The aim of this study was to establish the association between IR, assessed using the triglyceride and glucose index (TyG), and histopathological features of NAFLD lesions. METHODS: The study included 113 patients with metabolic syndrome. Fasting plasma glucose (FPG), fasting lipid profiles and liver enzymes were measured. IR was assessed by the TyG index. Liver biopsy was performed for assessment steatosis and fibrosis. RESULTS: the TyG index had a mean value of 8.93 ± 1.45, with a higher value in the patients with overweight (p = 0.002) and obesity (p = 0.004) characteristics than in the patients with normal weight. The TyG index mean value was 8.78 ± 0.65 in subjects without NASH, 8.91 ± 0.57 in patients with borderline NASH and 9.13 ± 0.55 in patients with definite NASH. A significant difference was found between subjects without NASH and the ones with definite NASH (p = 0.004), as well as in patients with early fibrosis vs. those with significant fibrosis. The analysis of the area under the ROC curve proved that the TyG index is a predictor of NASH (p = 0.043). CONCLUSION: the TyG index is a facile tool that can be used to identify individuals at risk for NAFLD.

Maternal and Fetal Metabolites in Gestational Diabetes Mellitus: A Narrative Review.

Gestational diabetes mellitus (GDM) is a major public health issue of our century due to its increasing prevalence, affecting 5% to 20% of all pregnancies. The pathogenesis of GDM has not been completely elucidated to date. Increasing evidence suggests the association of environmental factors with genetic and epigenetic factors in the development of GDM. So far, several metabolomics studies have investigated metabolic disruptions associated with GDM. The aim of this review is to highlight the usefulness of maternal metabolites as diagnosis markers of GDM as well as the importance of both maternal and fetal metabolites as prognosis biomarkers for GDM and GDM's transition to type 2 diabetes mellitus T2DM.

New strategies of diagnostic and therapeutic approach to emergencies in the evolution of patients with diabetes mellitus (Review).

Diabetes mellitus, known as the most widespread disease in the world, along with four other chronic diseases, involves major expenditures and significant human resources for care, thus representing a burden on any type of health care system especially due to its rapid evolution of acute and chronic complications. For the emergency department (ED), the requirements of patients with acute complications of diabetes, determine expenses which are three times higher than those for non-diabetic patients and their hospitalizations are four times more frequent. The acute complications for which patients with diabetes most frequently require the ED are hypoglycemic, hyperosmolar, or ketoacidosis coma as well as alterations of the general condition that is typical of hypoglycemia, diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state and new-onset hyperglycemia. Hypoglycemia and the Somogyi phenomenon are the most common complications of type 1 diabetes but they can also occur in patients with type 2 diabetes who are treated with insulin through its overdose. DKA can occur in type 1 and 2 diabetes either by administering inadequate doses of insulin or due to the existence of precipitating factors such as stress, acute myocardial infarction, infections, sepsis, and/or gastrointestinal bleeding. Hyperosmolar hyperglycemic status is the most common complication in patients with type 2 diabetes and DKA. Treating the acute complications of diabetes in the ED involves, besides taking immediate measures to assess and maintain vital functions, monitoring patients, assessing blood sugar, electrolytes, urea, creatinine, and bicarbonate, and applying appropriate immediate therapeutic measures for each type of acute diabetes complication.

Insulin resistance quantified by the value of HOMA-IR and cardiovascular risk in patients with type 2 diabetes.

Cardiovascular disease (CVD) is recognized as a leading cause of death worldwide. Obesity, dyslipidemia, insulin resistance (IR), interconnected pathological conditions constitute risk factors that are closely associated with CVD. The aim of the present study was to highlight the association of IR with cardiovascular risk (CVR). The epidemiological, cross-sectional, non-interventional study was conducted over 12 months (2019-2020) within a research grant and included a sample of 400 subjects divided into 2 subgroups: group 1 (control) subjects did not have diabetes (n=200) and group 2 had type 2 diabetes (T2DM) (n=200). The Framingham risk score (FRS) was calculated according to the 2008 general CVD risk model from the Framingham Heart Study. Subsequent to a correlation of the value of homeostasis model assessment of insulin resistance (HOMA-IR) with the degree of CVR, the IR was higher in both groups, and CVR also increased. After being quantified by the Spearman correlation coefficient, the correlation in group 2 was higher at 0.625 compared to group 1 where this coefficient had a value of 0.440. A high FRS (FRS of 20%) was significantly associated with IR. The results therefore show that HOMA-IR is an independent risk factor for high FRS. New therapies focused on decreasing IR may contribute to decreased CVD.

