Volume 05 · Issue 02 · 2013

Studies from Europe and Asia show that the incidence of childhood diabetes is increasing^[1,2,3,4]。 As early as 1988, Beijing Children's Hospital (hereinafter referred to as our hospital) participated in the national survey on the incidence of type 1 diabetes mellitus (T1DM) in children under 15 years old, and the surveillance incidence rate continued until 2000 without obvious increase^[3]。 However, after 2003, the incidence rate of T1DM in children under 15 years old in Beijing has increased significantly according to the data of newly diagnosed T1DM in our hospital, which is even higher than that of children under 15 years old in Beijing 10 years ago. At present, it has reached (1.30~2.25) /100,000^[4], consistent with the data of Beijing T1DM obtained by the 3C project jointly carried out by the International Diabetes Federation (IDF) and the Diabetology Branch of the Chinese Medical Association (CDS). What is the status of diabetes control in so many children with T1DM in China? What is the control status of children with T1DM abroad? What is affecting overall diabetes control effects?

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease mediated by pro-inflammatory autoreactive T lymphocytes, which directly or indirectly leads to the damage of insulin-secreting islet β cells and lifelong dependence on exogenous insulin. The prevalence of T1DM doubles every 20 years, especially among children under 5 years of age^[1]Therefore, it is of great significance to seek the clinical treatment of T1DM.

medical nutrition therapy (MNT) is an important part of the comprehensive treatment of type 1 diabetes, which emphasizes the ideal control of blood sugar, blood pressure and lipid metabolism while ensuring normal growth, development and physical activity. Successful diabetes management requires daily attention to nutritional prescriptions, especially the quality of meals and the carbohydrate intake contained in more accurate foods. 90% of diabetes mellitus occurring in children and adolescents is type 1 diabetes. Due to its growth and development needs, the insulin requirement often changes, and due to the special nutritional needs of the development stage, its diet and life should also be adjusted accordingly. The purpose of this article is to explain the principles, methods of use and the work of nutritionists of MNT in type 1 diabetes.

Innate immunity can be activated quickly after recognizing pathogenic microorganisms, and plays a very important role in the immune system. Natural immune cells recognize signaling molecules of pathogens by expressing different pattern recognition receptors (PRRs). These signaling molecules are important components of innate immunity and are collectively referred to as pathogen-associated molecular patterns (PAMPs). PRRs that have been discovered so far include Toll-like receptors (TLRs), retinoic acid inducible gene 1 (RIG-1) -like receptors (RLRs), and NOD-like receptors (NLRs)^[1,2]。 These PRRs recognize different PAMPs to cause the secretion of inflammatory cytokines and type 1 interferon, which play a host protective role. Type 1 diabetes mellitus (T1DM) is traditionally believed to be an autoimmune disease mediated by T lymphocytes, characterized by progressive destruction of pancreatic islet β cells and complete loss of insulin secretion. However, more and more evidence shows that innate immunity plays an important role in its pathogenesis. As an important PRRs, TLRs can recognize pathogenic microorganisms and endogenous danger signals. It is an important protein involved in innate immunity, and it is also a bridge between innate immunity and specific immunity. Revealing the role of TLRs in innate immunity is of great significance to elucidate the relationship between innate immunity and T1DM, explore the mechanism of immune response in patients with T1DM, and find new ways of immunomodulatory therapy.

Pioglitazone was approved by the State Food and Drug Administration of China to enter the Chinese market in 2000 as a hypoglycemic drug for adults with type 2 diabetes. Pyrrolitazone can preserve the function of pancreatic islet beta cells and control blood sugar for a long time. In the past ten years, it has been widely used in clinical practice, and its efficacy has been recognized. However, it has been recently reported that taking pioglitazone is associated with an increased risk of bladder cancer. This article discusses this problem.

The latest epidemiological survey shows that the prevalence of diabetes in adults over 20 years old in China is 9.7%, and the prevalence of pre-diabetes is 15.5%^[1]。 Abnormal glucose metabolism is closely related to lower extremity atherosclerotic disease (LEAD)^[2,3]。 There is no epidemiological data on LEAD in diabetic patients in China. Some local epidemiological investigations and the results of hospitalized diabetic patients show that the prevalence of LEAD in patients over 50 years old is 6.9% ~23.8%^[4,5,6]。 Diabetes with LEAD is not only a risk factor for diabetic foot disease, but also an important cause of amputation in patients with diabetic foot disease^[7,8]。 The risk of cardiovascular events and mortality of LEAD patients increased significantly, and the incidence of cardiovascular events was as high as 21.14% 1 year after diagnosis, which was comparable to the risk of recurrence of cardiovascular and cerebrovascular lesions^[9]。

To investigate the effects of exercises on expressions of serum amyloid A protein (SAA) and resistin-like molecules α(RELMα)in aorta of insulin-resistant(IR) rats induced by diets.

