Volume 10 · Issue 02 · 2018

Treatment of type 2 diabetes mellitus (T2DM) is a long-term process. Most newly diagnosed patients can initiate oral antidiabetic agents (OADs) treatment on the basis of lifestyle intervention; If there are significant clinical symptoms and blood glucose is significantly increased, short-term intensive insulin therapy can be given. After newly diagnosed patients are given intensive insulin therapy to relieve hyperglycemic toxicity, the function of pancreatic islet β cells may be partially recovered, and then an individualized treatment plan is given according to the patient's condition.

Diabetes is currently one of the most serious health problems in the world. According to data from the International Diabetes Federation in 2017, the number of adults with diabetes in the world has reached 425 million, and it is estimated that it may reach 629 million in 2045. China has become the largest absolute number of diabetic patients with 114 million countries. In the past 20 years, new hypoglycemic drugs have been emerging and widely used in clinical practice, but the improvement of blood sugar control in diabetic patients is not optimistic. So far, about half of patients have not achieved glycosylated hemoglobin (HbA_1c）<7% control target, there was no significant improvement in severe hypoglycemia and no significant long-term cardiovascular benefit^[1]。 With the deepening of research on the pathogenesis of diabetes, a series of new drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been marketed successively and have quickly occupied an important position in major guidelines relying on good clinical effects. In addition, the research and development of many new hypoglycemic drugs based on new targets has gradually entered phase II and III clinical trials, and it is foreseeable that the traditional hypoglycemic regimen will undergo great changes as a result. This paper summarizes the hot spots of new diabetes drugs in recent years.

sodium-glucose co-transporter 2 inhibitor (SGLT2i) is a new class of oral hypoglycemic drugs. SGLT2 is mainly distributed in the S1 segment of the proximal tubule of the kidney, and is responsible for 90% of the tubular glucose transport^[1]； SGLT2i can selectively inhibit the renal reabsorption of glucose. About 70 g of glucose, equivalent to 280 kcal (1 kcal =4.184 kJ) of calories, is excreted by urine every day, and belongs to a new class of drugs that are independent of insulin. Since its first launch in Europe in 2012, it has been found that such drugs are not only effective in reducing glycosylated hemoglobin (HbA) in patients with type 2 diabetes mellitus (T2DM)_1cIn addition, there are many additional benefits, such as weight loss, blood pressure reduction, reduction of urine protein and uric acid, etc^[2,3,4]Therefore, it has received widespread clinical attention. In 2015, the Food and Drug Administration (FDA) first reported cases of ketosis and ketoacidosis (DKA) in patients using SGLT2i, but the causal relationship between the two is still unclear. Therefore, this article reviews and discusses the mechanism of the relationship between SGLT2i and ketone bodies or DKA.

Recently, the most exciting hypoglycemic drug in the diabetes community is sodium-glucose co-transporter 2 inhibitor (SGLT2i), and its clinical application and role in diabetic complications have attracted much attention.

To investigate the relationship between the level of serum undercarboxylated osteocalcin (ucOC) with the development and progression of diabetic retinopathy (DR) in male patients with type 2 diabetes mellitus (T2DM).

A total of 125 male patients with T2DM cared at Tangshan Gongren Hospital from October 2015 to November 2016 were recruited as subjects, they were divided into three groups as: T2DM without DR group (NDR, n=45), T2DM none-proliferative DR group (NPDR, n=42) and T2DM with proliferative DR group (PDR, n=38). 50 male subjects without T2DM from the medical examination center were selected as normal control group (NC). Data including age, diabetes duration, body mass index, systolic blood pressure, diastolic blood pressure were recorded, and clinical biochemical indicators including fasting plasma glucose, glycated hemoglobin A_1c, triglyceride, total cholesterol, low-density lipoprotein-cholestrol, high-density lipoprotein-cholestrol (HDL-C), 24 h urinary albumin excretion rate (UAER) and fasting insulin were collected, homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, ucOC was measured by enzyme linked immunosorbent assay. Multiple-group comparisons were analyzed by one-way ANOVA or Kruskal-Wallis H test. Two-group comparisons were analyzed by LSD test or LSD test by rank conversion. Multivariate correlation analysis was used Pearson or Spearman correlation analysis. Risk factor screening was used multiple stepwise regression analysis.

(1) The serum ucOC level of T2DM groups were lower than NC group. The order of serum ucOC level from low to high were PDR, NPDR, NDR and NC [(1.4±0.6), (2.1±0.9), (2.7±0.9), (3.3±0.9) μg/L, F=63.149, all P<0.05]. (2) Serum ucOC was negatively associated with HbA_1c, HOMA-IR, 24hUAER (r=-0.379,-0.237,-0.429, all P<0.05), and was positively associated with HDL-C (r=0.223, P<0.05). (3) Logistic regression analysis showed that duration of diabetes, HOMA-IR, 24hUAER and ucOC were independent risk factors of DR in male T2DM patients (OR=0.396-2.523, all P<0.05).

The reduction of serum ucOC in male T2DM patients may be related to the development and progression of DR.

