Volume 07 · Issue 04 · 2015

For a long time, scientists have believed that effector cells in the immune system are defense cells against tumors and infectious diseases, while regulatory cells mainly act on sensitization and autoimmune responses. In recent years, many studies have shown that immune cells have many non-traditional immune effects, including participating in the occurrence and development of neurodegenerative diseases, cardiovascular diseases and metabolic diseases. A New Frontier of Scientific Research- -immunometabolism^[1], mainly to study the interaction between immunity and metabolism in physiology and disease. At present, the discipline has made remarkable progress in two aspects: on the one hand, it is recently believed that the natural or acquired immune system is involved in what was previously thought to be non-immune diseases, such as obesity, which produce metabolic and immune abnormalities, which can lead to susceptibility to type 2 diabetes, cardiovascular disease, cancer or neurodegenerative diseases. On the other hand, immune cells, such as lymphocytes, are influenced by the regulation of internal metabolism on multiple levels. It is an urgent scientific problem to clarify the cellular and molecular mechanism of the interaction between immunity and metabolism.

Adiponectin is a small-molecule polypeptide hormone that is mainly synthesized and secreted by adipose tissue^[1]。 Adiponectin forms a variety of polymers in adipocytes and is secreted into the bloodstream. Its main forms include trimers, hexamers and high molecular polymers (consisting of at least 18 monomers)^[2,3]。 Different forms of adiponectin polymers have their own target tissue specificity and biological regulatory effects. Of the three important polymers of adiponectin, the high-molecular polymer adiponectin is the most active subtype to prevent obesity-induced metabolic complications^[3]。

Adenosine monophosphate-activated protein kinase (AMPK) is an energy and nutrient-sensing molecule that specifically binds to the transcription factor sterol regulatory element binding protein (SREBP) and produces a phosphorylation reaction. AMPK-dependent phosphorylation and inhibition of SREBP activity may be the molecular pharmacological mechanisms of AMPK agonists, which provide new ideas for the development of drugs for the treatment of type 2 diabetes-related fatty liver and atherosclerotic diseases. The role of the integrated AMPK and SREBP nutrition sensing signaling pathway in the regulation of hepatocyte fat metabolism and its significance in the treatment of type 2 diabetes mellitus are discussed in this paper.

Mild chronic inflammation of white adipose tissue and some other tissues in obesity^[1]。 Early mouse experiments suggest that chronic inflammation leads to insulin resistance. Therefore, many clinical trials use anti-inflammatory drugs to treat type 2 diabetes. However, most clinical results demonstrate that anti-inflammatory therapy does not improve insulin sensitivity^[2,3]。 At present, the reasons for the failure of anti-inflammatory therapy are still controversial. The main cause of controversy is the insufficient understanding that inflammation regulates energy metabolism. The author believes that inflammatory factors are necessary factors to maintain energy consumption, which is called the "beneficial role" of inflammation in regulating metabolism^[4]。 This article will further demonstrate this view from the direction of obesity, dieting and exercise.

In recent years, due to the improvement of people's living standards and the change of lifestyle, the number of obese people in China has shown an explosive increase, and obesity has become a serious public health problem. How to prevent and treat weight loss has also become a scientific issue of great concern. Different from white adipocytes, whose main function is to store lipids, brown adipocytes can burn fat and promote energy metabolism, providing a new method for preventing and treating obesity and its related metabolic diseases^[1,2]。 In particular, the recent discovery of adult brown fat cells has caused a sensation in the field of obesity and diabetes research, and may become a boon for obese patients in the near future^[1]。

To assess the characteristics and glycemic control of type 2 diabetic patients currently treated with human insulin regimen in China, and find out the issues in diabetes management.

From April to July in 2013, type 2 diabetic outpatients on the therapy of human insulin or human insulin combined with oral antidiabetic drugs (OADs), meeting the inclusion and exclusion criteria, were selected from the endocrinology departments of 348 representative hospitals across China, and filled out the information form. General information of the patients, duration of diabetes, medical history, diabetes complications and concomitant diseases, blood glucose and treatment regiment were recorded.The percentage of patients achieving glycated hemoglobin A1c(HbA_1c) target <7.0% intergroup difference was compared with t test.