Taking the completely randomized method, a total of 30 Wistar rats were divided into 3 groups: normal control group(n=10) fed with normal diet, IR and exercises groups with high sugar and high fat diet(10 rats in each group). Eight weeks later, the index of insulin resistance was assessed to confirm that models were successfully made.The three groups were continually fed with the same diet as before, while the exercise group was administered with swimming training for eight weeks in addition. At the end of sixteen weeks experiment, Rats' blood were sampled for measuring the levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose (FBG), SAA, aorta RELMα mRNA and insulin (FINS) and the body weight(BW) were measured.The homeostasis model assessment index of IR(HOMA-IR)were calculated.Haematoxylin and eosin stain method was applied to observe morphology characteristics of aorta in groups. Difference of measurement data was compared with single factor analysis of variance.

The levels of BW, FBG, FINS, HOMA-IR, TC, TG, LDL-C, SAA, RELMα mRNA in IR group were higher than those in control group(t=-20.666~-3.681, all P<0.05), and the number of foam cell increased well (t=-20.596, P<0.05), while the levels of HDL-C were lower(t=8.950, P<0.05). The endothelial in the IR group were in disorder, and neointimal hyperplasia was found. After the intervention of exercise, the levels of SAA, RELMα mRNA, BW, FBG, FINS, HOMA-IR, TC, TG, LDL-C excercises group were decreased than those in IR group(t=2.524~8.640, P<0.05), and the number of foam cell decreased well(t=11.520, P<0.05), while the levels of HDL-C were higher(t=-2.094, P=0.05).

RELMα, SAA is relate to IR, aortic inflammation closely.Exercise could inhibit the level of SAA, RELMα mRNA.It is important for improving IR and reducing aorta inflammation reaction.

To investigate the role of toll like receptor 4(TLR4) pathway in regulation of monocyte chemoattractant protein-1 (MCP-1) by palmitate in human aortic vascular smooth muscle cells (HA-VSMC).

To study the time course and dose dependent effects of palmitate on MCP-1 gene expression, HA-VSMC were cultured and treated with 100, 200 or 400 μmol/L of palmitate for 6, 12 or 24 h, cells were then harvested at indicated time points, MCP-1 mRNA expression was analyzed with real-time polymerase chain reaction(RT-PCR) and the production of MCP-1 protein in cultural supernatant were tested using enzyme-linked immunosorbent assay(ELISA). To determine the involvement of signaling pathways in regulation of MCP-1 by palmitate, specific inhibitors that block protein kinase C(PKC), phosphotylinosital 3 kinase(PI3K), ceramide or nuclear factor(NF)-κB signaling were added to the serum-free media for 30 min followed by treatment with or without 400 μmol/L of palmitate for additional 6 h, thereafter, the mRNA and protein expression of MCP-1 were studied. To further clarify the role of TLR4 pathway in induction of MCP-1 by palmitate in HA-VSMC, recombinant adenovirus TLR4 shRNA virus (pGSadeno-TLR4) was constructed, and HA-VSMC were infected with pGSadeno-TLR4 to knockdown the expression of TLR4, infection with pGSadeno-GFP served as a negative control and the cells treated with phosphate buffer saline(PBS) were used as normal control. Ninety-six hours after infection, virus-containing medium was replaced with fresh DMEM medium, the cells were then cultured in the presence or absence of 400 μmol/L of palmitate for 6 h, nuclear protein of the cells was subsequently isolated and NF-κB p65 subunit binding activity was detected with ELISA, MCP-1 mRNA and protein expression were determined. The single-factor analysis of variance was used in data comparison among the groups.

