Volume 08 · Issue 09 · 2016

nonalcoholic fatty liver disease (NAFLD) is an acquired metabolic stress liver injury closely related to genetic susceptibility and insulin resistance (IR). The disease spectrum includes nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and its associated cirrhosis and hepatocellular carcinoma (HCC)^[1,2]。 With the prevalence of obesity and type 2 diabetes mellitus (T2DM), NAFLD has become the first chronic liver disease in China, with a prevalence rate of more than 15% in ordinary adults, and more and more NAFLD occurs in patients with chronic viral hepatitis and alcohol abuse^[3,4]。 As an important component of metabolic syndrome, the main causes of death in NAFLD patients are cardiovascular disease (CVD) and malignant tumors^[1,2]NASH, especially in patients with progressive liver fibrosis, significantly increased liver disease death, and up to 13.3% of T2DM patients died of liver cirrhosis and HCC^[5,6]。 Therefore, NAFLD and T2DM are mutually causal, and IR is their common pathogenesis. At present, it is urgent to strengthen clinical research on the prevention and treatment of NAFLD combined with T2DM, and pay attention to the screening, prevention, treatment and monitoring of NAFLD and T2DM.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is 30% in the general adult population, and as high as 60% to 70% in diabetic and obese patients^[1]。 NAFLD is not only a liver disease that progresses from simple hepatocellular steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and even liver cancer, but also a liver manifestation of metabolic syndrome. So far, there is a lot of evidence that NAFLD can predict the occurrence and development of type 2 diabetes mellitus (T2DM). Are all liver fat deposits harmful to the body? Previous studies have shown that mild liver fat deposition does not increase the risk of diabetes. Mild elevation of free fatty acids (FFA) in the liver can synthesize neutral triglycerides (TG) and store them in the liver; The compensatory increase of liver TG can be regarded as a protective response of the body against FFA to hepatocyte injury^[2]。 So, to what extent can liver fat deposition initiate abnormal glucose and lipid metabolism? In other words, what is the threshold for liver fat content that causes abnormal glycolipid metabolism? It is very important to answer this question. If such a threshold exists, it is of great significance for early precise diagnosis of fatty liver and earlier prevention of diabetes. This paper discusses the current quantitative evidence for NAFLD to predict the onset of T2DM.

nonalcoholic fatty liver disease (NAFLD) is a metabolic stress-induced liver damage closely related to insulin resistance (IR) and genetic susceptibility^[1]The pathological changes are mainly hepatocellular steatosis, and its disease spectrum includes nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma. IR is the core pathophysiological basis of NAFLD, which is manifested by the decrease of the body's insulin-responsive glucose transport capacity, and then the pancreas excessively secretes insulin to meet the needs of cellular glucose uptake and utilization to compensate and maintain glucose metabolism homeostasis^[2]。 With the progression of IR, it not only promotes the overload of pancreatic islet β cells to secrete insulin, which impairs the secretion function, causing the occurrence of type 2 diabetes mellitus (T2DM), but also aggravates liver inflammation and fibrosis, which further damages the liver and aggravates IR, forming a vicious circle^[3]。 NAFLD is co-occurring with T2DM, and liver fatty changes tend to progress to end-stage liver disease^[4]Doubling the risk of liver cancer^[5]While the patient's glycolipid disorder is more difficult to correct^[6], significantly increased mortality from T2DM-related cardiovascular complications^[1,7]。 Therefore, how to choose a reasonable treatment strategy, adopt individualized comprehensive treatment to control blood sugar and delay the deterioration of liver disease, and reduce the risk of cardiovascular disease is of great significance for improving the prognosis of patients with NAFLD combined with T2DM.

In the past two decades, the prevalence of overweight/obesity in China has increased year by year, showing an epidemic trend. According to data from the China Health and Nutrition Survey (CHNS)^[1], the prevalence of overweight/obesity in adults increased from 13.4% to 26.4% over the 17-year period from 1993 to 2009, with an overall linear increase; The prevalence of abdominal obesity in adults increased from 18.6% to 37.4%, with an average annual increase of 1.1%, which was significantly higher than the growth rate of overweight/obesity. Obesity is a potential risk factor for diabetes, cardiovascular disease and other metabolic diseases and tumors. Weight loss treatment includes lifestyle (diet and physical exercise) adjustment, medical medication and surgical treatment. Scientific and rational nutritional therapy combined with exercise intervention is still the most effective and safe basic treatment at present. In recent years, there has been some international consensus on the nutritional management of obesity/overweight^[2,3]。 However, obesity/overweight management centered on nutrition and lifestyle interventions must be adapted to specific regional dietary habits and sociocultures. In order to give full play to the role of medical nutrition therapy in the prevention and treatment of obesity, this consensus is specially formulated in combination with many evidences published at home and abroad and the collective wisdom of experts, so as to make medical weight loss more scientific, standardized and easy to implement.

