Volume 09 · Issue 01 · 2017

Hundreds of rivals compete for the flow, and those who strive first. 2016 is a milestone year after the founding of Chinese Journal of Diabetes.

China is the world's second largest economy and the country with the largest diabetic population, with a total of about 100 million people suffering from diabetes^[1,2]。

Diabetes mellitus is a clinical syndrome caused by the interaction of genetic and environmental factors, which mainly manifests as beta cell dysfunction and insulin resistance and ultimately leads to disorder of glucose metabolism. Chronic complications and complications of diabetes mellitus are the main causes of disability and death, but the specific mechanism of diabetes mellitus is not elucidated. Recent studies have shown that oxidative stress is closely related to diabetes and its complications/comorbidities. nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor, which plays an important role in the body's anti-oxidative stress and cell protection. Nrf2 is the most important endogenous antioxidant stress pathway discovered at present. This article will focus on the role of Nrf2 in diabetes and its complications/comorbidities.

In mammals, the dynamic balance of energy intake and consumption maintains the energy homeostasis of the body's metabolism. When the energy balance tends to intake one side, obesity is inevitable, and a series of metabolic problems will follow, such as type 2 diabetes (T2DM), cardiovascular and cerebrovascular diseases and nonalcoholic fatty liver disease (NAFLD), etc. fibroblast growth factor 21 (FGF21) is a novel factor that has significant effects on reducing body weight and increasing insulin sensitivity. Its specific regulatory mechanism from upstream to downstream has become a hot spot in the field of basic research. Our recent findings elucidate the molecular mechanism by which the FGF21-mTORC1 (mTORC1, mammalian target of rapamycin complex 1) pathway regulates hepatic insulin sensitivity. How does FGF21 feel the body's nutritional status and regulate the metabolic balance of the whole body? This article will discuss the molecular regulatory mechanism and clinical research progress.

In recent years, with the change of people's lifestyle, non-alcoholic fatty liver diseases (NAFLD) have become one of the major public health problems. In the past decade, the prevalence of NAFLD in western countries has increased to 20% to 30%, and in obese people, the incidence of NAFLD is even more than 50%^[1]。 In some parts of our country, the prevalence of adult NAFLD has also exceeded 15%^[2]。 In addition to the health and psychological problems caused by NAFLD itself, its accompanying various related diseases, such as type 2 diabetes, cardiovascular and cerebrovascular diseases, liver fibrosis and cirrhosis, seriously threaten human physical and mental health and quality of life, and also greatly increase the economic burden on families and society.

In July 2016, at the Endocrinology Conference of the whole army in Enshi, Hubei Province, editor-in-chief Weng Jianping suggested that I write some experiences on how to do scientific research, which made me very confused about how to finish the manuscript. In September 2016, at the Chengdu Western Diabetes Forum, I reported "Concept Proposal and Clinical Practice of Metabolic Hypertension". Director Yang Ying of the editorial department of Chinese Diabetes Journal suggested that I write some experiences around this topic.

To explore the clinical and genetic features in a pedigree of maturity onset diabetes of the young (MODY) due to a novel glucokinase inactive mutation (GCK-MODY).

The clinical and genetic data of a dominantly inherited GCK-MODY family from Peking Union Medical College Hospital in December, 2015 were retrospectively analyzed. The proband was a 31-year-old female, who was found elevated fasting plasma glucose (7.3 mmol/L) during early pregnancy accompanied with increased glycated hemoglobin level (6.6%). The levels of serum lipid profiles and hypersensitive C reactive protein were normal. She was diagnosed with pregestational diabetes mellitus. The proband's immediate family members had three generations of diabetes history. The affected family members developed diabetes between 40 and 55 years old. Lifestyle intervention or metformin was the adopted treatments for hyperglycemia. Until now there were no obvious diabetes complications reported in this pedigree. The function of genetic variation was predicted by genetic function software and compared with Human Gene Mutuation Database.

