Volume 04 · Issue 01 · 2012

Heavenly rituals start again, and the annual law is renewed. The ferry of time carried the Chinese Diabetes Journal and the readers, authors and editors of the magazine, together through more than 300 shining days in 2011, and began a new cycle.

Genome-Wide association study (GWAS) is a research method that uses modern gene chip technology at the whole genome level to detect high-density genetic markers in large population DNA, so as to find the genetic factors of multi-gene complex diseases such as diabetes and obesity, and can find the gene mutation loci related to the occurrence and development of diseases^[1,2]。 In the field of diabetes, approximately 50 type 1 diabetes susceptibility sites have been mapped by GWAS to date^[3]More than 40 type 2 diabetes susceptibility sites^[4]The discovery of these genetic markers not only increases the ability of early prediction of disease, but also provides new ideas for the pathogenesis of diabetes. However, we also note that these genetic markers found by GWAS are mostly common variants with weak effects, and they can only explain a small part of the heritability of the disease^[5]。 At present, the ability of known genetic markers to predict the heritability of type 1 diabetes has reached 90%, but the ability to predict the heritability of type 2 diabetes is only about 65%^[6]。 What can GWAS, which has been in the field of diabetes research for nearly 5 years, tell us? It mainly includes the following aspects.

In recent years, diabetes is rapidly prevalent all over the world and has become one of the global public health problems. The China National Diabetes and Metabolic Disorders Study, completed in May 2008, showed that China has become The world's largest diabetic country^[1]。 In developed countries, type 2 diabetes accounts for 85% to 95% of the total number of diabetics, while in developing countries this proportion is even larger. Type 2 diabetes is a complex genetic disease caused by the combination of genetic factors and environmental factors. At present, the genetic research of type 2 diabetes is mainly led by European and American scholars, and the research shows that there is racial heterogeneity in the onset of diabetes. Compared with the Caucasian population, Chinese Han people have more obvious central obesity and poor islet β cell reserve function^[2]They are more susceptible to type 2 diabetes, so Chinese people tend to have diabetes at a lower level of obesity. In view of the differences between Chinese Han population and European population, while we verify the susceptibility loci of type 2 diabetes found in European population in Chinese population, it is more important to look for the susceptibility loci unique to Chinese population.

In China, diabetes has become a major public health problem, and the onset age of patients is getting younger^[1]diabetic patients in Asia are characterized by early onset and susceptibility to diabetic kidney disease^[2,3,4]。 Although the research of type 2 diabetes susceptibility genes has made great progress in recent years^[5]However, the research on genetic factors of diabetic complications is still lagging behind. This article will make a brief introduction to the current status of genetic research of diabetic nephropathy in diabetic complications.

To investigate the associations of two obesity susceptibility genetic variants: melanocortin 4 receptor(MC4R) and potassium channel tetramerisation domain containing 15 (KCTD15) single nucleotide polymorphisms rs17782313 and rs11084753 with type 2 diabetes mellitus (T2DM) and T2DM-related traits in Chinese Han population.

A total of 1177 type 2 diabetic (male 504 and female 673) and 1113 subjects with normal glucose tolerances (male 316 and female 797) were recruited from Beijing communities and outpatients of Peking University People's Hospital. The participants with a BMI ≥28.0 kg/m² as obesity group and those with a BMI of 18.5-23.9 kg/m² as normal weight group from normal glucose tolerance subjects were chosen for study. MC4R-rs17782313 and KCTD15-rs11084753 were genotyped by using MassARRAY iPLEX system. The rates among the groups were compared by χ ² test.

After adjusting age, sex and body mass index (BMI), no associations between rs17782313 and rs11084753 with T2DM was found under additive, dominant or recessive models (P>0.05). Under the dominant model, it's confirmed that rs17782313 was associated with obesity after adjusted for age and sex, with a odds ratio of 1.43 (95%CI 1.01-2.02), P=0.042, but no association was found under additive and recessive models. No association was found between rs11084753 and obesity under the up-mentioned three genetic models. In addition, analysis of clinical features in normal glucose tolerance subjects showed no differences in age, BMI, waist to hip ratio, fasting plasma glucose, OGTT 2-hour glucose and fasting serum insulin among three genotypes of rs17782313 and rs11084753 (all P>0.05), respectively.