A total of 75 168 eligible patients with type 2 diabetes were included in this study, 41 199 males and 33 969 females. The mean age was (59±10) years. The mean duration of diabetes was (8 ± 5) years. The mean duration of diabetes before initiating human insulin was (4 ± 4)years. Of the patients, 79.83% started insulin therapy due to the poor glycemic control with oral hypoglycemic agents. The mean dose of human insulin was (30±11) U/day. The proportion of patients receiving basal-bolus, prandial, basal, and premixed insulin regimen was 7.37% , 8.25% , 6.71% and 77.66% , respectively. The total percentage of patients achieving HbA_1c target was 31.84%. The rates of achieving HbA_1c target between the patients with and without regular self-monitoring of blood glucose, insulin dosage was stable or not, with or without hypoglycemia, with or without svere hyperglycemia, waited 30 min for the meal after injection or not, developed healthy diet habits or not, with physical training or not, with or without concomitant diseases were all significantly different(χ²=8.30- 2056.59, all P<0.05).

Poor glycemic control with oral hypoglycemic agents is the main reason for insulin initiation. Timely initiating insulin may bring clinical benefit.

To analyze the predictive parameters for therapeutic efficacy of metformin monotherapy in Chinese newly diagnosed patients with type 2 diabetes.

Subjects who were treated with metformin monotherapy for 48 weeks from "Study on the Mechanism of acarbose in Chinese Newly diagnosed Type 2 Diabetic Patient" (MARCH study) from November 2008 to June 2011 were enrolled. To assess the predictive parameters for therapeutic efficacy, a multiple linear regression analysis was performed, taking glycosylated hemoglobin (HbA _1c) reduction as a dependent variable, and baseline parameters as independent variables.

(1) A total of 354 patients (208 men and 146 women) with type 2 diabetes were enrolled. The mean age was(50±9)yrs, and the mean duration of diabetes was (3.3±5.0) months. (2) Multiple linear regression analysis indicated that baseline HbA_1c, fasting plasma glucose (FPG)(β =- 0.924, 0.216, t=- 27.71, 6.24, all P<0.01), diastolic blood pressure (DBP), homeostasis model assessment of insulin resistance (HOMA-IR), area under the curve of glucagon (AUC_glucagon) and area under the curve of plasma glucagon-like peptide-1 (AUC_GLP-1) (β =- 0.075- 0.076, t=- 2.33- 2.49, all P<0.05) were independent influencing factors for ΔHbA_1c at week 12; (3) HbA_1c (β=-0.860, t=-23.40, P<0.01) and FPG (β= 0.106,t=2.89, P=0.004)were independent influencing factors for ΔHbA _1c at week 48.

Metformin may be more effective in patients with newly diagnosed type 2 diabetes with higher baseline HbA_1c, HOMA-IR, AUC_GLP-1 and lower FPG and AUC_glucagon.

To provide a more reasonable therapeutic schedule for congenital hyperinsulinism (CHI) children and to analyze the clinical characteristics and follow-up data of the 12 cases with CHI whose symptoms alleviated spontaneously.

We choosed 12 patients with CHI whose symptoms alleviated spontaneously, hospitalized in Beijing Children's Hospital from December 2008 to January 2014,as research subjects. The clinical data and post follow-up data were analyzed retrospectively.

The 12 patients can maintain normal blood glucose for at least three months without drug treatment or after stopping the drug, which suggest that the group of children with CHI could relieve itself. The hypoglycemia relieved in 4 patients only by strengthening the feeding, and the other 8 children relieved gradually after diazoxide and (or) octreotide treatment. The onset age of the 12 children were all less than one year, and most of them younger than six months at onset (10/12). Most of them were appropriate for gestational age (7/12), 4 patients of them were born as macrosomia and the other one was small for gestional age. Seven cases of them alleviated in less than one year old (7/12), and the latest age of alleviation was 6 years. Four children were found carrying the mutation of ABCC8 gene.

Some children with CHI have the tendency of spontaneous remission, and the follow-up time should be extended. Especially for children with CHI who are not responsive to diazoxide, surgical treatment should be conside red cautiously to avoid serious surgical complications .