GCK gene sequencing showed all of the affected members had a novel heterozygotic deletion c.1289_1294 del TGACGC mutation (p.lys 430fs) . Genetic function software suggested that this mutation led to not only splice site changes, but also premature termination codon. Literature review found there were above 680 kinds of GCK-MODY, which were dominantly inherited and had stable fasting hyperglycemia (5.5~7.8 mmol/L) without overt diabetes complication. Fasting hyperglycemia occurs in neonatal period but usually only can be found in medical check-up or during pregnancy. Therefore, it could be easily misdiagnosed as gestational diabetes mellitus. GCK-MODY rarely depends on pharmacotherapy except for during pregnancy and has a good prognosis.

GCK-MODY is a kind of monogenic diabetes with good prognosis and early pregnancy is a sensitive period for screening. Overtreatment should be avoided once the diagnosis is made.

To explore the gene mutations of the 13 children diagnosed as congenital hyperinsulinism(CHI).

A total of 13 children with CHI (8 boys and 5 girls) hospitalized in Beijing Children's Hospital from September 2006 to November 2015 and their parents were chosen as the study subjects. Genetic sequencing analysis of CHI related genes were done with the second generation sequencing technology. The abrupt change points of the patients were validated with the first generation sequencing technology and the same points in the patients' parents were sequenced as well.

A W777X heterozygous mutation of ABCC8 gene was detected in case 1, an L1439P heterozygous mutation of ABCC8 gene was detected in case 7 and his father, a R16P heterozygous mutation of ABCC8 gene was detected in case 13 and his father, a N463I heterozygous mutation of GLUD1 gene was detected in case 4, an H507Y heterozygous mutation of GLUD1 gene was detected in case 11, and an E496K heterozygous mutation of SLC16A1 gene was detected in case 9. No mutation was found in the other 7 patients and their parents.The patients showed different responses to diazoxide.

ABCC8, GLUD1 and SLC16A1 gene mutations can cause CHI. Different gene mutations have different treatment responses to diazoxide. Some patients with glutamate dehydrogenase hyperinsulinism tend to be self-cured.

To investigate the relationship between glycosylated hemoglobin (HbA_1c) and cardiac systolic function in patients with coronary artery revascularization.

Hospitalized patients who underwent coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) at Beijing Anzhen Hospital from January 2010 to December 2010 were selected from the electronic medical records system. Participants were stratified by the presence of diabetes mellitus, HbA_1c higher than 6.5% and 8.0%, and ejection fraction (EF) higher than 50%, respectively. Multivariate Logistic regression was used to analyze the correlation between HbA_1c and EF in patients with coronary revascularization.

(1) Of 294 parients, 211 (71.8%) were male and 83 (28.2%) were female, with a mean age of (61±10) years. 124 patients (42.2%) were with diabetes mellitus. (2) The levels of fasting plasma glucose (FPG), HbA_1c and triglyceride (TG) were higher in patients with diabetes than those without diabetes, and the above three indexes were higher in patients with EF<50% than those EF≥50% , the differences were statistically significant (P<0.05). (3) The number of patients with EF<50% was higher in those with HbA_1c≥6.5% (20.7% vs 12.0%, χ ²= 4.403, P<0.05). HbA_1c≥6.5% was associated with increased risk of heart failure after adjustment for related influencing factors (OR= 2.204, 95% CI: 1.135-4.283).

HbA_1c ≥ 6.5% may be associated with decreased cardiac function after CABG or PCI.

To explore the effect of exenatide on food habits in obese patients with type 2 diabetes mellitus (T2DM).

A total of 32 obese patients with T2DM inadequately controlled by metformin were selected and treated with 5 mg for 4 weeks and 10 mg for 12 weeks of exenatide twice daily. Weight, body mass index (BMI), waist circumference, hip circumference, waist hip ratio (WHR), fasting blood glucose (FPG), glycated hemoglobin A_1c (HbA_1c), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and blood pressure were measured before and after exenatide treatment. The change of daily food intake and other diet condition were recorded with a questionnaire survey. Comparision of means was done by paired t-test with quantitative data and rank-sum test with orderly qualitative data.