In Chinese Han population, MC4R-rs17782313 and KCTD15-rs11084753 are not associated with type 2 diabetes, although a borderline association signal between MC4R-rs17782313 and obesity is detected.

To investigate the association of the genetic polymorphisms at endothelial nitric oxide synthase(eNOS) locus with the risk of coronary artery disease(CAD) in type 2 diabetics in China.

A total of 412 type 2 diabetics with chest pain treated from March 2005 to October 2010 were included in this study, of whom 266 individuals with coronary artery disease were enrolled in group CAD (171 males and 95 females, average age (64±9 )yrs) and 146 cases without CAD were set as controls (67 males and 79 females, average age (62±10) yrs). Two haplotype-tagging single nucleotide polymorphisms (SNPs) in eNOS gene were selected: rs1799983 (G>T) and rs2070744 (T>C). Genotypes of the 2 SNPs were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The frequencies of genotypes and alleles at the loci were compared between the two groups.

The frequencies of allele T at SNP rs1799983 were 10.4% in the group CAD and 9.3% in the controls, respectively. The carriers of allele T at rs1799983 had a tendency with a higher risk of CAD compared to non-carriers (OR=1.214, but P>0.05). The frequency of allele C at rs2070744 was 10.5% in the group CAD and 9.4% in the controls. The carriers of allele C at rs2070744 had a higher risk of CAD compared to non-carriers (OR=1.117, but P>0.05). No significant associations of the 2 SNPs with CAD risk was found in the studied population even after adjusted for the other known CAD risk factors, such as gender, age, body mass index, course of diabetes, history of hypertension and lipid metabolism disorders.

It suggests that the rs1799983 and rs2070744 at eNOS locus may not be the key risk factors for CAD in the Chinese patients with type 2 diabetes mellitus.

To investigate the correlation of the plasma tumor necrosis factor-alpha (TNF-α) levels and the distribution frequency of single nucleotide polymorphisms (SNP)-308 in children.

A total of 265 children were randomly divided into obese group(n=147)and non-obese group(n=118). All subjects were evaluated for waist circumference (WC), hip circumference, waist to hip ratio (WHR), percentage of body fat(BF%), blood pressure, triglycerides(TG), total cholesterol(TC), high density lipoprotein-cholesterol(HDL-C), low density lipoprotein-cholesterol (LDL-C), fasting blood glucose (FBG), fasting insulin (FINS), plasma TNF-α levels and homeostasis model assessment for insulin resistance (HOMA-IR).TNF-α gene -308 polymorphism were assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Chi-square test with count data andt-test or ANOVA was used for data analysis.

The plasma TNF-α levels increased in obese children compared to non-obese children (t=8.855, P<0.05). The A allelic frequency ofTNF-α gene SNP-308 in children with obesity and health control were 10.6% and 6.8%, respectively. No significant differences in allele (χ²=2.296, P>0.05) or genotype(χ²=2.082, P>0.05)frequency of SNP-308 between obese and health children. The differences of plasma TNF-α, WC, WHR, systolic blood pressure, BF%, TC, LDL-C, FBG, FINS and HOMA-IR in children with wild homozygous GG and carriers of A allele ofTNF-α polymorphism gene did not show significance in statistics.

There was no association between TNF-α gene SNP-308 and children obesity.

To compare the efficacy and safety of insulin glulisine and insulin lispro combined with insulin glargine in patients with diabetes mellitus.

This was a multi-centre randomly controlled study. Thirty four patients with type 1 and 450 patients with type 2 diabetes mellitus with a HbA1c level of 6.5% to 11.0% and more than 3 months of continuous insulin treatment immediately prior to study entry were enrolled from February 2007 to June 2008. After 4-week run-in period with insulin lispro (three times a day, 0-15 min before the meals) combined with insulin glargine treatment (once daily before breakfast) , all the subjects were randomized (3∶1) to receive a 12-week treatment with insulin glulisine or insulin lispro in combination with insulin glargine. The data collected at the visit after the 4-weeks run-in period was defined as the baseline data. The change in HbA1c, blood glucose, treatment satisfaction and incidence of hypoglycemia after the treatment was recorded and compared. The data of the two groups were compared by using an ANOVA model.