To analyze the different levels of serum bilirubin in different glucose metabolism status between monozygotic twins and to explore the new markers of abnormal glucose metabolism.

Fifty-five pairs of twins from January to September 2014 were registered in the cohort study, aged 18- 70 yrs. Oral glucose tolerance test (OGTT) was performed and glucose level was recorded 2 hours (2 hPG) after taking 75 g glucose. The individuals with diabetes and impaired glucose tolerance (IGT) were pooled to be abnormal glucose metabolism group (DM + IGT) while normal glucose subjects were pooled as NGT group. Serum biochemistry index was analyzed. Spearman correlation analysis was used to analyze the relationship of serum direct bilirubin and blood glucose in the subjects with abnormal glucose metabolism.

(1)Enrolled nine pairs of twins were all females, aged 50-62 yrs. Nine pairs of twins whose abnormal glucose tolerance was different were analyzed in the study. Among nine pairs of twins, 4 pairs were characterized as one with type 2 diabetes mellitus (T2DM) and the other with normal glucose tolerance (NGT1); 5 pairs were characterized as one with impaired glucose tolerance (IGT) and the other with normal glucose tolerance (NGT2).(2)Compared with NGT group, DM/IGT group had higher waist-to-hip ratio (0.89±0.05 vs 0.85±0.07, t=2.38, P<0.05) , higher triglyceride level((2.3±1.4)vs(1.0±0.6)mmol/L,t= 3,14,P<0.05), but lower serum level of direct bilirubin((3.1±0.8)vs(4.5±1.2)μmol/L,t=- 5.26,P<0.05). (3)Spearman correlation analysis showed direct bilirubin level was negatively correlated with 2 hPG in DM/IGT group(r=- 0.625, P<0.05). (4) Logistic regression analysis further confirmed the negative correlation between direct bilirubin and 2 hPG (OR=0.246,95%CI 0.66- 0.922,P<0.05). After adjusting for triglyceride and waist-to-hip ratio, direct bilirubin was no related with abnormal glucose metabolism (OR=0.366,95%CI 0.050-2.665,P>0.05). Conclusion One with lower serum bilirubin level may be at higher risk of abnormal glucose metabolism in monozygotic twins.

To investigate whether elevated levels of serum complement factor 3 (C3) increase the risk of developing type 2 diabetes mellitus (T2DM).

This was a nested casecontrol study. Non-diabetic inhabitants from a community in Chongqing were enrolled and followed up for 5 years. Clinical data were collected. Oral glucose tolerance test (OGTT) was performed at baseline and every 1- 2 years. Controls were randomly selected in a 1∶1 ratio to match new T2DM cases according to age, gender, and body mass index(BMI). Odds ratios (OR) for T2DM were calculated by conditional Logistic regression analysis.

A total of 255 subjects out of the 3 510 subjects developed T2DM during the 5-year follow-up. There were 141 males and 114 females in the T2DM group, aged (61±10) yrs vs (61±10) yrs in control group. The levels of serum C3 was higher in T2DM group than in control group at baseline((1.29±0.23) vs (1.25 ± 0.21) g/L, t=-2.017, P<0.05) .After adjusting for age, gender, BMI, smoking history, family history of diabetes, physical activity, low density lipoprotein cholesterol levels and systolic blood pressure, the risk of developing T2DM was still closely associated with elevated serum C3 levels(OR=1.652, 95%CI: 1.004-2.717, P<0.05). This correlation occurred mainly in the subjects with age >55 yrs old, BMI≥ 24 kg/m², total cholesterol≥5.2 mmol/L or triglyceride<1.70 mmol/L(OR= 1.138- 2.156, all P<0.05).

Serum C3 levels may predict the development of T2DM.

To investigate the current status of the fear of hypoglycemia in hospitalized type 2 diabetes mellitus with the history of hypoglycemia.

Total of 396 type 2 diabetes patients with the history of hypoglycemia were recruited by multi-centers purposive sampling method. The Mean (SD) age of the 396 participants was 55.4(9.34) years, 218 being male. The subjects were investigated with Chinese version of Hypoglycemia Fear SurveyII-Worry Scale (CHFSII-WS), self-rating depression scale(SDS), self-rating anxiety scale(SAS) and demographic survey questionnaire. T test and one-way AVOVA and multiple linear regression analysis were used to analyze the data.