A total of 30 cases finally completed the study. After 16-week exenatide treatment, weight, BMI, waist circumference, FPG and HbA_1c were significantly decreased (t=3.805-6.488, P<0.01); WHR, TC, TG, LDL-C, BP were also significantly declined(t=2.086-2.718, P<0.05); while HDL-C was markedly increased(t=-3.491, P<0.01). The total food intake was significantly decreased (Z=-3.349, P<0.01). Among them, the intakes of cereals (Z=-3.400, P<0.01), oil(Z=-3.761, P<0.01), livestock and poultry meat (Z=-2.530, P<0.05) and salt (Z=-1.964, P<0.05) were significantly decreased; while the intake of vegetables was dramatically increased (Z=-2.445, P<0.05). The frequency of bedtime snacks were significantly declined (Z=-2.429, P<0.05).

Exenatide can optimize eating habits of obese patients with T2DM, control weight, improve glucose and lipid metabolism and regulate blood pressure.

To observe the effects of liraglutide on proliferation and apoptosis of human umbilical cord mesenchymal stem cells (HUC-MSCs) in vitro, and further to investigate the relationship with phosphatidylinositol 3 kinase/serine-threonine kinase (PI3K/AKT) signaling pathway.

HUC-MSCs cultured in DMEM/F12 media were treated with varying concentrations of liraglutide(10^-9, 10^-8, 10^-7 mol/L and control) for 24 and 48 hours separately. In order to explore the best concentrations and application time, cell proliferation was detected by cell counting kit-8 (CCK-8) assay, apoptosis rate was detected by flow cytometry. LY294002, the specific inhibitor of PI3K, was added in the culture at 20 μmol/L concentration. The cyclic adenosine monophosphate (cAMP) concentration was detected by ELISA, the protein expression of serine-threonine kinase (AKT) and phosphorylated AKT (P-AKT) were measured by Western blotting. Difference between two groups was analyzed by t test, and variance analysis was used for multiple variables analysis.

Compared with 10^-9 mol/L group (0.52±0.10) , 10^-8 mol/L group (0.68±0.07) and control group (0.44±0.09) separately, cell proliferation was increased significantly in 10^-7 mol/L liraglutide group (0.78±0.04) after 24 hours (t=8.383, 4.167, 12.100, all P<0.05). Compared with 10^-9 mol/L group (3.295±0.346) and control group (16.315±0.474) , apoptosis rate was decreased significantly in 10^-7 mol/L liraglutide group (1.380±0.255) (t=6.299, 39.272, all P<0.05); Compared with control group and LY294002 group separately, the concentration of cAMPwas increased significantly in liraglutide group (t= 14.307, 23.378, all P<0.05) , and the expression of p-AKT/AKT was increased in liraglutide group (t=7.861, 8.486, all P<0.05); Compared with liraglutide group, the concentration of cAMP and the expression of p-AKT/AKT were all decreased in liraglutide + LY294002 group(t=16.473, 3.172, all P<0.05).

Liraglutide can promote proliferation and inhibit apoptosis of HUC-MSCs and the optimal concentration and culture time are 10^-7 mol/L and 24 hours. The mechanism may be related to the activation of the PI3K/AKT signaling pathway.

Blood glucose fluctuation, i.e. blood glucose variability, refers to the unstable state of blood glucose level changing between high and low values, which is a hot spot in the field of diabetes treatment at present. Studies have shown that blood glucose fluctuation is an important factor affecting the occurrence and development of diabetic complications, and it is independent of fasting blood glucose (FPG), postprandial blood glucose and glycosylated hemoglobin (HbA)_1c) outside^[1]。 Blood glucose standard deviation is considered to be a classically valid measure to assess blood glucose fluctuations^[2]。 The circadian rhythm variation of blood pressure is an independent risk factor for cardiovascular and cerebrovascular damage^[3]Diabetic patients with postprandial hyperglycemia or nocturnal hypertension have higher cardiovascular and cerebrovascular risk^[4]。 As the prevalence of hypertension in patients with type 2 diabetes mellitus (T2DM) increases year by year, the relationship between blood sugar fluctuation and circadian rhythm of blood pressure has attracted more and more attention. At present, most studies have used ambulatory blood pressure monitoring (ABPM) or ambulatory blood glucose monitoring (CGM) alone, while relatively few people have performed ABPM and CGM at the same time. In this paper, patients with T2DM combined with hypertension were selected as the research objects. ABPM and CGM were used to evaluate the fluctuation of blood glucose and circadian rhythm variation of blood pressure, and the correlation between them was discussed.