To assess the association between cardiac dysfunction and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM).

One hundred and nine patients with T2DM treated in Xinhua Hospital Diabetes and Endocrinology Ward from June, 2015 to December, 2015 were recruited in this study. Of the patients, 60 were diagnosed with NAFLD and 49 without by the controlled attenuation parameter(CAP). According to the CAP values, patients were divided into three groups: low CAP group (CAP<231 db/m,n=36), medium CAP group (231≤CAP<289 db/m,n=36) and high CAP group (CAP≥289 db/m, n=37). All patients underwent M-type/Doppler flow echocardiography to obtain cardiac structural and functional parameters. Data were compared between groups by using t or F test.

It was found that patients with both T2DM and NAFLD had significantly lower peak early diastolic velocity measured at lateral mitral valve annulus(E_m), and higher trans-mitral peak early diastolic velocity(E)/E_m ratio and E/mean values of peak early diastolic velocity measured at both medial an lateral mitral valve annulus(E_mean) ratio than patients without NAFLD (t=2.117, -2.164, -2.224, all P<0.05). Patients with both T2DM and NAFLD had also significantly lower left ventricular ejection fraction(EF) than patients with only T2DM (59% ± 6% vs 62% ± 6%, t=2.169, P<0.05). The prevalence of left ventricular diastolic dysfunction (LVDD) in patients with both T2DM and NAFLD was higher than that in patients with only T2DM (90.0% vs 71.4%, χ ²=6.209, P<0.05). However, all cardiac structural parameters were not significantly different between these two groups (all P>0.05). Patients with high CAP have significantly lower E_m, E_mean, E_m/peak late diastolic velocity measured at lateral mitral valve annulus(A_m) ratio, and higher E/E_m and E/E_mean ratios than patients with low and medium CAP (F=3.876, 3.425, 2.933, 2.942, 3.303, all P< 0.05). EF values were also significantly lower in patients with high CAP than those in patients with low and medium CAP(F=6.819, P<0.05). CAP values were negatively correlated with E_m, E_mean, and EF (R=-0.230, -0.221, -0.381, all P<0.05) and positively correlated with E/E_m and E/E_mean (R=0.211, 0.227, both P<0.05). There were no significantly differences in prevalences of left ventricular hypertrophy and LVDD across three CAP groups(χ²=1.777, 7.280, both P>0.05).

NAFLD is a risk factor for cardiac diastolic dysfunction in patients with T2DM, but not for cardiac structural changes.

To explore the role of hepatic c-Jun N-terminal protein kinase(JNK) signaling pathway in diabetic rat with nonalcoholic fatty liver disease(NAFLD), and the intervention effect of liraglutide.

Twenty-four male Wistar rats (4-week old) were randomly divided into control group (NC, n=6) and type 2 diabetic model group(n=18) with random number table. The model group were given high-fat high-glucose feeding and abdominal injection of little dosage of streptozotocin (30 mg/kg) to set up type 2 diabetic models. And the successfully-established 14 model rats were divided into diabetic group(DM, n=7) and diabetic + liraglutide group(LIR, n=7) with random number table. Control rats were fed with standard rodent chow diet. LIR group were injected intraperitoneally with liraglutide 100 μg/kg twice daily for 8 weeks, while rats in NC and DM groups were injected with distilled water for 8 weeks. Body weight was measured weekly. Blood samples were collected after rats were terminated and serum levels of lipids, tumor necrosis factor-α(TNF-α), nuclear factor kappa B(NF-κB), alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were all detected. Liver tissue samples were collected for histological analysis, and hepatic protein expression of JNK and phosphorylated JNK(p-JNK) was measured by immunohistochemistry and Western blotting methods. Data were analyzed by one-way analysis of variance, SNK- q, nonparametric tests and Spearman correlation analysis.

Histological staining showed liver steatosis and inflammation in DM rats while these pathological alterations were improved in LIR group. Hepatic p-JNK/JNK ratio was significantly higher in DM group than that in NC group(1.3(0.8,2.0) vs 1(0, 1), Z=-3.055, P< 0.05), while it was decreased remarkably by liraglutide treatment(Z=-2.320, P<0.05). Compared with that in NC group, the hepatic p-JNK/JNK protein expression in DM group was elevated for (2.60±0.03) folds, while it was elevated for (2.10 ± 0.05) folds in LIR group. Serum levels of TNF-α and NF-κB were positively correlated with hepatic p-JNK/JNK ratio with Spearman correlation analysis(r=0.623, 0.722, both P<0.05).