After 12-week of treatment, HbA1c reduced from 8.7%±1.2% to 7.9%±1.0% in insulin glulisine group, and from 8.8%±1.2% to 7.9%±1.0% in insulin lispro group (compared with baseline, t=-12.55 and -8.88, both P<0.05). Fasting plasma glucose(FPG) decreased significantly compared with baseline in both groups: for insulin glulisine group, from (8.6±2.8) mmol/L to (7.7±2.5)mmol/L, and for insulin lispro group, from (8.6±2.5) mmol/L to (7.8±2.2)mmol/L (compared with baseline,t=-6.55 and -2.98, both P<0.05). The 2 h post-prandial glucose (2 h PPG) decreased significantly in insulin glulisine group (from (10.6±3.8)mmol/L to (10.2±3.7)mmol/L,t=-2.07, P=0.04), but it was no difference in insulin lispro group (from (10.9±4.0) mmol/L to (10.4±3.5) mmol/L, t=-1.37, P>0.05). The incidence of all categories of symptomatic hypoglycemia was comparable between the two groups (33.9% vs 34.7%) during treatment period. An increase of satisfaction scores after treatment was found both in the insulin glulisine group (from 29±5 to 31±5,t=6.81 P<0.05) and insulin lispro group (from 29±5 to 31±4,t=4.21, P<0.05).

It showed that when used in combination with insulin glargine, insulin glulisine is clinical equivalent to insulin lispro in decreasing HbA1c and plasma glucose in Chinese patients with diabetes mellitus. Both regimens are well tolerated and safe.

To investigate the effects and mechanism of glucagon-like peptide-1 (GLP-1) on rat skeletal muscles.

Rat skeletal muscle cells were cultivated in vitro. MTT method was used to check the effects of GLP-1 and insulin (INS) on survival of skeletal muscle cells. Glycogen synthase (GS) and phospho-glycogen synthase kinase-3α/β (pGSK-3α/β) were measured by using immunohistochemistry. Impact of GLP-1 on phosphatidylinositol 3 kinase (PI3K) pathway was confirmed by Western blotting. Rat skeletal muscle cells were divided into the control group, GLP-1 group, LY294002 group, and GLP-1+ LY294002 group. The expressions of GS and pGSK-3α/β were compared between the groups. Analysis of variance (ANOVA) was used for data analysis.

Western blotting results indicated that following GLP-1 intervention, positive particles were found in rat skeletal muscle cells at 15 and 30 min, and 1, 2 and 8 h. In comparison with the GLP-1 group, the expression of pGSK-3α/β of the control group, LY294002 group, and GLP-1+ LY294002 group was significantly decreased (0.93±0.11, 0.52±0.05, 0.65±0.07, and 0.54±0.21, respectively;t values were 5.751, 3.651, and 2.811, respectively; all P<0.05), and the expression of GS was significantly decreased (0.84±0.14, 0.28±0.05, 0.34±0.22, and 0.57±0.08, respectively;t values were 6.390, 3.260, and 2.801, respectively; all P<0.05).

This study suggests that GLP-1 may increase the activity of GS in skeletal muscle cells through activating GSK-3 pathway.

To investigate the prevalence of mutation of potassium inwardly-rectifying channel KCNJ11 gene in type 2 diabetes mellitus with pancreatic dysfunction in Shanghai.

Forty-one patients(30 male, 11 female) with type 2 diabetes mellitus were enrolled, whose average age was (57±12) years old and fasting C-peptide were all less than 0.20 μg/L in OGTT test and with negative antibody test. General data such as age, gender, family history, anthropometric parameters were collected.The PCR-direct sequencing was employed to detect the KCNJ11 gene mutation and analyze the frequencies of the discovered mutations and variants.We compared genotype frequency differences between our experiment and The International HapMap Project Chinese database by the chi-square test.

