The Implication of Elevated Serum Myoglobin Level in Acute Diabetic Complications of Ketoacidosis and Hyperglycemic Hyperosmolar State: A Real-World Study.

Objective: To investigate the implications of elevated myoglobin (MYO) in acute diabetic conditions of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). Materials and methods: This study integrates in-patient data from Shanghai Pudong Hospital from 2019 to 2023. Laboratory data were compared between stable T2D patients (without acute diabetic complications), DKA, and HHS patients. The multilinear regression explored variables relevant to the elevated MYO in DKA and HHS. The dynamics of MYO, the survival rate, and associated risk factors in HHS were determined. Results: Except for triglyceride, procalcitonin, low-density lipoprotein, islet cell autoimmune antibodies, N-terminal Pro-brain natriuretic peptide (NT-ProBNP), and brain natriuretic peptide (BNP), there were significant differences in age, gender distribution, duration of diabetes, type of diabetes, and other referred laboratory data (p<0.05). The age, gender, creatine kinase (CK), estimated glomerular filtration rate (eGFR), and free triiodothyronine (FT3) in DKA, whereas osmolar, uric acid (UA), and cardiac troponin I (cTNI) in the HHS, were significant determinants of elevated MYO, respectively (p<0.05). The dynamic of MYO in HHS was in line with the survival trend, where the percentage of death was 29.73%, and aging with higher procalcitonin levels was a key risk factor. Besides, the cumulative survival rates between patients with or without bone fracture or muscle injury were substantially different. Conclusion: This real-world study demonstrated DKA and HHS potentially have unique causes for increased MYO. By utilizing the appropriate regression parameters, we could forecast the progression of increased MYO in groups of DKA and HHS, while based on risk factors of aging, severity of infection, and different MYO sources, we could predict the prognosis of HHS.

Deciphering the SOX4/MAPK1 regulatory axis: a phosphoproteomic insight into IQGAP1 phosphorylation and pancreatic Cancer progression.

OBJECTIVE: This study aims to elucidate the functional role of IQGAP1 phosphorylation modification mediated by the SOX4/MAPK1 regulatory axis in developing pancreatic cancer through phosphoproteomics analysis. METHODS: Proteomics and phosphoproteomics data of pancreatic cancer were obtained from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Differential analysis, kinase-substrate enrichment analysis (KSEA), and independent prognosis analysis were performed on these datasets. Subtype analysis of pancreatic cancer patients was conducted based on the expression of prognostic-related proteins, and the prognosis of different subtypes was evaluated through prognosis analysis. Differential analysis of proteins in different subtypes was performed to identify differential proteins in the high-risk subtype. Clinical correlation analysis was conducted based on the expression of prognostic-related proteins, pancreatic cancer typing results, and clinical characteristics in the pancreatic cancer proteomics dataset. Functional pathway enrichment analysis was performed using GSEA/GO/KEGG, and most module proteins correlated with pancreatic cancer were selected using WGCNA analysis. In cell experiments, pancreatic cancer cells were grouped, and the expression levels of SOX4, MAPK1, and the phosphorylation level of IQGAP1 were detected by RT-qPCR and Western blot experiments. The effect of SOX4 on MAPK1 promoter transcriptional activity was assessed using a dual-luciferase assay, and the enrichment of SOX4 on the MAPK1 promoter was examined using a ChIP assay. The proliferation, migration, and invasion functions of grouped pancreatic cancer cells were assessed using CCK-8, colony formation, and Transwell assays. In animal experiments, the impact of SOX4 on tumor growth and metastasis through the regulation of MAPK1-IQGAP1 phosphorylation modification was studied by constructing subcutaneous and orthotopic pancreatic cancer xenograft models, as well as a liver metastasis model in nude mice. RESULTS: Phosphoproteomics and proteomics data analysis revealed that the kinase MAPK1 may play an important role in pancreatic cancer progression by promoting IQGAP1 phosphorylation modification. Proteomics analysis classified pancreatic cancer patients into two subtypes, C1 and C2, where the high-risk C2 subtype was associated with poor prognosis, malignant tumor typing, and enriched tumor-related pathways. SOX4 may promote the occurrence of the high-risk C2 subtype of pancreatic cancer by regulating MAPK1-IQGAP1 phosphorylation modification. In vitro cell experiments confirmed that SOX4 promoted IQGAP1 phosphorylation modification by activating MAPK1 transcription while silencing SOX4 inhibited the proliferation, migration, and invasion of pancreatic cancer cells by reducing the phosphorylation level of MAPK1-IQGAP1. In vivo, animal experiments further confirmed that silencing SOX4 suppressed the growth and metastasis of pancreatic cancer by reducing the phosphorylation level of MAPK1-IQGAP1. CONCLUSION: The findings of this study suggest that SOX4 promotes the phosphorylation modification of IQGAP1 by activating MAPK1 transcription, thereby facilitating the growth and metastasis of pancreatic cancer.