To investigate the characteristics of early-onset type 2 diabetes mellitus (T2DM) and its influencing factors with depression.

A total of 237 patients at the age of 40-60 years hospitalized in the Department of Endocrinology of Quanzhou First Hospital affiliated to Fujian Medical University from June 2015 to May 2016 were included. According to the age of diabetes diagnosis, these patients were divided into early-onset T2DM group (EDM, age of onset was no more than 40 years, n=72) and late-onset T2DM group (LDM, age of onset was after 40 years, n=165). Clinical data including family history and the score of sexual dysfunction were collected and compared. Binary logistic regression analysis was used for analyzing the risk factors with depression in patients with premature T2DM.

(1) Compared with LDM group, EDM group had a higher percentage of smoking, drinking and family history of depression [62.50% (45/72) vs 41.82% (69/165), 45.83% (33/72) vs 27.27%(45/165), 4.17% (3/72) vs 0 (0/165), 87.00% (60/72) vs 23.60%(39/165), χ ²=8.589, 7.821, 14.888, 79.922, all P<0.01]. (2) Logistic regression analysis showed that initial age of T2DM diagnosis, body mass index (BMI), atherosclerosis, level of C peptide and sexual dysfunction were the influencing factors of depression in men in EDM group [the value ofOR (95%CI) was 0.699 (0.592-0.824) , 2.112 (1.392-3.205) , 0.000 (0.000-0.007) , 0.984 (0.976-0.993) , 101 473.811 (535.586-19 225 546.110) , respectively, all P<0.001].

At the age of 40-60, the proportion of depression is higher in patients with early onset T2DM than in late onset T2DM. Initial age of T2DM diagnosis, atherosclerosis, BMI, level of C peptide and sexual dysfunction maybe the influencing factors of depression in male EDM patient.

To explore the effect of different diabetic risk score in screening for diabetes mellitus in the health check-up population, and to analyze the risk factors of abnormal glucose metabolism.

Diabetes risk scores screening was conducted in people who participated physical examination in Medical Examination Center of Beijing Hospital in 2015. The area under the curve (AUC) of the receiver operating characteristic curve was used to reflect the accuracy of the screening method. The relevant risk factors of abnormal glucose metabolism were used by multivariate logistic regression analysis.

(1) The AUC of screening for diabetes by Chinese diabetes risk score (C-DRs) was 0.83 [95% confidence interval (CI) 0.811-0.843], and the best cut-point value was 26.5. The sensitivity was 83.48%, the specificity was 61.45%, and the Younden index was 0.45 (P<0.05). (2) Age [odds ratio (OR)=2.646, 95%CI: 1.707-4.101], family history of diabetes (OR=13.103, 95%CI: 6.076-28.259), BMI≥25 kg/m² (OR=2.400, 95%CI: 1.609-2.580), male abdominal circumference≥90 cm (OR=3.869, 95%CI: 1.687-8.872), female abdominal circumference≥85 cm (OR=1.787, 95%CI: 1.183-2.699), hypertention (OR=7.812, 95%CI: 1.560-39.113), high triglyceride (TG) (≥1.7 mmol/L) (OR=1.751, 95%CI: 1.138-2.696), smoking history (OR=3.974, 95%CI: 2.085-7.474), less than 150 min moderate physical activity per week (OR=10.446, 95%CI: 5.304-20.574), more than 100 g carbohydrates per meal (OR=58.581, 95%CI: 24.899-137.826) were risk factors for abnormal glucose metabolism (all P<0.05). (3) In combination with the above risk factors used to screen for diabetes, the AUC was 0.88 (95%CI: 0.862-0.890), the best cut-point value was 31.5, the sensitivity was 88.60%, the specificity 68.68%, the Jordanian index was 0.57 (P<0.05).

C-DRs is more suitable for diabetes screening in Chinese population. Combined with the factors as: less than 150 min moderate physical activity per week, more than 100 g carbohydrates per meal, smoking history, and high triglycerides, can improve the sensitivity and specificity of screening for diabetes mellitus.

To evaluate the association between programmed cell death 1 (PDCD1) gene variants and type 1 diabetes mellitus (T1DM).

A case-control study was conducted in 585 T1DM patients from August 2014 to December 2016 in the Department of Endocrinology of the First Affiliated Hospital of Nanjing Medical University and 761 healthy controls in the same period in this region. PDCD1 rs2227981 and rs2227982 genotypes were analyzed by SNaPshot and the association of rs2227981 and rs2227982 locus genotype and allele frequency distribution with T1DM susceptibility was analyzed.

