Insulin resistance and Metabolic dysfunction-associated steatotic liver disease (MASLD): Pathways of action of hypoglycemic agents.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by overweight/obesity, and the presence of type 2 diabetes mellitus is the most important criterion. We propose an independent disease perspective without exclusion criteria and with less heterogeneity and greater impact because, according to the National Health and Nutrition Survey (ENSANUT), in Mexico, 25 % of adults over 60 years of age suffer from diabetes, and 96 % of those over 50 years of age have abdominal obesity. Due to the impact of insulin resistance in the pathophysiology of MASLD, which results in damage to hepatocytes, this work aims to provide an overview of the action pathways of hypoglycemic agents such as glucagon-like-1 receptor agonist and peroxisome proliferator-activated receptor-gamma agonists, whose importance lies in the fact that they are currently undergoing phase 2 studies, as well as dipeptidyl peptidase 4 inhibitors and sodium-glucose co-transporter type 2 inhibitors, which are undergoing phase 1 study trials.

Clinical Spectrum of USP8 Pathogenic Variants in Cushing's Disease.

Cushing's disease (CD) is a life-threatening condition with a challenging diagnostic process and scarce treatment options. CD is caused by usually benign adrenocorticotrophic hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs), known as corticotropinomas. These tumors are predominantly of sporadic origin, and usually derive from the monoclonal expansion of a mutated cell. Somatic activating variants located within a hotspot of the USP8 gene are present in 11-62% of corticotropinomas, making USP8 the most frequent genetic driver of corticotroph neoplasia. In contrast, other somatic defects such as those affecting the glucocorticoid receptor gene (NR3C1), the BRAF oncogene, the deubiquitinase-encoding gene USP48, and TP53 are infrequent. Moreover, patients with familial tumor syndromes, such as multiple endocrine neoplasia, familial isolated pituitary adenoma, and DICER1 rarely develop corticotropinomas. One of the main molecular alterations in USP8-driven tumors is an overactivation of the epidermal growth factor receptor (EGFR) signaling pathway, which induces ACTH production. Hotspot USP8 variants lead to persistent EGFR overexpression, thereby perpetuating the hyper-synthesis of ACTH. More importantly, they condition a characteristic transcriptomic signature that might be useful for the clinical prognosis of patients with CD. Nevertheless, the clinical phenotype associated with USP8 variants is less well defined. Hereby we discuss the current knowledge on the molecular pathogenesis and clinical picture associated with USP8 hotspot variants. We focus on the potential significance of the USP8 mutational status for the design of tailored clinical strategies in CD.

Low-Normal Thyroid Function Is Not Associated with Either Non-Alcoholic Fatty Liver Disease or with Metabolic Dysfunction-Associated Fatty Liver Disease.

BACKGROUND: The association of low-normal thyroid function (LNTF) with non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) is controversial; thus, the aim of this study is to determine this association. METHODS: NAFLD was evaluated by controlled attenuation parameter of transient elastography. Patients were classified by MAFLD criteria. LNTF was defined as TSH levels of 2.5 to 4.5 mIU/L and were divided into three different cut-off points (>4.5 to 5.0, >3.1, and >2.5 mIU/L). Associations between LNTF, NAFLD, and MAFLD were evaluated by univariate and multivariate logistic regression analyses. RESULTS: A total of 3697 patients were included; 59% (n = 2179) were male, and median age and body mass index were 48 (43-55) years and 25.9 (23.6-28.5) kg/m2, respectively, and 44% (n = 1632) were diagnosed with NAFLD. THS levels of 2.5 and 3.1 showed significant associations with the presence of NAFLD and MAFLD; however, LNTF did not show an independent association with the presence of NAFLD or MAFLD in multivariate analysis. According to different cut-off points, patients with LNTF presented similar risks for NAFLD as the general population. CONCLUSION: LNTF is not associated with NAFLD or MAFLD. Patients with high LNTF are equally at risk for NAFLD as the general population.

Impact on Prevalence of the Application of NAFLD/MAFLD Criteria in Overweight and Normal Weight Patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. Recently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed and adapted to body mass index (BMI). This study describes the impact on prevalence of the application of both criteria in overweight and lean patients. METHODS: Patients who were evaluated for liver steatosis by transient elastography were included and divided according to BMI (≥25 kg/m2 and <25 kg/m2) and classified as NAFLD or MAFLD, according to metabolic abnormalities. Differences in prevalence were evaluated applying both criteria. A multivariate analysis was performed to evaluate independent associations of metabolic abnormalities and liver steatosis in lean patients. RESULTS: 3847 patients were included. In overweight patients (61%), the prevalence NAFLD was 63.6% and 65.3% for MAFLD (p = 0.22). In contrast, the prevalence of MAFLD was lower (7.9% vs. 18.3%, p ≤ 0.001) in lean patients. In this group, higher age, fasting glucose, triglycerides, and waist circumference showed independent association with liver steatosis. CONCLUSION: The application of NAFLD/MAFLD criteria did not show prevalence differences in overweight patients. With MAFLD criteria, the prevalence is lower in lean patients, but patients with high risk of progression of liver disease for steatosis were identified, according to their metabolic abnormalities.