To summarize the clinical features in a case of stiffman syndrome combined with latent autoimmune diabetes in adults (LADA).

A 61-year old male patient who presented with progressive trunk muscle stiffness, ankylosis and paroxysmal painful spasm for 3 years was admitted to hospital in April 2016. He was diagnosed with type 2 diabetes 2 years prior and initially stabilized by oral medicine of metformin and acarbose. His fasting plasma glucose (FPG) was 15.29 mmol/L, glycosylated hemoglobin (HbA_1c) was 10.60%, glutamic acid decarboxylase antibody (GADA) was 39.0 mU/L, thyroid globulin (TG) antibody was 1 044 mU/L and he presented with absolute insulin deficiency.

Clonazepam and baclofen were used to relieve muscle stiffness. After insulin treatment for 3 months, the patient's HbA_1c was 7.4%, GADA was 36.4 mU/L, TG antibody was 1 068 mU/L and insulin deficiency was persistant. Literature review revealed that GADA was involved in the pathogenesis of LADA, stiffman syndrome, thyroiditis and other autoimmune diseases.

The result shows extremely high titers of GADA can trigger multiple autoimmune antigen and result in stiffman syndrome, LADA concomitant with other autoimmune diseases. It is recommended that diabetic patients with neurological symptoms should be screened for islet autoantibodies to identify the types of the disease and guide treatment.

Metabolic syndrome (MS) is a state in which multiple cardiovascular metabolic risk factors cluster in individuals, including obesity, hyperglycemia, dyslipidemia, and hypertension. With the global obesity epidemic, MS has received more and more attention, but there are many versions of its diagnostic criteria in the process of evolution, which brings great confusion to scientific research and clinical work. For example, the earliest World Health Organization (WHO, 1999), the Third Report on Adult Treatment Programs of the National Cholesterol Education Program (ATP III, 2001), the European Insulin Resistance Study Group (EGIR, 1999), the American College of Clinical Endocrinologists (AACE) (2003), and later the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI, 2005), the International Diabetes Federation (IDF, 2005) and the IDF Epidemic Prevention Task Force Joint Transition Statement (JIS, 2009) standards. In addition, China has also tried to establish its own diagnostic criteria. In 2004, the Diabetology Branch (CDS) of the Chinese Medical Association established the first MS standard in China^[1]In 2007, the China Joint Committee for the Formulation of Guidelines for the Prevention and Treatment of Dyslipidemia in Adults (JCDCG) put forward the JCDCG 2007 standard on the standard of CDS 2004^[2]。 In the latest 2013 edition of the Chinese Diabetes Prevention and Treatment Guidelines, the MS-CDS 2013 standard was formally proposed on the basis of evidence-based medical evidence^[3]。

According to the 2014 National Physical Fitness Monitoring Bulletin issued by the State Sports General Administration on November 25, 2015, the overweight and obesity rates of the elderly in China in 2014 were 41.6% and 13.9% respectively, up 1.8% and 0.9% respectively compared with 2010^[1]。

With the development of comprehensive management of chronic diseases and hierarchical medical treatment, the role of primary medical institutions in diabetes prevention and treatment will be strengthened, and its importance will be more and more emphasized. However, in real life, there are still many problems in the prevention and treatment of diabetes and its complications in primary hospitals in China, especially in insulin therapy, and the misunderstanding is more prominent.