JNK pathway activation may play an important role in the development of NAFLD in type 2 diabetic rats. Liraglutide may improve diabetic NAFLD through decreasing JNK phosphorylation and reducing liver inflammation response.

To investigate and compare the optimal screening tool for impaired fasting glucose(IFG) subjects, impaired glucose tolerance(IGT) subjects and undiagnosed diabetes, using waist circumstance(WC) and waist-to-height ratio(WHtR) in Shanghai.

A total of 18 062 participants (aged ≥35 years) were enrolled from the Shanghai Chronic Disease and Risk Factor Surveillance in 2013. Correlational analyses of WC and WHtR with IFG and IGT were conducted using Pearson correlation method. The receiver operating characteristic (ROC) analysis was used to compare their predictive ability for IFG, IGT and undiagnosed diabetes. According to the recommended cut-off value, screening of the three abnormal glucose status was performed using WC, WHtR and/or body mass index (BMI).

Both WC and WHtR were positively correlated with FPG (r=0.161, 0.153, P<0.05 all above) and 2 hPG (r=0.182, 0.225, P<0.05 all above). The AUCs of WC and WHtR in screening IGT, IFG and undiagnosed diabetes were 0.620(95%CI: 0.611-0.629),0.636 (95%CI: 0.628-0.645, Z=2.549, P<0.05), respectively. The same result was obtained among female patients in screening IGT (0.663 vs 0.636, Z=-2.386, P<0.05). The AUC of WC in screening IGT (0.617, 95%CI: 0.605-0.629) was significantly lower than that of WHtR(0.646, 95% CI: 0.635-0.658, Z=-3.418, P<0.01). However, no difference between WC and WHtR in screening IFG and undiagnosed diabetes was shown (P>0.05). The difference of the best cut-off value of WC and WHtR between male and female subjects was 3-5 cm and 0.01, respectively. Among 4 screening algorithms by combining BMI in parallel or in serial, the specificity of WC combing BMI in serial was the highest for the screening of IFG, IGT, undiagnosed diabetes, and abnormal glucose subject (67.61%, 69.17%, 68.94%, and 72.46%, respectively). The sensitivity of WHtR combing BMI in parallel was the highest (76.10%, 82.79%, 83.89%, and 81.63%).

WHtR is a better option than WC in screening IGT for females. There is almost no gender difference in the optimal cut off values of WHtR for screening of IGT, IFG and undiagnosed diabetes.

To investigate the effects of liraglutide on renal function, the glomerular morphology in electron microscope and oxidase subunit of dihydronicotinamide adenine dinuclectide phosphate(NADPH) —P22phox and P47phox in kidney in rats with insulin resistance(IR).

Fifty-four male Wistar rats were divided into normal diet group(group A, n=16) and high-fat diet group(n= 38). Hyperinsulinemic-euglycemic clamp test was performed at the waking state after 8 weeks feeding. Glucose infusion rate(GIR) was measured to determine if IR rats model was successful. The rats with high-fat diet were randomly divided into three groups: high-fat diet group(group B, n=11), liraglutide 100 μg/(kg·d) group (group C, n=11), liraglutide 200 μg/(kg·d) group(group D, n=11). The rats with normal diet was group A(n=11). Daily subcutaneous injections of saline were given group A, B, while liraglutide intervention was given in group C,D. After 2 weeks, biochemical markers were measured in each group. Realtime Quantitative PCR and Western blotting were used for detecting the expression of P22phox and P47phox in kidney. Renal ultrastructure was observed by transmission electron microscope. LSD t test was performed in comparison between the two groups, while one way variance analysis for multiple groups comparison.