Utilize multi-metabolic parameters as determinants for prediction of skeletal muscle mass quality in elderly type2 diabetic Chinese patients.

BACKGROUND: Sarcopenia, an age-related disorder characterized by loss of skeletal muscle mass and function, is recently recognized as a complication in elderly patients with type 2 diabetes mellitus (T2DM). Skeletal muscles play a crucial role in glycemic metabolism, utilizing around 80% of blood glucose. Accordingly, we aimed to explore the relationship between glucose metabolism and muscle mass in T2DM. METHODS: We employed the AWGS 2019 criteria for diagnosing low muscle mass and 1999 World Health Organization (WHO) diabetes diagnostic standards. This study included data of 191 individuals aged 60 and above with T2DM of Shanghai Pudong Hospital from November 2021 to November 2022. Fasting C-peptide (FPCP), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG) and postprandial 2-hour C-peptide (PPCP), glycated hemoglobin A1c (HbA1c), glycated albumin (GA), serum lipids spectrum, renal and hepatic function, hemoglobin, and hormone were measured. Based on the findings of univariate analysis, logistic regression and receiver operating characteristic (ROC) curves were established. RESULTS: Participants with low muscle mass had significantly lower alanine and aspartate aminotransferase, and both FPCP and PPCP levels (P < 0.05). Compared with those without low muscle mass, low muscle mass group had significantly higher FPG, HbA1c, GA levels (P < 0.05). Body fat (BF, OR = 1.181) was an independent risk factor for low muscle mass. PPCP (OR = 0.497), BMI (OR = 0.548), and female (OR = 0.050) were identified as protective factors for low skeletal muscle. The AUC of BMI was the highest, followed by the PPCP, gender and BF (0.810, 0.675, 0.647, and 0.639, respectively), and the AUC of the combination of the above four parameters reached 0.895. CONCLUSIONS: In this cross-sectional study, BMI, Female, and PPCP associated with T2DM were protective factors for low muscle mass. BF was associated with T2DM and risk factor for low muscle mass.

Retinal microcirculation: A window into systemic circulation and metabolic disease.

The retinal microcirculation system constitutes a unique terminal vessel bed of the systemic circulation, and its perfusion status is directly associated with the neural function of the retina. This vascular network, essential for nourishing various layers of the retina, comprises two primary microcirculation systems: the retinal microcirculation and the choroidal microcirculation, with each system supplying blood to distinct retinal layers and maintaining the associated neural function. The blood flow of those capillaries is regulated via different mechanisms. However, a range of internal and external factors can disrupt the normal architecture and blood flow within the retinal microcirculation, leading to several retinal pathologies, including diabetic retinopathy, macular edema, and vascular occlusions. Metabolic disturbances such as hyperglycemia, hypertension, and dyslipidemia are known to modify retinal microcirculation through various pathways. These alterations are observable in chronic metabolic conditions like diabetes, coronary artery disease, and cerebral microvascular disease due to advances in non-invasive or minimally invasive retinal imaging techniques. Thus, examination of the retinal microcirculation can provide insights into the progression of numerous chronic metabolic disorders. This review discusses the anatomy, physiology and pathophysiology of the retinal microvascular system, with a particular emphasis on the connections between retinal microcirculation and systemic circulation in both healthy states and in the context of prevalent chronic metabolic diseases.

PDCL3 is a prognostic biomarker associated with immune infiltration in hepatocellular carcinoma.