The median score of CHFSII-WS was 9.00 points (interquartile range, 5- 16 points). The t-test showed that the scores of CHFSII-WS was significantly associated with gender, family history, anxiety and depression (t=-3.797,2.010,3.809,3.479, all P<0.05). The F-test showed that age, marital status, frequency of hypoglycemia, severity of hypoglycemia (F= 6.617,2.644,3.327,3.246, all P<0.05) were significantly associated with the scores of CHFSII-WS. Regression analysis showed that severe hypolycemia, anxiety, female, divorced and the frequency of hypoglycemia were significant factors of patients' fear of hypoglycemia (adjustedR²=0.229, F=5.905, P< 0.05).

In the clinical practice, the nursing stuff should pay attention to the evaluation of the patients' fear of the hypoglycemia and provide the health education of hypoglycemia in patients with type 2 diabetes.

To evaluate the inhibitory effects and the mechanisms of simvastatin and fluvastatin on insulin synthesis from pancreatic islets in rats.

The pancreatic islets were isolated from ninety eight-week-old male Wistar rats(body weight 250-300 g) by injecting collagen through the bile duct. The isolated pancreatic islets were divided into control group(treated with 11.1 mmol/L RPMI 1640), simvastatin group and fluvastatin group. Insulin content in pancreatic islets from rats was measured by radioimmunoassay(RIA), and the mRNA expression was accessed by real- time polymerase chain reaction after treatment for 24 hours with simvastatin or fluvastatin(100 μmol/L). The human insulin promoter-luciferase vector was constructed and MIN6 cells were transfected by the vector. The activity of insulin promoter was measured by the dual-luciferase reporter assay system after the treatment by simvastatin and fluvastatin for 24 and 48 hours respectively.One-way analysis of variance was carried out to analyze all the data.

Compared with that in control group, the RIA results showed the insulin content was significantly decreased after the treatment of simvastatin and fulvastatin for 24 hours by 21.1% and 27.1% respectively(q'=5.08 and 6.54,P<0.05). Fulvastatin and simvastatin significantly inhibited the expression of insulin mRNA, the insulin mRNA were significantly decreased in both fulvastatin group and simvastatin group (0.155±0.013 vs 0.265±0.030, 0.153±0.031 vs 0.265±0.030,q'=9.488, 9.661,P<0.05) . Compared with that in control group, the activity of luciferase was significantly inhibited by simvastatin treatment for 24 hours (1.11±0.26 vs 1.29±0.39,q'=3.55,P<0.05) and fluvastatin treatment for 48 hours (1.14±0.29 vs 1.29± 0.35,q'=5.76,P<0.01).

Simvastatin and fluvastatin inhibite the insulin synthesis by inhibiting the expression of insulin mRNA in rat pancreatic islet β cells, which may be related to its inhibitory effect on the activity of insulin promoter.

To investigate the renal protective effects of spironolactone(SPR)and its possible mechanism indiabetic db/db mice.

Sixteen diabetic db/db mice were randomly divided into two groups by random number table:DM-SPR group(n=8)and DM group(n=8). Littermate db/m mice (NC group, n=10) were usedas normal control.Six-week-old DM-SPR mice were treated with SPR [20 mg/(kg·d)], while DM and NC group were both treated with nomal saline(NS) for 12 weeks.During the experiment, blood glucose, blood pressure and urinary albumin/creatine were measured. After the treatment for 12 weeks, all the mice were sacrificed and thekidneys were collected. Glomerular ultrastructure were observed undertransmission electron microscope. The mRNA expression of inflammation cytokines monocyte chemotactic protein-1(MCP-1), interleukin(IL)-1β,CD68 and fibrosis index collagen Ⅳ, fibronectin, transforming growth factor-β(TGF-β) were detected by realtime polymerase chain reaction(RT-PCR). One-way analysisofvarianceand q test were used for dataanalysis among groups.