(1) Compared with group A, the expression of P22phox and P47phoxin were significantly increased in group B (P22phox mRNA: 4.9±0.4 vs 1.0±0, P22phox protein: 2.72±0.20 vs 1.27±0.24; P47phox mRNA:4.8±0.8 vs 1.0 ± 0, P47phox protein: 2.17 ± 0.39 vs 1.13 ± 0.15, t=4.225-16.041, all P<0.05). (2) Compared with the group B, the expression level of P22phox and P47phox were decreased in liraglutide groups (P22phox mRNA: 2.3 ± 0.4, 4.5 ± 0.4, 4.9 ± 0.4 in group D,C,B, respectively; P22phox protein 1.75 ± 0.13, 2.32 ± 0.21, 2.72 ± 0.20; P47phox mRNA: 2.2 ± 0.3, 3.6 ± 0.4, 4.8 ± 0.8, in group D, C, B, respectively; P47phox protein: 1.30±0.18, 1.66±0.15, 2.17±0.39), and group D decreased more significantly than group C (t=6.482, 3.401, 4.875, 2.067, all P<0.05). (3) The basement membrane of glomerular in group B was uneven thickness, with part of the podocytes swelling, or even disappear. It was improved after the intervention of liraglutide, especially in group D.

Reducing oxidative stress by inhibiting the expression of P22phox, P47phox in kidney, maybe one of the kidney protection mechanisms of liraglutide on IR rats.

To observe the effect of long noncoding RNA(lncRNA)-urothelial carcinoma associated 1 (UCA-1) on the phosphatidylinositol 3-kinase-serine/threonine kinase (PI3K-Akt) signal pathway of 293T adipocyte and glucose uptake activity, and to explore the possible molecular mechanism.

Renal 293T epithelial cells were divided 5 groups: blank control group, empty plasmid as negative control group, nonsense disorderly sequence RNA negative control group (si-scramble, si-scr), over expression UCA-1 group (group UCA-1), and the silent UCA-1 group (si-UCA-1). UCA-1 was overexpressed or silenced by plasmids or specific siRNAs transfection in 293T. Then the effect of UCA-1 on the PI3K-Akt signal pathway of 293T cells was measured by Western blotting, and the RNA level and transcription activity of PTEN (phosphatase and tensin homolog deleted on chromosome ten) were detected by real-time fluorescence quantitative PCR and luciferase reporter assay, respectively. 2-deoxy-³H-D-glucose incorporation assay was performed to measure the glucose uptake activity of 293T cells. The t test was performed in comparison between the two groups, while one way variance analysis for multiple groups comparison.

Compared with the control group, the mRNA of PTEN and transcription activity in group UCA-1 was decreased (1.07 ± 0.05 vs 0.24 ± 0.05, 1.07 ± 0.05 vs 0.23 ± 0.03, t=14.257, 15.192, respectively, both P<0.01); Compared with the si-UCA-1group, the level of mRNA of PTEN and transcription activity in si-scr group dramatically increased (1.02±0.03 vs 12.47±0.17, 1.02±0.03 vs 12.53± 0.43, t=15.816, 14.527, both P<0.01). The glucose uptake activity was also increased in UCA-1 group (3.78 ± 0.39) times than the control group(t=6.711, P<0.05), and the restore expression of PTEN could reverse the regulation of UCA-1 on the glucose uptake activity (P>0.05).

UCA-1 can activate the PI3K-Akt signal pathway of 293T cells and enhance the glucose uptake activity by inhibiting PTEN expression.

growth hormone tumor is a solid tumor formed by the abnormal proliferation of adenopituitary growth hormone-releasing cells. Excessive secretion of growth hormone (GH) can lead to acromegaly in adults and gigantism before puberty. Excessive GH stimulates the decomposition of adipose tissue, increases the free fatty acids in plasma, increases the concentration of triglycerides, induces insulin resistance and hyperinsulinemia. About 20% of somatoma patients develop abnormal glucose tolerance or diabetes, but complicated diabetic ketoacidosis (DKA) is rare. Adolescent pituitary microadenoma with onset of DKA is more rare in clinic. A case diagnosed in the Department of Endocrinology and Metabolism of our hospital is reported below.

glucose transporter 2 (GLUT-2) is a member of the glucose transporter family. As an important carrier of glucose and fructose transport, small intestine GLUT-2 plays an important role in glucose metabolism and regulating glucose homeostasis. The role of small intestine GLUT-2 in intestinal glucose transport, the characteristics of its translocation and the regulatory factors are reviewed in this paper. The regulatory factors of GLUT-2 are mainly described from three aspects: intracellular signaling molecules, membrane-related receptors and channels, endocrine and paracrine hormones, and the localization mechanism of GLUT-2 in small intestine brush margin under obesity, diabetes and other pathological conditions is further reviewed.

Since Banting first extracted insulin for the treatment of diabetic patients in 1921, insulin has gone through hundreds of years of development, from animal insulin and human insulin to present insulin analogs. In the research and development of every meal insulin, solving the malabsorption and the clinical problems caused by the malabsorption are the reasons and motivation for the development of new formulations.