Persistent hyperinsulinemic hypoglycemia in infants is one of the most common causes of persistent hypoglycemia in infants. The knowledge of molecular defects leading to persistent hyperinsulinemic hypoglycemia in infants has been rapidly growing in recent years. According to the responsible genes, this ailment can be divided into five types. However, no molecular defect can be yet found in as many as 50% of the patients.

Objective To investigate the effect of insulin and gliclazide therapy on endoplasmic reticulum (ER) stress and insulin sensitivity in the liver of type 2 diabetic rats.Methods A high fat diet plus a low-dose of streptozotocin was implemented to create a type 2 diabetic rats which were randomly divided into diabetes mellitus (DM) group,insulin treatment (INS) group and gliclazide treatment (GT)group; and healthy rats were as normal control group.Diabetic rats in INS and GT groups were given neutral protamine hagedorn (NPH) insulin and gliclazide respectively for 3 weeks.Protein expression levels of immunoglobulin binding protein (Bip),spliced X-box binding protein 1 (XBP-ls),phosphorylated c-Jun on serine 73 (p-c-Jun),phosphorylated insulin receptor substrate 1 on serine 307 (p-IRS-1),and glucose-6-phosphatase (G6Pase) in liver homogenate were detected by Western blotting.Results Compared with the normal rats,Bip and XBP-Is in the DM group were up-regulated (0.28 ±0.07 vs 0.90 ±0.10 for Bip;0.41 ± 0.07 vs 0.95 ±0.07 for XBP-1 s; both P ＜ 0.01 ) ; p-c-Jun (0.59 ± 0.18 vs 1.94 ± 0.03 ),p-IRS-1( 1.73 ± 0.18 vs 5.32 ± 0.22) and G6Pase (0.11 ± 0.01 vs 0.45 ± 0.01 ) were increased ( all P values ＜0.01 ).In the INS group,all of aforementioned changes were reversed (0.90 ± 0.10 vs 0.25 ± 0.04 for Bip; 0.95 ±0.07 vs 0.47 ±0.01 for XBP-1s; 1.94 ± 0.03 vs 0.50 ±0.10 for p-c-Jun; 5.32 ± 0.22 vs 1.59 ±0.32 for p-IRS-1 ; 0.45 ±0.01 vs 0.15 ±0.02 for G6Pase,all P values ＜0.01 ).In the GT group,all of aforementioned changes were also attenuated ( 0.90 ± 0.10 vs 0.53 ± 00.02 for Bip ; 0.95 ± 0.07 vs 0.78±0.02 for XBP-1s; 1.94 ±0.03 vs 1.33 ±0.11 for p-c-Jun; 5.32 ±0.22 vs 3.13 ±0.02 for p-IRS-1; 0.45 ± 0.01 vs 0.25 ± 0.01 for G6Pase,all P values ＜ 0.05).Furthermore,all of aforementioned protein levels were down-regulated more obviously in the INS group comparing to the GT group ( all P values ＜ 0.01 ).Conclusions Both insulin and gliclazide therapy could relieve ER stress and e-Jun N-terminal kinase activity and improved insulin sensitivity.The effect of insulin on Bip,XBP-1s,p-c-Jun,p-IRS-1 and G6Pase protein expressions is more obvious than that of glilcazide,which indicates besides lowering glucose,insulin might have protective effects of anti-inflammation,anti-oxidative stress or stimulation of lipid redistribution.

ovel GCK-E339K mutation might be linked to this MODY2 pedigree.

[Objective] The aim of our study was to seek the mutations in MODY1～5 genes in Chinese population by direct sequencing in probands from families with early-onset type 2 diabetes.[Methods] Variants screening in MODY 1-5 genes were performed by PCR and direct sequencing in 19 probands from early-onset type 2 diabetes families.[Results] We found no mutation but many polymorphisms.There were 6,5,15,1,and 1 variants in MODY 1-5 genes respectively.[Conclusion] Our negative results in MODY genes suggest the genetic heterogeneity of different populations.Mutations in MODY 1-5 genes might not be the cause of diabetes in those 19 families.