BACKGROUND: Phosducin-like 3 (PDCL3) is a member of the photoreceptor family, characterized by a thioredoxin-like structural domain and evolutionary conservation. It plays roles in angiogenesis and apoptosis. Despite its significance, research on the biological role of PDCL3 in liver hepatocellular carcinoma (LIHC) remains limited. This study aims to explore the prognostic value and potential mechanisms of PDCL3 in cancer, particularly in LIHC, through bioinformatics analysis. METHODS: RNA-seq data and corresponding clinical information for pan-cancer and LIHC were extracted from the TCGA database to analyze PDCL3 expression and survival prognosis. Differential expression of PDCL3 was analyzed using the HPA database. GO and KEGG enrichment analysis were performed for PDCL3-associated genes. The relationship between PDCL3 expression and various immune cell types was examined using the TIMER website. Clinical samples were collected, and immunohistochemistry and immunofluorescence experiments were conducted to validate the differential expression of PDCL3 in LIHC and normal tissues. In vitro assays, including CCK-8, wound healing, Transwell, and colony formation experiments, were employed to determine the biological functions of PDCL3 in LIHC cells. RESULTS: Analysis from TIMER, GEPIA, UALCAN, and HPA databases revealed differential expression of PDCL3 in various tumors. Prognostic analysis from GEPIA and TCGA databases indicated that high PDCL3 expression was associated with poorer clinical staging and prognosis in LIHC. Enrichment analysis of PDCL3-associated genes revealed its involvement in various immune responses. TCGA and TIMER databases showed that high PDCL3 expression in LIHC decreased tumor immune activity by reducing macrophage infiltration. PDCL3 exhibited positive correlations with multiple immune checkpoint genes. Immunohistochemistry (IHC) and immunofluorescence (IF) experiments confirmed elevated PDCL3 expression in LIHC tissues compared to adjacent normal tissues. In vitro experiments demonstrated that PDCL3 promoted LIHC cell proliferation, migration, invasion, and colony-forming ability. CONCLUSION: PDCL3 is highly expressed in various cancer types. Our study suggests that elevated PDCL3 expression in hepatocellular carcinoma is associated with poorer prognosis and may serve as a potential diagnostic biomarker for LIHC. PDCL3 may regulate the biological functions of LIHC by modulating immune infiltration. However, the precise regulatory mechanisms of PDCL3 in cancer warrant further investigation.

The Rapid Changes in Bodyweight and Glycemic Control Are Determined by Pre-status After Bariatric Surgery in Both Genders in Young Chinese Individuals.

PURPOSES: The primary aim of this clinical study is to identify the factors associated with rapid glycemic, bodyweight, and lipid profile remission in young obese patients following bariatric surgery. MATERIALS AND METHODS: In a total of 131 Chinese in-patients at Shanghai Pudong Hospital, China, we retrospectively analyzed in-patient data of metabolic parameters, including BMI, waist circumference, blood pressure (BP), and blood laboratory tests, such as plasma lipids and lipoprotein, hemoglobulin A1c (HbA1c), and oral glucose tolerance tests (OGTT) before bariatric surgery. We followed up these indices at the first month, third months, half-year, and one year later. RESULTS: The results showed that bodyweight, BP, fasting plasma glucose (FPG), HbA1c, and triglyceride (TG) levels decreased significantly in one to three months following surgery in both male and female patients (p<0.05). We demonstrated that age (male: ß=-0.181; female: ß=-0.292) and the pre-operation HbA1c levels (male: ß=0.935; female: ß=0.919) were independent predictors of HbA1c reduction in both young obese male and female patients in three months after surgery. For body weight loss, age (ß=-0.229) and pre-operation bodyweight (ß=0.735) are the predictors in females, but only pre-operation body weight (ß=0.798) is the independent predictor in obese young male patients. CONCLUSION:  This study discovered that changes in bodyweight were determined by age, pre-operation status of bodyweight, and HbA1C in obese young Chinese.

The Metabolic Characteristics of Patients at the Risk for Diabetic Foot Ulcer: A Comparative Study of Diabetic Patients with and without Diabetic Foot.

Backgrounds and Objective: Diabetic foot is a relatively severe complication in patients with type 2 diabetes (T2D), with peripheral neuropathy and angiopathy frequently serving as risk factors. However, it is unknown how the other major systemic metabolic factors impacted the profile of these patients, besides glucose management. Thus, we investigated the distinct characteristics of patients with diabetic foot ulcers and their relationships with angiopathy. Materials and Methods: We obtained the laboratory data of 334 diabetic patients at Shanghai Pudong Hospital from 2020 to 2023. The comparisons were performed between the groups with or without diabetic foot, including glucose metabolism, lipids profile, liver and kidney function, thyroid function, and serum iron. The association between metabolic factors and lower extremity computed tomography angiography (CTA) was analyzed. Results: We found significant disparities between groups in relation to age, serum protein content, liver transferase, serum creatinine, estimated glomerular filtration rate (eGFR), serum uric acid (UA), small dense low-density lipoprotein (sdLDL), lipoprotein A (LP(a)), apolipoprotein A1 (APOA1), thyroid function, serum iron, and hemoglobin (Hb) (p<0.05). The Spearman correlational analyses showed that the severity of CTA, categorized by the unilateral or bilateral plaque or occlusion, was positively significantly correlated with UA (r=0.499), triglyceride (TG) (r=0.751), whereas inversely correlated with serum albumin (r=-0.510), alanine aminotransferase (r=-0.523), direct bilirubin (DBil) (r=-0.494), total bilirubin (TBil) (r=-0.550), Hb (r=-0.646). Conclusion: This cross-section investigation showed that compared to T2D only, the patients with diabetic foot ulcer (DFU) might display similar glucose metabolic control context but adverse metabolic profiles, and this profile is associated with macrovascular angiopathy characteristics and their severity.