At the 18-week, the levels of blood glucose and glycated hemoglobin A1c(HbA_1c) were both significantly higher in DM groupand DM-SPR groupthan those in NC group(glucose:q=-12.09, -14.49; HbA_1c:q=-8.86, -11.90, all P< 0.05),and there was no significant difference between DM group and DM-SPR group(q=-2.17, -2.09, all P> 0.05).There was no significant differences in systolic and diastolic pressure among the three groups(F=2.05, 2.75, bothP>0.05).There was significant differences in urinary albumin/creatine among the three groups(F= 9.12,P<0.05), it was higher in the DM group than that in the NC group(q=-5.79, P<0.05),and it was lower in the DM-SPR group than that in the DM group(q=4.03, P<0.05). In the DM group, reduction of fenestrated endothelium, thickening of glomerular basement memebrane(GBM)and diffuse effacement of podocyte foot process were commonly found underelectron microscope,while SPR treatment effectively improved theseinjuries.RT-PCR analysis showed that there were significant differences in mRNA expression of inflammatory cytokines CD68,MCP-1,IL-1β and fibrosis indexes TGF-β1, collagenⅣ, fibronectin among the three groups(F=4.38 to 9.85, all P<0.05); the expression of above mentioned indexes were all elevated in the DM groupwhen compared with those in the NC group(q=-6.18 to -3.53, allP<0.05), and the SPR treatment effectively decreased the expression of those indexes when compared with those in DM group(q=0.23 to 4.64, all P<0.05).

SPRplays protective rolesin the diabetic nephropathy in db/db mice, which maybe mediated by attenuatinginflammation and fibrosis.

To determine the expression of three types of amylin receptors in rat islet β cells and explore their possible roles in cytotoxic effect of human amylin.

Reverse transcription-polymerase chain reaction(RT-PCR), immunofluorescent staining were used to determine expression of amylin receptors in rat islet β cell line INS-1 and normal β cells. The influence of amylin incubation on mRNA transcription of three receptor activity-modifying proteins (RAMPs) was observed by real time RT-PCR, and change of RAMP1 distribution on cell membrane was observed by immunofluorescent staining. In cytotoxicity experiment, INS-1 cells were first incubated with amylin or amylin receptor antagonist AC253 alone or the two reagents together for 24 hours or 48 hours, and survival rate of the cell was measured by MTT test. RAMP1 antibody at different concentrations together with amylin were also applied to incubate cells for 24 hours and then MTT test was carried out. Group data were compared by using t test with the P value set at 0.05.

RT-PCR and immunofluorescent staining demonstrated that three types of amylin receptor presented in rat islet β cells. RAMP2 and RAMP3 mRNA transcription decreased to 0.77 ± 0.10 ( t=2.546, P<0.05) and 0.66 ± 0.09 (t= 4.559, P<0.05) respectively, while, RAMP1 mRNA was slightly increased to 1.25±0.17(t=-3.084, P<0.05) after 24 hours' treatment with human amylin. Cell membrane distribution of RAMP1 was also slightly increased. Treatment with human amylin for 24 h significantly evoked cell death with cell viability decreased to 70%±13% (t=4.409, P<0.05). Application of amylin receptor antagonist AC253 significantly promoted cell viability to 94% ± 16% compared with cells that incubated with human amylin alone (t=-3.341, P<0.05). While for cells treated for 48 hours, no obvious increase of cell survival was detected. Application of RAMP1 antibody diluted at 1∶ 500 and 1∶1 000 with human amylin also significantly promoted cell viability to 94%±12% and 96%±11% respectively when compared with incubation with human amylin alone (t=- 4.904,-5.565, both P<0.05). Isotype IgG had no such effect.

Three amylin receptors are expressed in rat islet β cells. Amylin receptor, especially RAMP1, may involve in cytotoxicity of human amylin.

To predict the biological process in which long non-coding RNA (lncRNA) uc.417 might be involved by a series of bioinformatics analysis, and detect its expression in brown adipocytes, so as to lay foundations and provide theoretical basis for the further studies of lncRNA uc.417 biological functions in brown preadipocytes and obesity.