Only one synonymous mutation (S274S) was found in one participant. Moreover, we also identified four variants in this study, rs5215, rs5218, rs5219 and rs1800854.The allele frequencies of the four variants had no significant differences between our study and HapMap Chinese database (the χ ² value was 0.010, 0.391, 0.025, 0.407, respectively, and all P>0.05).

The KCNJ11 gene mutation may not the major cause of diabetes patients with pancreatic dysfunction.

Recent studies have found that adipose tissue can not only store energy, but also an important secretory organ. It secretes a variety of bioactive molecules and regulates the body's energy metabolism through endocrine, paracrine and autocrine modes. Among them, acylation promoting protein (ASP) is a small molecule basic plasma protein of 76 amino acids secreted by adipocytes and fibroblasts, with an isoelectric point (PI) =9.0 and a molecular weight of 8932. It affects the adipose tissue glucose transport and free fatty acid storage, and plays an important role in the maintenance of energy balance^[1]。 Studies have shown that ASP has a certain correlation with diabetes, but it has not been seenASPReport of the relationship between genetic polymorphisms and type 2 diabetes mellitus (T2DM). Therefore, the purpose of this study is to investigate the Uyghur and Han patients in XinjiangASPRelationship between polymorphism of rs7257062 locus and T2DM and lipid metabolism.

Type 2 diabetes mellitus (T2DM) is a complex disease caused by the combination of genetic and environmental factors. The familial aggregation of T2DM, the high consistency of identical twin incidence, and the high incidence in some ethnic populations all strongly suggest the role of genetic factors in its pathogenesis. Related studies predict that 30% to 70% of the risk of T2DM patients can be attributed to genetic susceptibility^[1]。 At the same time, T2DM is genetically heterogeneous, and its phenotype is controlled by the polygenic genetic background and complex environmental factors. Specifically, each patient may have different combinations of susceptibility genes, and non-patient populations can also aggregate various genetic and environmental disease susceptibility factors to varying degrees; In terms of individual genetic or environmental factors, susceptibility genes can exist in both patient and non-patient populations, and the difference is only in frequency. Therefore, it is not easy to confirm the T2DM susceptibility gene. So far, the number of T2DM susceptible genes and their interactions have not been fully defined, but the fruitful results of T2DM-related Genome-Wide Association Studies (GWAS) since 2007 are still encouraging. In this paper, the strategies and achievements of searching for T2DM susceptibility genes, the current status of relevant research in China and the significance of such research are reviewed.

Menopause refers to the permanent absence of menstruation caused by the decline of ovarian function and then the decline of estrogen. The decline of estrogen brings hot flashes, night sweats, sleep disorders, urogenital atrophy, osteoporosis, etc., which seriously affect the quality of life of postmenopausal women. A large number of clinical studies have shown that menopause is a risk factor for metabolic syndrome^[1,2,3,4]Moreover, the risk of metabolic syndrome is closely related to the number of years of menopause. Cho et al.^[5]A survey of 618 non-menopausal women and 384 postmenopausal women found that the risk of developing metabolic syndrome after menopause had been increasing and did not begin to decline until 14 years after menopause. Different years of menopause have different effects on various components of metabolic syndrome: the risk of central obesity and elevated blood sugar is the highest within 5 years of menopause, hypertension is the most likely to occur in 5 to 9 years of menopause, and the risk of increased blood triglycerides is the greatest in 10 to 14 years of menopause.

As a kind of intestinal endocrine cells, L cells are scattered in the gastrointestinal tract, secreting glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), polypeptide YY (PYY) and other important peptide hormones, which can promote insulin secretion, control appetite, and control blood sugar and body mass. Recent studies have shown that patients with type 2 diabetes have impaired GLP-1 secretion, and drugs based on GLP-1 have been used in the clinical treatment of type 2 diabetes. This paper focuses on the research progress of L cells.

Diabetic peripheral neuropathy is one of the complications of diabetes, which usually manifests as peripheral nerve damage, and a few manifests as single peripheral nerve damage, such as oculomotor nerve and abducens nerve paralysis causing restricted eye movement or eyelid ptosis. However, monosomal nerve damage has received increasing attention in recent years^[1]。 Among them, there are few reports of muscular atrophy of both hands as the main clinical manifestation^[2]And it needs to be differentiated from diabetes complicated with carpal tunnel syndrome, diabetic muscular infarction, amyotrophic lateral sclerosis, thoracic outlet syndrome, etc. A case of diabetic hand muscle atrophy caused by damage of ulnar nerve and median nerve is reported, and its diagnostic experience is summarized by differential diagnosis.