The Association Between Sarcopenia and Diabetes: From Pathophysiology Mechanism to Therapeutic Strategy.

Diabetes and sarcopenia are emerging as serious public health issues. Sarcopenia, an age-related disorder characterized by loss of skeletal muscle mass and function, is recognized as a new complication in elderly patients with type 2 diabetes mellitus (T2DM). Type 2 diabetes is characterized by insulin resistance, chronic inflammation, accumulation of advanced glycation products and increased oxidative stress, which can negatively affect skeletal muscle mass, strength and function leading to sarcopenia. There is a mutual interrelationship between T2DM and sarcopenia in light of pathophysiology mechanism and long-term outcome. T2DM will accelerate the decline of muscle mass and function, which will in turn lead to glucose metabolism disorders, reduced physical activity and the risk of diabetes. However, the specific mechanism involved has not been thoroughly studied. Therefore, this review aims to explore the pathophysiology and therapeutic strategy related to sarcopenia and diabetes and provide insight for future investigations, which is of great significance for improving the quality of life in the elderly with diabetes and concurrently reducing the incidence of related complications.

Therapeutic Approaches for Nonalcoholic Fatty Liver Disease: Established Targets and Drugs.

Nonalcoholic fatty liver disease (NAFLD), as a multisystemic disease, is the most prevalent chronic liver disease characterized by extremely complex pathogenic mechanisms and multifactorial etiology, which often develops as a consequence of obesity, metabolic syndrome. Pathophysiological mechanisms involved in the development of NAFLD include diet, obesity, insulin resistance (IR), genetic and epigenetic determinants, intestinal dysbiosis, oxidative/nitrosative stress, autophagy dysregulation, hepatic inflammation, gut-liver axis, gut microbes, impaired mitochondrial metabolism and regulation of hepatic lipid metabolism. Some of the new drugs for the treatment of NAFLD are introduced here. All of them achieve therapeutic objectives by interfering with certain pathophysiological pathways of NAFLD, including fibroblast growth factors (FGF) analogues, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon-like peptide-1 (GLP-1) agonists, G protein-coupled receptors (GPCRs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), farnesoid X receptor (FXR), fatty acid synthase inhibitor (FASNi), antioxidants, etc. This review describes some pathophysiological mechanisms of NAFLD and established targets and drugs.

The Neuronal and Non-Neuronal Pathways of Sodium-Glucose Cotransporter-2 Inhibitor on Body Weight-Loss and Insulin Resistance.

With the emergence of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the treatment of type 2 diabetes mellitus (T2DM) has achieved a new milestone, of which the insulin-independent mechanism could produce weight loss, improve insulin resistance (IR) and exert other protective effects. Besides the well-acknowledged biochemical processes, the dysregulated balance between sympathetic and parasympathetic activity may play a significant role in IR and obesity. Weight loss caused by SGLT-2i could be achieved via activating the liver-brain-adipose neural axis in adipocytes. We previously demonstrated that SGLT-2 are widely expressed in central nervous system (CNS) tissues, and SGLT-2i could inhibit central areas associated with autonomic control through unidentified pathways, indicating that the role of the central sympathetic inhibition of SGLT-2i on blood pressure and weight loss. However, the exact pathway of SGLT2i related to these effects and to what extent it depends on the neural system are not fully understood. The evidence of how SGLT-2i interacts with the nervous system is worth exploring. Therefore, in this review, we will illustrate the potential neurological processes by which SGLT2i improves IR in skeletal muscle, liver, adipose tissue, and other insulin-target organs via the CNS and sympathetic nervous system/parasympathetic nervous system (SNS/PNS).

The Mechanism of Sodium-Glucose Cotransporter-2 Inhibitors in Reducing Uric Acid in Type 2 Diabetes Mellitus.

Hyperuricemia is a common comorbidity in patients with type 2 diabetes mellitus (T2DM), as insulin resistance (IR) or hyperinsulinemia is associated with higher serum uric acid (SUA) levels due to decreased uric acid (UA) secretion, and SUA vice versa is an important risk factor that promotes the occurrence and progression of T2DM and its complications. Growing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT-2i), a novel anti-diabetic drug initially developed to treat T2DM, may exert favorable effects in reducing SUA. Currently, one of the possible mechanisms is that SGLT2i increases urinary glucose excretion, probably inhibiting glucose transport 9 (GLUT9)-mediated uric acid reabsorption in the collecting duct, resulting in increased uric acid excretion in exchange for glucose reabsorption. Regardless of this possible mechanism, the underlying comprehensive mechanisms remain poorly elucidated. Therefore, in the present review, a variety of other potential mechanisms will be covered to identify the therapeutic role of SGLT-2i in hyperuricemia.

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors.

Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the "overstimulated" renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.