The sequence, position and structure characteristics of lncRNA uc.417 was acquired from UCSC database, and target genes of lncRNA uc.417 were predicted by Ensemble database. The brown preadipocytes were removed, collagenase digestied, incubated and induced to differentiate into mature brown fat cells from C57BL/6J mice. The expression of lncRNA uc.417, homeotic gene B6 (HOXB6) and homeotic gene B7 (HOXB7) were dected using real-time quantitative polymerase chain reaction(PCR). Student's t test was used to compare their expression level during the differention.

LncRNA uc.417 had highly conserved property among different species. The chromosomal regions of lncRNA uc.417 had many cis element binding locations and epigenetic regulation clues, and the possible candidate target genes were HOXB6 and HOXB7. The relative expression of lncRNA uc.417 in differentiation day 4 was significantly higher than day 2 (2.07±0.77 vs 0.89±0.18, t= 4.103, P< 0.01) , day 8 was significantly higher than day 6 (10.68±3.28 vs 3.12±0.88,t=-4.238, P<0.01) .

The expression of lncRNA uc.417 in brown adipocytes increases during the differentiation. It may play a crucial role in the process of brown preadipocyte-adipocyte transition via regualting the downstream target genes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease involved by T and B lymphocytes, which is mainly caused by the specific destruction of pancreatic islet β cells by autoimmune system, which leads to absolute insulin deficiency in the body. Therefore, the effective means to accurately diagnose T1DM and explore its pathogenesis is the detection of autoantigen components. A large number of clinical trials have shown that the onset of T1DM is closely related to a variety of autoantibodies in vivo, including islet cell antibody (ICA), protein tyrosine phosphatase antibody (IA-2A), insulin autoantibody (IAA) and glutamate decarboxylase antibody (GADA)^[1,2,3,4]。 The combined detection of these autoantibodies is a sensitive diagnostic index, which can improve the positive rate of islet autoantibodies^[5]Especially for those at high risk, but its sensitivity and specificity are not satisfactory in general population screening. For early screening and diagnosis of T1DM, it is urgent to explore new molecular targets. Human zinc transporter 8 (ZnT8) is one of the important members of the newly discovered zinc transporter family. It is located in pancreatic islet β cells and a small number of α cells. It is an islet-specific zinc transporter and plays a vital role in the synthesis, storage and secretion of insulin. In T1DM, with the continuous exploration of the role of ZnT8, the research of ZnT8 as the therapeutic target is gradually becoming a hot spot. Therefore, the determination of the immunoreactive epitope of ZnT8 can be used to improve the risk stratification prediction of high-risk patients with T1DM, and can be used as an early marker for clinical prediction of disease progression, which will reveal the immunological pathogenesis of T1DM and provide new research strategies for the prevention and treatment of T1DM. In addition, polypeptide vaccines targeting ZNT8-specific epitopes may become a new approach for early prevention of T1DM. The role of ZnT8 antigen and its T and B lymphocyte epitopes in type 1 diabetes mellitus was reviewed.

Bromocriptine is a selective dopamine D2 receptor (D2R) agonist, which is a classic drug for the treatment of hyperprolactinemia and tremor paralysis. Studies have found that bromocriptine can affect glucose and lipid metabolism in mammals and humans. Its fast-release dosage form, cycloset, has been proven to reduce blood sugar and lipid in animal studies and clinical studies, and has good safety. In 2009, the U.S. Food and Drug Administration approved cycloset for the hypoglycemic treatment of type 2 diabetes (T2DM), which is the first drug to regulate blood sugar through the central nervous system. This article introduces the progress of bromocriptine and other dopamine receptor agonists in the treatment of T2DM.

Polycystic ovary syndrome (PCOS) is a common endocrine disease characterized by thin menstruation, ovulation disorder and hyperandrogenism in women of childbearing age. It was found that PCOS patients have significant adipose tissue dysfunction, and some secreted proteins produced by adipose tissue, i.e. adipokines, play an important role in the occurrence and development of PCOS. Past studies have observed a decrease in beneficial adipokines such as adiponectin (APN) and an increase in the pro-inflammatory factor tumor necrosis factor-alpha (TNF-alpha) in patients with PCOS. This paper mainly expounds the relationship between adipokines and PCOS discovered in recent years.