ABSTRACT
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.
ABSTRACT
La apnea obstructiva del sueño (AOS) y el síndrome hipoventilación-obesidad (SHO) son patologías que se encuentran estrechamente asociadas a la obesidad como principal factor de riesgo, hasta un 70% de los pacientes con AOS son obesos. Ambas patologías comparten procesos fisiopatológicos comunes, donde destaca la inflamación sistémica, lo que, sumado a la hipoxia crónica intermitente y la fragmentación del sueño característicos de la AOS, aumenta considerablemente el riesgo de presentar comorbilidades metabólicas como síndrome metabólico, alteraciones en el metabolismo de la glucosa (resistencia a la insulina y diabetes mellitus tipo 2), y hígado graso metabólico. En esta revisión narrativa, se describirán los mecanismos identificados en estas asociaciones, así como la prevalencia y la evidencia sobre el tratamiento de la AOS y del SHO
Obstructive sleep apnea (OSA) and obesity-hypoventilation syndrome (OHS) are pathologies that are closely associated with obesity as the main risk factor, up to 70% of patients with OSA are obese. Both pathologies share common pathophysiological processes, where systemic inflammation stands out, which, added to the intermittent chronic hypoxia and sleep fragmentation characteristic of OSA, considerably increases the risk of presenting metabolic comorbidities such as metabolic syndrome, alterations in the metabolism of the glucose (insulin resistance and type 2 diabetes mellitus), and metabolic fatty liver. In this narrative review, the mechanisms identified in these associations will be described, as well as the prevalence and evidence on the treatment of OSA and OHS
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Sleep Apnea, Obstructive/metabolism , Sleep Apnea, Obstructive/epidemiology , Obesity Hypoventilation Syndrome/metabolism , Obesity Hypoventilation Syndrome/epidemiology , Risk Factors , Sleep Apnea, Obstructive/therapy , Metabolic Syndrome , Hypoxia/physiopathologyABSTRACT
OBJECTIVE：To study the i mprovement effects of α-lipoic acid on glucose metabolism disorder of insulin resistant HepG2 cells. METHODS ：The effects of 25-1 000 µmol/L α-lipoic acid on survival rate of human hepatoma cell HepG2 were determined by MTT assay so as to determine the concentration of α-lipoic acid. Negative control group ，insulin resistance group （1× 10－7 mol/L insulin ），combination resistance group （30 µmol/L sodium arsenite+ 1×10－8 mol/L insulin ），α-lipoic acid low- concentration，medium-concentration and high-concentration groups were set up. HepG 2 cells were treated with α-lipoic acid for 12 h and then cultured with corresponding concentration of sodium arsenite or/and insulin for 24 h. The glucose oxidase method was used to detect the glucose consumption ，colorimetric method was used to detect hexokinase activity and pyruvate kinase activity ， and anthrone method was used to detect glycogen content. Western blot assay was used to detect the protein expression of GLUT 4， p-GSK3β and GSK3β as well as the ratio of p-Akt/Akt and p-GSK3β/GSK3β. RESULTS：25，50，100 µmol/L α-lipoic acid had no significant effect on the survival rates of HepG 2 cells（P＞0.05），and survival rates of H epG2 cells were higher than 96％，so they were used as the low ，medium and high concentration for follow-up study. Compared with negative control group ，glucose consumption，the activities of hexokinase and pyruvate kinase ，glycogen content ，protein expression of GLUT 4 and p-GSK 3β，the ratio of p-Akt/Akt and p-GSK 3β/GSK3β were decreased significantly in insulin resistance group and combined resistance group， while the protein expression of GSK 3β was increased significantly（P＜0.05）. Compared with combination resistance group ，the glucose consumption （except for α-lipoic acid low- concentration group ），the activities of h exokinase（except for α-lipoic acid low-concentration and medium-concentration groups ） andpyruvate kinase （except for α-lipoic acid low-concentration com and medium-concentration groups ）， glycogen contents ， protein expression of GLUT 4 （except for α-lipoic acid mail：bliang163@163.com low-concentration group ）and p-GSK3β，the ratio of p-Akt/ Akt（except for α-lipoic acid low-concentration and medium-concentration groups ）and p-GSK 3β/GSK3β（except for α-lipoic acid low-concentration groups ）were increased significantly in α-lipoic acid groups ，while protein expression of GSK 3β（except for α-lipoic acid low-concentration and medium-concentration groups ） was decreased significantly （P＜0.05）；glycogen content ， protein expression of GLUT 4 and the ratio of p-GSK 3β/GSK3β in α-lipoic acid high-concentration group as well as the protein expression of p-GSK 3β in α-lipoic acid medium-concentration and high-concentration groups were improved significantly （P＜0.05）. CONCLUSIONS：α-lipoic acid can improve the disorder of glucose metabolism in insulin resistant HepG 2 cells，the mechanism of which may be associated with the increase of glucose consumption ，the activities of glucose metabolism related enzymes and glycogen content ，and expression up-regulation of the phosphorylation levels of Akt and GSK 3β protein，the expression of GLUT 4 and p-GSK 3β proteins，down-regulation of the expression of GSK 3β protein.
ABSTRACT
Objective To study glucose metabolism in patients with liver cirrhosis and to explore the relationship between glucose and liver function.Methods 164 liver cirrhosis patients with abnormal glucose metabolism were divided into A,B and C groups according to Child-Turcotte-Pugh(CTP)classification system.Glucose metabolic disorder and relation between blood sugar level and liver function were observed and analyzed.Results We divided the patients into three subgroups according to their blood sugar levels:hypoglycemia group,impaired fasting glucose group and diabetes mellitus group.Patients of Grade C were with the highest incidence of hypoglycemia,with a P value P