An Update of Medical Nutrition Therapy in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a serious and frequent pregnancy complication that can lead to short and long-term risks for both mother and fetus. Different health organizations proposed different algorithms for the screening, diagnosis, and management of GDM. Medical Nutrition Therapy (MNT), together with physical exercise and frequent self-monitoring, represents the milestone for GDM treatment in order to reduce maternal and fetal complications. The pregnant woman should benefit from her family support and make changes in their lifestyles, changes that, in the end, will be beneficial for the whole family. The aim of this manuscript is to review the literature about the Medical Nutrition Therapy in GDM and its crucial role in GDM management.

Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects.

INTRODUCTION: Non-alcoholic steatohepatitis (NASH) is a progressive form of liver steatosis that involves a risk of progression towards fibrosis, cirrhosis, and end-stage liver disease. Low-grade inflammation is recognized to be involved in non-alcoholic fatty liver disease (NAFLD) pathogeny. Additionally, adipose tissue dysfunction plays an important role in the development of metabolic diseases. PATIENTS, MATERIALS AND METHODS: We conducted a study on 68 patients with liver steatosis confirmed through liver biopsy during the surgery. In all the patients, we recorded anthropometric parameters and we performed blood tests for systemic inflammation [high-sensitivity C-reactive protein (hs-CRP), fibrinogen] and serum adipokines related to adipose tissue inflammation (leptin, adiponectin). Additional to histopathological examination, we also performed the immunohistochemical study of inflammatory mononuclear cells. RESULTS: The 68 patients had a mean age of 56.57±4.94 years old, had a mean value of hs-CRP of 2.30±0.91 mg∕L, a mean value of leptin of 14.02±17.02 ng∕mL and a mean value of adiponectin of 7.54±0.38 mg∕L. In all the cases studied by liver biopsy, the steatosis exceeded 5% of hepatocytes, but the frequency of NASH was 26.47%. Cluster of differentiation (CD)45-positive, CD4-positive, and CD8-positive T-lymphocytes predominated in the studied cases. We obtained a statistically significant high association between definite NASH and the values of hs-CRP, serum adiponectin and leptin∕adiponectin ratio (p<0.0001). CONCLUSIONS: Systemic and adipose tissue inflammation was statistically significant associated with histological lesions of steatosis and NASH, suggesting that the determination of hs-CRP and serum adipokines in dynamics in patients with NAFLD is predictive for the progression of the disease.

Triglyceride and glucose index: a useful tool for non-alcoholic liver disease assessed by liver biopsy in patients with metabolic syndrome?

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is associated with metabolic impairments, being a component of metabolic syndrome. Considering the involvement of fat accumulation and insulin resistance in NAFLD, triglyceride and glucose (TyG) index was proposed as a marker of NAFLD progression. The "gold standard" for the evaluation of liver lesions characteristic for NAFLD remains the liver biopsy. The aim of this study was to establish the links between TyG index, assessing insulin resistance, and histopathological lesions of liver samples obtained by liver biopsy in patients with metabolic syndrome. PATIENTS, MATERIALS AND METHODS: We conducted a study over a period of three years, including 113 adult patients with metabolic syndrome in whom hepatic disorders were assessed by liver biopsy and insulin resistance was evaluated by TyG index. RESULTS AND DISCUSSIONS: In our study, steatosis had a frequency of 92.03%, being identified 26 cases with mild steatosis, 48 with moderate steatosis and 31 with severe steatosis. Regarding non-alcoholic steatohepatitis (NASH), the frequency of this disorder in our study group was 29.2% in the subjects with liver steatosis, while liver fibrosis had a frequency of 53.09%. When we analyzed the relationships between TyG index and the presence of each type of lesion necessary for NASH diagnosis, we obtained statistically significant differences for the presence of hepatocyte ballooning (p=0.01) and a high statistically significance for the NAFLD activity score (NAS) (p<0.0001). CONCLUSIONS: TyG index is a facile tool that can be used to identify patients at risk for advanced NAFLD lesions evaluated by liver biopsy.