Objective To investigate the effect of early insulin therapy on NF-KB pathway and inflammatory cytokine responses in fiver of diabetic rat.Methods NF-KB p65 DNA binding was assayed with ELISA-based assay kit,cytokine gene expressions were quantified with real-time PCR and phosphoenolpyruvate carboxykinase(PEPCK),NF-KB and inhibitor KB(IKBα)protein levels wlere assayed with Westem blot.Results Compared with control,hepatic PEPCK protein level in the untreated diabetic rat increased by 40%.Early insulin and gliclazide treatment normalized PEPCK protein level.The abundance of IKBα protein was significantly decreased and nuclear NF-KB p65 DNA binding activity was incteased in untreated diabetic rats.IKBot protein content increased and NF-KB p65 DNA binding decreased during early intervention treatment.mRNAs encoding IL-1β and TNFα were increased,which were reduced to normal levels after insulin and gliclazide treatment.Conclusions It is suggested that early insulin treatment inhibits NF-KB activity and inflammatory cytokine responses in fiver that are involved in the aniefioration of insulin resistance in diabetic rats.Such results misht be due to indirect antiinflammatory effects of insulin thus relieving glucotoxicity and lipotoxicity in pefipherM tissues.

Objective: To observe the endoscopic morphology of gastric varices of patients with portal hypertension type one isolated gastric varices (IGV-1) and to explore the etiology, treatment and prognosis of portal hypertension IGV-1. Methods: From January 2006 to June 2018, at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and North Branch of Ruijin Hospital, 54 patients with portal hypertension IGV-1 were retrospectively analyzed. The varices were classified according to the endoscopic morphology and the etiology treatment, therapeutic efficacy and prognosis were also analyzed. Descriptive method was used for statistical analysis. Results: Among the 54 patients with portal hypertension IGV-1, the endoscopic morphology of varices were tuber type in 24 patients (44.4%), grape string type in nine patients (16.7%), strip type in five patients (9.3%), dendritic type in three patients (5.6%) and mixed type in 13 patients(24.1%). Etiological analysis showed that the primary disease of 34 cases (63.0%) were hepatogenic, 11 cases (20.4%) were pancreatic origin, and nine cases (16.7%) were from other diseases. As to treatment, three cases (5.6%) were treated with adhesive, two cases (3.7%) were treated with sclerotherapy, and 49 cases (90.7%) were treated with combination of adhesive and sclerotherapy. Therapeutic efficacy evaluation showed that 46 cases (85.2%) were significantly effective, eight cases were effective, 0 case was ineffective, and all the 54 cases (100.0%) were improved. The prognostic analysis showed that 35 cases (64.8%) had no bleeding in five years and eight cases (14.8%) had no bleeding in 10 years. Nine patients (16.7%) died, including six cases of pancreatic cancer, two cases of liver failure and one case of gastrointestinal bleeding. Conclusions The endoscopic morphology of IGV-1 portal hypertension in mainly tuber type. The main cause is hepatogenic and the combination of adhesive and sclerotherapy is beneficial to the regression of gastric varices.