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease.

Background and aims: Oxidative stress (OS) induces the production of fibroblast growth factor 21 (FGF21). Previous data have revealed that FGF21 protects cells from OS injury and death, making it a potential therapeutic option for many diseases with increased OS. However, the association of this growth factor with OS markers in humans with chronic kidney disease (CKD) remains unknown. This study aims to evaluate the association of serum FGF21 with serum total antioxidant capacity (TAC) and oxidized low-density lipoproteins (OxLDL) in subjects in different stages of kidney disease. Methods: This is a cross-sectional study that included 382 subjects with different stages of CKD, irrespective of type 2 diabetes (T2D) diagnosis. Associations of serum FGF21 with OxLDL, TAC, sex, age, body mass index (BMI), fasting plasma glucose, estimated glomerular filtration rate (eGFR), T2D, and smoking, were evaluated through bivariate and partial correlation analyses. Independent associations of these variables with serum FGF21 were evaluated using multiple linear regression analysis. Results: Serum FGF21 was significantly and positively correlated with age (r = 0.236), TAC (lnTAC) (r = 0.217), and negatively correlated with eGFR (r = -0.429) and male sex (r = -0.102). After controlling by age, sex, BMI, T2D, smoking, and eGFR; both TAC and OxLDL were positively correlated with FGF21 (r = 0.117 and 0.158 respectively, p < 0.05). Using multiple linear regression analysis, eGFR, male sex, T2D, OxLDL, and TAC were independently associated with serum FGF21 (STDß = -0.475, 0.162, -0.153, 0.142 and 0.136 respectively; p < 0.05 for all) adjusted for age, BMI, smoking, and fasting plasma glucose. Conclusion: A positive association between serum FGF21 and OS has been found independently of renal function in humans. Results from the present study provide novel information for deeper understanding of the role of FGF21 in OS in humans with CKD and T2D; mechanistic studies to explain the association of serum FGF21 with oxidative stress in CKD are needed.

A Higher Fructose Intake Is Associated with Greater Albuminuria in Subjects with Type 2 Diabetes Mellitus.

The aim of this single center cross-sectional study was to investigate the association between fructose intake and albuminuria in subjects with type 2 diabetes mellitus (T2DM). This is a single center cross-sectional study. One hundred and forty-three subjects with T2DM were recruited from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. The median daily fructose intake was estimated with a prospective food registry during 3 days (2 week-days and one weekend day) and they were divided into low fructose intake (<25 g/day) and high fructose intake (≥ 25 g/day). Complete clinical and biochemical evaluations were performed, including anthropometric variables and a 24-hour urine collection for albuminuria determination. One hundred and thirty-six subjects were analyzed in this study. We found a positive significant association between daily fructose intake and albuminuria (ρ= 0.178, p=0.038) in subjects with type 2 diabetes mellitus. Other variables significantly associated with albuminuria were body mass index (BMI) (ρ= 0.170, p=0.048), mean arterial pressure (MAP) (ρ= 0.280, p=0.001), glycated hemoglobin (A1c) (ρ= 0.197, p=0.022), and triglycerides (ρ= 0.219, p=0.010). After adjustment for confounding variables we found a significant and independent association between fructose intake and albuminuria (ß= 13.96, p=0.006). We found a statistically significant higher albuminuria (60.8 [12.8-228.5] versus 232.2 [27.2-1273.0] mg/day, p 0.002), glycated hemoglobin (8.6±1.61 versus 9.6±2.1 %), p= 0.003, and uric acid (6.27±1.8 versus 7.2±1.5 mg/dL), p=0.012, in the group of high fructose intake versus the group with low fructose intake, and a statistically significant lower creatinine clearance (76.5±30.98 mL/min versus 94.9±36.8, p=0.014) in the group with high fructose intake versus the group with low fructose intake. In summary we found that a higher fructose intake is associated with greater albuminuria in subjects with T2DM.

Fibroblast growth factor 21 and its novel association with oxidative stress.

Fibroblast growth factor 21 (FGF21) is an endocrine-member of the FGF family. It is synthesized mainly in the liver, but it is also expressed in adipose tissue, skeletal muscle, and many other organs. It has a key role in glucose and lipid metabolism, as well as in energy balance. FGF21 concentration in plasma is increased in patients with obesity, insulin resistance, and metabolic syndrome. Recent findings suggest that such increment protects tissue from an increased oxidative stress environment. Different types of physical stress, such as strenuous exercising, lactation, diabetic nephropathy, cardiovascular disease, and critical illnesses, also increase FGF21 circulating concentration. FGF21 is now considered a stress-responsive hormone in humans. The discovery of an essential response element in the FGF21 gene, for the activating transcription factor 4 (ATF4), involved in the regulation of oxidative stress, and its relation with genes such as NRF2, TBP-2, UCP3, SOD2, ERK, and p38, places FGF21 as a key regulator of the oxidative stress cell response. Its role in chronic diseases and its involvement in the treatment and follow-up of these diseases has been recently the target of new studies. The diminished oxidative stress through FGF21 pathways observed with anti-diabetic therapy is another clue of the new insights of this hormone.