Six hours after treatment, the mRNA expression of MCP-1 in control group and 100, 200, 400 μmol/L palmitate group were 1.00±0.02, 3.30±2.84, 8.21±4.31 and 11.25±2.73, respectively( F=7.57, P<0.05); the protein expression of MCP-1 were (127±10), (147±10), (163±18) and (194±14) ng/L, respectively (F=7.81, P<0.05). Palmitate significantly induced mRNA and protein expression of MCP-1 in a dose dependent manner, while the time dependent effect was not obvious, these effects were also observed when the cells were treated with palmitate for 12 h or 24 h. Six hours after treatment with various inhibitors of different signaling pathway, the MCP-1 mRNA level in control group, palmitate group, palmitate+ parthenolide group, palmitate+ chelerythrine group, palmitate+ wortmannin group and palmitate+ myriocin group were 1.00±0.02, 10.80±1.23, 3.49±0.28, 10.84±0.24, 11.24±0.27 and 10.62±0.36, respectively(F=1313.07, P<0.05); the protein expression of MCP-1 were (132±8), (218±12), (152±4), (213±12), (225±7) and (226±9) ng/L, respectively(F=106.83, P<0.05). Knockdown of TLR4 with pGSadeno-TLR4 significantly inhibited palmitate induced increase in mRNA and protein expression of MCP-1 and NF-κB p65 binding activity (1.88±0.33 vs 10.80±1.23, (154±10) vs (218±12) ng/L, 0.48±0.12 vs 1.24±0.16,F=591.86, 659.16, 118.37, all P<0.05), while the control virus pGSadeno-GFP implicated no effects.

Palmitate may induce MCP-1 expression in HA-VSMC through activation of TLR4/NF-κB pathway.

To analyze the clinical characteristics of hospitalized type 1 diabetic patients (T1DM).

Type 1 diabetics admitted to the Department of Endocrinology of Chinese PLA General Hospital from January 1986 to February 2012 were reviewed. All the 742 patients were divided into two groups: adult-onset group(n=516) and non-adult-onset group(n=226), according to the cut point of 18 years; and the newly diagnosed 325 patients were further divided into diabetic ketoacidosis (DKA) group(n=68) and non-DKA group(n=257) according to whether patients were associated with ketoacidosis at the onset. The differences in clinical and biochemical characteristics were compared between the groups. Differences in measurement data were compared with least significant difference t test when the data obeyed normal distribution with homogeneity in variance.

A total of 742 patients were enrolled in this study. Of them, 402 were males and 340 were females. The mean age at the onset was 23(1-61) years. One hundred and fifty-four(20.8%) patients had a family history of diabetes. The adult-onset group accounted for 69.5%(516/742), and the body mass index(BMI) of this group was (16.3 ± 9.0) kg/m². Compared with the non-adult-onset group, the adult-onset group had a higher level of serum uric acid ((274±122) vs (243±97) μmol/L, t=2.631, P<0.05), a higher incidence of hypertension(14.9% vs 7.1%, χ²=8.818, P<0.05), and a lower level of glycated hemoglobin A1c(HbA1c) (9.7%±3.1% vs 10.7%±2.8%,t=3.221, P<0.05), a lower prevalence of DKA(20.9% vs 24.3%, χ²=4.276, P<0.05), and a lower dosage of insulin ((0.7±0.3) vs (0.9±0.4) U/kg,t=5.061, P<0.05). Furthermore, more patients used insulin pump or multiple daily injection(MDI) in adult-onset group(0.2% vs 16.4%, 57.6% vs 64.6%, respectively, χ²=16.269, 1.517, both P<0.05). Compared with the non-DKA group, the DKA group presented significantly higher fasting blood glucose levels((23±10) vs (19±8) mmol/L,t=3.688, P<0.05). No significant difference was found in gender, age, family history of diabetes, postprandial blood glucose or HbA1c levels between the two groups (allP>0.05). Total of 417 patients had been diagnosed as T1DM on admission, and cases with diabetic retinopathy or kidney disease accounted for 37.4% and 26.9%, respectively. Thirty patients had other autoimmune diseases, 70% of which (n=21) were autoimmune thyroid diseases.

The annual number of T1DM patients gradually increased in our clinic. Compared with the non-adult-onset group, the adult-onset group has a higher serum uric acid level and incidence of hypertension and a lower HbA1c.

To investigate the clinical features of various glucose metabolism disorders in patients with hepatocellular carcinoma (HCC).