AIM:To investigate the effects of mitogen-inducible gene 6(MIG6)overexpression on palmitic acid(PA)-induced endoplasmic reticulum stress-associated steatosis in hepatocytes.METHODS:A mouse model of non-alcoholic steatohepatitis was established by feeding twenty C57BL/6J mice a high-fat diet for 26 weeks.The mice were ran-domly divided into two groups:normal diet control group and high-fat diet group,and their livers were retained for subse-quent experiments.The PA was used to induce lipid accumulation in HepG2 cells and AML12 cells,and the cells were di-vided into two groups:BSA(10%BSA)group and PA(500 μmol/L PA)group.The MIG6 overexpression was induced by transfecting HepG2 and AML12 cells with human and mouse MIG6 overexpression plasmids,respectively.The cells were divided into four groups according to their different treatment conditions:(1)negatiive+BSA group(transfected with nega-tive control plasmid+10%BSA);(2)MIG6+BSA group(transfected with MIG6 overexpression plasmid+10%BSA);(3)negative+PA group(transfected with negative control plasmid+500 μmol/L PA);(4)MIG6+PA group(transfected with MIG6 overexpression plasmid+500 μmol/L PA).Lipid accumulation in hepatocytes was assessed by oil red O staining,and RT-qPCR was used to detect the mRNA expression level of MIG6 in liver tissues.The protein levels of MIG6,lipid synthesis-related molecules fatty acid synthase(FASN)and sterol regulatory element-binding protein 1(SREBP1),and endoplasmic reticulum stress-related proteins glucose regulated protein 78(GRP78)and C/EBP homologous protein(CHOP)in hepatocytes were detected using Western blot.RESULTS:High-fat diet increased the triglyceride content in the liver tissue of C57BL/6J mice induced lipid accumulation in hepatocytes and suppressed the mRNA expression level of MIG6(P<0.01).PA intervention increased the protein levels of lipid synthesis-related molecules such as FASN and SREBP1,and endoplasmic reticulum stress markers GRP78 and CHOP in hepatocytes,but inhibited MIG6 protein levels(P<0.01).We transfected hepatocytes with MIG6 overexpression plasmid,which significantly increased MIG6 protein levels,decreased GRP78 and CHOP protein levels in hepatocytes(P<0.01),significantly attenuated PA-induced lipid accumulation in hepatocytes,and down-regulated FASN and SREBP1 protein levels(P<0.01).These results indicate that MIG6 overexpression inhibited PA-induced endoplasmic reticulum stress and attenuated lipid accumulation in hepato-cytes.CONCLUSION:Overexpression of MIG6 inhibits lipid accumulation in hepatocytes by suppressing endoplasmic reticulum stress.

OBJECTIVETo investigate the association of Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 gene with type 2 diabetes mellitus and its clinical characteristics.

METHODSThe genotypes of Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 gene were determined by polymerase chain reaction-restriction fragment length polymorphisms assay in 401 unrelated subjects of the Han population in the southern part of China (including 180 subjects with normal glucose tolerance and 221 type 2 diabetic patients). The clinical data were also analyzed.

RESULTSThe allele frequencies in the case and control groups were 96.15%,96.11% for P and 3.85%, 3.89% for A; the genotype frequencies were 92.77%, 92.22% for PP, 6.78%, 7.78% for PA and 0.45%, 0 for AA. The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 was not significantly associated with type 2 diabetes. The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 in diabetes patients was associated with increased waist circumference and waist to hip ratio. The Pro12Ala polymorphism in Chinese population was similar to that in Japanese population and was different from that in European and American population.

CONCLUSIONThe above data showed that the Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 was not significantly associated with type 2 diabetes, but it could be associated with abdominal obesity in type 2 diabetes. The significant difference of Pro12Ala of peroxisome proliferator-activated receptor-gamma2 among various races was observed.

Adult ; Alanine ; genetics ; Alleles ; Amino Acid Substitution ; Blood Glucose ; metabolism ; Body Constitution ; Body Mass Index ; Cholesterol ; blood ; Cholesterol, HDL ; blood ; Cholesterol, LDL ; blood ; Diabetes Mellitus, Type 2 ; blood ; genetics ; pathology ; Female ; Gene Frequency ; Genotype ; Humans ; Insulin ; blood ; Male ; Middle Aged ; Proline ; genetics ; Receptors, Cytoplasmic and Nuclear ; genetics ; Transcription Factors ; genetics ; Triglycerides ; blood

China ; Diabetes Mellitus ; diagnosis ; Female ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases ; diagnosis

In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis-a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.
Humans ; Mice ; Animals ; Non-alcoholic Fatty Liver Disease/metabolism* ; NF-kappa B/metabolism* ; Organelle Biogenesis ; Retrospective Studies ; Mice, Inbred C57BL ; Obesity/metabolism* ; Liver ; Inflammation/metabolism* ; Body Weight ; Lipid Metabolism ; Lipids ; Diet, High-Fat/adverse effects*