Insulin was first used clinically in North America in January 1922, and its immediate effect elated the global endocrinology community. Then, in February 1923, mass production of insulin began in Eli Lilly and Company, USA^[1]。 When did insulin begin to be used clinically in China? Available data show that in July 1923, Peking Union Medical College Hospital has begun to use insulin to treat diabetes. The medical record number of this medical record is 5524. In the discharge section on the front page of the medical record, it is written impressively: This is the first case of diabetes ever treated with insulin in this hospital! (This is the first diabetic patient treated with insulin in our hospital!). Considering the special status of Peking Union Medical College Hospital in China's medical field in the 1920s, its first use of insulin therapy is probably the first use of insulin in China. This medical record is presented to colleagues in the diabetology community.

Diabetes is a serious endangerment to human health. Even under the existing drug treatment, the control status is still very severe. The research results show that about two-thirds of diabetic patients in developed countries are not effectively managed and controlled, and the status of diabetes control in developing countries, especially China, is even less optimistic. The outpatient survey in large and medium-sized cities in China in 2003, 2004 and 2006 showed that only 1/4 of diabetic patients reached the standard of glycosylated hemoglobin (HbA1c) (<6.5%)。 Combined use of hypoglycemic drugs is the main measure to improve blood sugar control at present. When the first-line hypoglycemic drug metformin cannot achieve good blood sugar control, the addition of other hypoglycemic drugs such as thiazolidinediones, sulfonylureas, and dipeptidyl peptidase-4 (DPP-4) inhibitors can effectively control blood sugar. Among them, the combination of DPP-4 inhibitor vildagliptin and metformin has not only good efficacy, but also low incidence of adverse events, good safety and tolerability, and is one of the ideal combination combinations.

In patients with type 2 diabetes, chronic hyperglycemia can promote progressive islet beta cell failure, a phenomenon known as glucotoxicity. However, the effects of chronic hyperglycemia on the self-metabolism of pancreatic islet beta cells have not been fully understood by humans. Recently, an unbiased metabolite analysis method was used to observe the time course of core metabolic patterns of rat pancreatic islet beta cell line INS-1E exposed to high concentrations of glucose and its relationship with insulin gene expression.

Neonatal diabetes is caused by mutations in adenosine triphosphate-sensitive potassium channels, and children can be treated with sulfonylureas instead of insulin injections. In adenosine triphosphate-sensitive potassium channel-dependent diabetic mouse models, chronic administration of sulfonylurea therapy avoids hyperglycemia and decreased islet beta cell numbers. Interestingly, adenosine triphosphate-sensitive potassium channel mutations can take on a relapse-remission form in different patients, but the mechanism is unclear.

Previous studies have found that islet platelet reactive protein-1 deletion can cause islet hyperplasia. An article published inDiabetesThe above studies confirmed that endothelial-derived platelet reactive protein-1 has an important effect on pancreatic islet beta cell function.

Recently, a study suggested that advanced glycation end products may directly lead to insulin secretion defects by impairing mitochondrial function and promote the development of type 1 diabetes.

Myoendoplasmic reticulum calcinase 3 and Myoendoplasmic reticulum calcium adenosine triphosphatase 2b in the endoplasmic reticulum of pancreatic islet β cells have regulatory effects on the concentration of free calcium ion in the endoplasmic reticulum. An article published inDiabetesAdenovirus encoding the low-affinity calcium ion receptor D4 localized in the endoplasmic reticulum under the control of insulin boosters is used to monitor myoplasmic reticulum calcase3^(＋/＋)and myoplasmic reticulum calcase3^(–/–)The concentration of free calcium ion in the endoplasmic reticulum of mouse islet β cells was recorded, and the concentration of free calcium ion in cytoplasm was also recorded. The effects of myoendoplasmic reticulum calcase3 on insulin secretion and endoplasmic reticulum stress of mouse β cells were observed.