A retrospective analysis of various glucose metabolism situations in 698 patients with HCC was performed from January 2003 to December 2007 in the Second and the First Affiliated Hospital of Shantou University Medical College. The patients were divided into 4 groups according to glucose metabolism status: normal glucose group(472 cases), hypoglycemia group(20 cases), pre-diabetes group(76 cases) and diabetes group(130 cases). Analysis of variance (ANOVA) and Kruskal-Wallis H test were employed to compare differences of age and laboratory chemical indicators among the 4 groups.

Among 698 HCC patients, 563 were male and 135 were female, with an average age of (55±13) years. The patients in pre-diabetes and diabetes groups were significantly older than those in normal glucose group ((58±13), (60±13) and (53±15) years, respectively; all P<0.05); the patients in diabetes group were older than those in hypoglycemia group((51±14) years,P<0.05). The level of total cholesterol in diabetes group was significantly lower than that in normal glucose group((4.7±1.7) vs (4.0±1.7) mmol/L,t=2.266, P<0.05).

In patients with HCC, the patients with diabetes mellitus are older than those with normal blood glucose and hypoglycemia, and total cholesterol is lower in patient with diabetes mellitus than that in patients with normal blood glucose.

To investigate the relation of Notch intracellular domain 1 (NICD1) protein expression and glomerular podocytes apoptosis of mice under high glucose (HG) culture medium and find out whether HG activated Notch pathway in podocytes via other pathways, in order to provide a potential direction to treat diabetic nephropathy.

NICD1 protein expression was detected in HG-induced mouse podocytes at indicated time points. Cells were divided into seven groups: normal glucose group, high glucose group, high glucose + γ-secretase inhibitor (GSI, inhibits the activation of Notch1) group, high glucose + p38 mitogen-activated protein kinase (MAPK) inhibitor group, high glucose + Janus kinase 2 (JAK2) inhibitor group, high glucose + transforming growth factor-β typeⅠ receptor (TβRⅠ) inhibitor group and high glucose + phosphoinositide 3 kinese/protein kinase B (PI3K/Akt) inhibitor group. NICD1 expression was detected by immunocytochemistry and Western blot. Apoptosis rate of HG-induced podocytes was analyzed by flow cytometry (FCM) and DeadEnd™ fluorometric TUNEL system. We used t-testing to compare the difference between two groups and one way analysis of variance to test the differences among groups.

HG stimulation in podocytes increased NICD1 protein level than normal glucose group (0.079±0.010). NICD1 expression began to increase at 12 h after the stimulation of HG (0.443±0.075), reached the peak at 48 h (0.746±0.034) and slightly decreased at 72 h (0.658±0.056, F=6.235, P<0.01). Apoptotic cells increased in HG-induced podocytes at 48 h, which was inhibited after treatment of GSI (P<0.01). JAK2 (0.193±0.096) and TβRⅠ inhibitors (0.225±0.067)suppressed HG-induced activation of Notch pathway in podocytes (t=6.781, 4.287, both P<0.01).

Notch pathway maybe mediates HG-induced podocytes apoptosis via JAK/STAT and TGF-β₁/Smad pathways.

Type 1 diabetes mellitus (T1DM) is a metabolic disease characterized by insulin deficiency and glucose metabolism disorders caused by autoimmune-mediated selective islet B cell damage^[1]。 T1DM can occur at any age, but it is more common in childhood and adolescence. T1DM accounts for about 5% of the total number of diabetes in China and 5% to 10% of diabetes in the United States. At the same time, T1DM is one of the most common chronic diseases in children^[2]。 So far, studies have shown that autoimmune mechanism plays an important role in the pathophysiological mechanism of T1DM. The following is a review of the recent progress of related immunological research.

It is well known that the current symptomatic treatment is not effective in curing type 1 diabetes (T1DM), and the ideal treatment for T1DM is to induce immune tolerance in the body. The commonly used immune intervention method in clinic is the use of systemic immunosuppressants. Although it can delay the progression of autoimmune diseases, the side effects of the drugs themselves and their effects on the systemic immune system make them face many challenges. Therefore, antigen-specific immunotherapy is the direction of curing T1DM, that is, by recognizing islet-specific antigens, acting on pancreatic islets or local pancreatic lymph nodes, exerting immunomodulatory functions without affecting the systemic immune response. The following is a summary of the current research progress.