Insulin Resistance and Chronic Kidney Disease in Patients with Type 1 Diabetes Mellitus.

Background and Aims. Diabetes mellitus (DM) is a chronic disease which can evolve towards devastating micro- and macrovascular complications. DM is the most frequent cause of chronic kidney disease (CKD). Insulin resistance plays an important role in the natural history of type 1 diabetes. The purpose of the study was to determine the prevalence of CKD in T1DM and the correlation with insulin resistance (IR) in patients with CKD. Materials and Methods. The study was conducted over a period of three years (2010-2013) and included patients with DM registered in the Clinical Centre of Diabetes, Nutrition and Metabolic Diseases of Dolj county. The study design was an epidemiological, transversal, noninterventional type. Finally, the study group included 200 subjects with type 1 DM. Insulin resistance (IR) was estimated by eGDR. The subjects with eGDR ≤ 7.5 mg/kg/min were considered with insulin resistance. Results. CKD was found in 44% of the patients. Analyzing statistically the presence of CKD, we found highly significant differences between patients with CKD and those without CKD regarding age and sex of the patients, the duration of diabetes, glycosylated hemoglobin (HbA1c), the estimated glucose disposal rate (eGDR), and the presence of hypertension, dyslipidemia, and hyperuricaemia. In patients with CKD, age and diabetes duration are significantly higher than in those who do not have this complication. CKD is more frequent in males than in females (50.9% men versus 34.5% women, p = 0.022). From the elements of metabolic syndrome, high blood pressure, hyperuricemia, and dyslipidemia are significantly increased in diabetic patients with CKD. eGDR value (expressed as mg·kg-1·min-1) is lower in patients with CKD than in those without CKD (15.92 versus 6.42, p < 0.001) indicating the fact that patients with CKD show higher insulin resistance than those without CKD. Conclusions. This study has shown that insulin resistance is associated with an increased risk of CKD, but, due to the cross-sectional design, the causal relationship cannot be assessed. However, the existence of this causality and the treatment benefit of insulin resistance in type 1 diabetes are issues for further discussion.

Insulin resistance is associated with all chronic complications in type 1 diabetes.

BACKGROUND: Insulin resistance (IR) is present in type 1 diabetes mellitus (T1DM) and is suggested to be related to chronic diabetic complications. The primary aim of our study was to assess IR in T1DM patients with and without chronic complications. A secondary aim was to evaluate the possible association between IR and chronic diabetic complications. METHODS: This cross-sectional study enrolled 272 patients with T1DM. Insulin resistance was quantified using the estimated glucose disposal rate (eGDR). Associations between eGDR and each diabetes complication were first evaluated using binary logistic regression, then multiparametric logistic regression with stepwise selection of covariates. The discriminative value of eGDR was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Estimated GDR was lower in patients with chronic diabetic complications (6.1 vs. 6.9 mg/kg per min [P = 0.02] for retinopathy; 6.3 vs. 7.3 mg/kg per min [P < 0.01] for nephropathy; 6.5 vs. 7.6 mg/kg per min [P < 0.01] for neuropathy; and 5.2 vs. 7.5 mg/kg per min [P < 0.01] for cardiovascular complications). In univariate analysis eGDR was associated all diabetic complications. These associations remained significant after adjustment for different variables in the final regression models. In addition, eGDR was a good discriminator for each diabetic complication, with an area under the curve between 0.609 and 0.759. CONCLUSIONS: Patients with chronic diabetic complications are more insulin resistant than those without complications. Moreover, IR was independently associated with the presence of each chronic diabetic complication, and seems to be a good discriminator for them all.