Insulin therapy is the basic treatment for type 1 diabetes, but insulin alone sometimes fails to achieve the blood glucose standard^[1]Hypoglycemia and postprandial hyperglycemia are often difficult points in treatment. Glucagon-like peptide-1 (GLP-1) has a glucose-dependent effect on regulating blood glucose, and exenatide, as the first GLP-1 analogue used in clinic, is indicated for type 2 diabetes. There are some research reports abroad that exenatide is used in type 1 diabetes, but no reports have been seen in China. Recently, we treated 2 patients with type 1 diabetes with continuously increased blood glucose and uncontrollable blood glucose fluctuations with exenatide combined with insulin pump, and achieved good results. The report is as follows.

Type 1 diabetes, due to the absolute deficiency of insulin, leads to increased vulnerability of the disease, which is often manifested by alternating hyperglycemia and hypoglycemia. Avoiding or reducing blood glucose fluctuation in patients with type 1 diabetes mellitus has become the focus and difficulty of clinical treatment. With the consent of the patients and their parents, Sun Liangge's research group added exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, to two adolescent patients with type 1 diabetes who had poor insulin pump therapy. It was observed that exenatide further reduced the blood glucose level, made the disease control more stable, and reduced the insulin dosage, suggesting that exenatide can be used for the adjuvant treatment of type 1 diabetes.

Sponsored by Diabetes Branch of Chinese Medical Association and hosted by the Sixth People's Hospital affiliated to Shanghai Jiaotong University, the "Annual Meeting of Blood Glucose Monitoring Group and the 4th International Forum on Blood Glucose Monitoring" was held in Shanghai on November 17th, 2012. More than 200 experts in related fields from all over the country attended this forum. The conference was first opened by Professor Yan Shijie, Executive Vice President and Secretary General of Shanghai Medical Association, and Professor Ji Linong, Chairman of Diabetes Branch of Chinese Medical Association. At the same time, Professor Jia Weiping, deputy chairman of Diabetes Branch of Chinese Medical Association and leader of blood glucose monitoring group, introduced the important work carried out by blood glucose monitoring group in the past year. Professor John Mastrototaro from the United States, Professor Oliver Mast from Germany and Professor Peng Yongxiang from Hong Kong were invited to give keynote speeches. At the same time, Professor Ji Linong, Weng Jianping, Jia Weiping, etc. conducted extensive and in-depth academic discussions on the research status and clinical application progress of blood glucose monitoring in China.

NH2-terminal brain natriuretic peptide precursor (NT-proBNP) levels at circulating levels are a marker of acute heart failure and are associated with an increased risk of cardiovascular disease. However, research data on the potential role of NT-proBNP as a biomarker in vascular complications in patients with type 1 diabetes are scarce. The aim of the EURODIAB prospective study was to investigate whether serum NT-proBNP levels are associated with microvascular and macrovascular complications in patients with type 1 diabetes. The project was a cross-sectional, controlled study of 507 cases of type 1 diabetes complications. Case group (n=345) with one or more diabetic complications, the control group (n=162) without any diabetic complications. NT-proBNP levels were determined by two-site electrochemiluminescence immunoassay and its correlation with complications was investigated.

Atherosclerosis is an independent risk factor for population mortality and cardiovascular mortality. The extent of atherosclerosis can be measured by a non-invasive method, pulse wave velocity (PWV). Adiponectin is an adipocytokine, which has the effects of increasing insulin sensitivity, anti-atherosclerosis and anti-inflammation. Although studies have shown that plasma adiponectin levels are inversely correlated with the degree of atherosclerosis in patients with essential hypertension, the relationship between plasma adiponectin levels and PWV in young patients with type 1 diabetes has been rarely reported.

Diabetic retinopathy and dominant nephropathy are manifestations of target organ involvement in diabetic microangiopathy, while the early manifestation of kidney injury in type 1 diabetic patients is microalbuminuria. Retinal involvement is present in most diabetic patients with dominant nephropathy, however not all diabetic patients with retinopathy develop dominant nephropathy. The purpose of this study was to investigate the incidence, risk factors and the relationship between retinopathy, microalbuminuria and dominant nephropathy in patients with type 1 diabetes.

Previous studies have shown that the intracellular and extracellular structures of the glomerular hematuria barrier in OVE26 (OVE) transgenic mice are very sensitive to damage, and this animal model can reflect the urinary albumin excretion rate (UAE), which is of great value for the study of human diabetic nephropathy. This study aimed to confirm that the effects of oxidative stress on podocyte cells contribute to the damage of the glomerular filtration barrier in OVE mice.