Our study indicated that the frequency of CC, CT and TT genotype of rs2227981 in T1DM patients were 50.6%, 40.0% and 9.4% respectively and 56.6%, 37.2% and 6.3% respectively in healthy subjects. PDCD1 rs2227981 polymorphism was significantly associated with T1DM (OR=1.25, 95%CI: 1.06-1.48, P=0.01). Allelic gene C and T frequency were 70.6% and 29.4% in T1DM group, and 75.1% and 24.8% in control group, the T allele increased the risk of T1DM (OR=1.26, 95%CI: 1.06-1.49, P=0.009). The frequency of TT, TC and CC genotype of rs2227982 in T1DM patients were 20.2%, 51.8% and 28% respectively and 25.8%, 49% and 25.2% respectively in healthy subjects. PDCD1 rs2227982 polymorphism was also associated with T1DM (OR=1.18, 95%CI: 1.02-1.38, P=0.031). Allelic gene T and C frequency were 46.1% and 53.9% in T1DM group, and 50.3% and 49.7% in control group, the C allele increased the risk of T1DM (OR=1.15, 95%CI: 1.01-1.30, P=0.028).

The results indicate that PDCD1 rs2227981 and rs2227982 polymorphism are associated with increased risk of T1DM.

To investigate the effect and potential mechanism of glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide on fibroblast growth factor-21 (FGF-21) production in mouse pancreatic β cell line Min6.

Min6 cells were incubated for 24 h with liraglutide in the presence or absence of the GLP-1 receptor antagonist exendin (9-39). The expressions of FGF-21 mRNA and protein were detected by RT-PCR and western blotting analyses. Supernatant FGF-21 levels were measured by ELISA. In the mean time, after Min6 cells were incubated with 10 nmol/L liraglutide and/or 5 μg/ml neutralizing anti-FGF-21 IgG for 24 h, supernatant insulin levels were measured by ELISA. Different group comparisons were performed using one-way variance analysis and LSD- t test.

Compared with control group, 1, 10 and 100 nmol/L liraglutide dose-dependently upreglulated the expression levels of FGF-21 mRNA (1.26±0.24, 1.52±0.41 and 1.21±0.26 vs 1, F=3.523, P=0.021) and protein (1.61±0.27, 1.70±0.45 and 1.27±0.10 vs 1, F=5.052, P=0.006), and increased the levels of FGF-21 secretion [(0.21±0.05), (0.25±0.08) and (0.26±0.07) vs (0.19±0.06) μg/mg, F=16.44, P=0.007] in Min6 cells. The above effects of 10 nmol/L liraglutide could be eliminated by addition of exendin (9-39) [mRNA level, 0.85±0.15 vs 1.31±0.16, t=4.133, P=0.026; protein level, 1.27±0.13 vs 1.74±0.06, t=10.55, P=0.009; secretion level,(0.23±0.11) vs (0.26±0.10) μg/mg protein, t=4.159, P=0.025]. Moreover, compared with control group, 10 nmol/L liraglutide stimulated insulin secretion in Min6 cells [(1.22±0.47) vs (0.55±0.23) μg/mg protein, t=3.19, P=0.024], which could be abolished by blocking FGF-21 action with anti-FGF-21 IgG [(0.67±0.28) vs (1.22±0.47) μg/mg protein, t=4.371, P=0.007].

Liraglutide enhances FGF-21 production in mouse pancreatic β cell line Min6 in a GLP-1 receptor-dependent manner. FGF-21 may be involved in the stimulating effect of liraglutide on insulin secretion from Min6 cells in an autocrine or paracrine fashion.

To observe the effects of metformin on hepatic lipid accumulation in high-fat-diet-induced C57BL/6J mice and discuss its mechanism.

Non-alcoholic fatty liver disease (NAFLD) models were established by feeding C57BL/6J mice with a high-fat-diet for 6 weeks. C57BL/6J mice aged 10 weeks were divided into three groups as followings: normal diet group (ND group, n=10, fed with a normal chow diet), high-fat diet group (HFD group, n=12, fed with a high fat diet and given 300 μl of saline by gastric perfusion once a day) and metformin group (Met group, n=12, fed with a high-fat diet and given 300 μl of saline dissolving with 300 mg/kg of metformin by gastric perfusion once a day). Body weight, the amount of food intake, serum lipids, hepatic enzymes, hepatic lipid infiltration, contents of hepatic triglyceride (TG), total cholesterol (TC) and expression levels of proteins related to lipid metabolism in liver tissue were compared among those 3 groups after 4-week intervention. The t test was performed in data comparisons between two groups, while one-way analysis of variance was applied for comparisons among multiple groups.

Compared with HFD group, body weight of mice in Met group decreased significantly [(32.9±1.1) vs (36.4±1.1) g, t=2.257, P<0.05]. However, there was no significant differences in the amount of food intake between HFD and Met group (t=1.191, P>0.05). Compared with HFD group, the concentrations of TG, low-density lipoprotein-cholesterol, alanine transaminase and aspartate aminotransferase were prominently decreased by metformin intervention (t=2.285-2.860, all P<0.05). Compared with HFD group, the hepatic lipid infiltration was notably alleviated in Met group (t=28.000, P<0.001). Moreover, the contents of TG and TC in liver tissue were remarkably decreased in Met group (t=2.394, 2.281, both P<0.05). Compared with HFD group, phosphorylation of adenosine monophosphate-activated protein kinase α (AMPKα) and acetyl coenzyme A carboxylase were significantly enhanced whereas protein expressions of sterol regulatory element binding transcription factor 1-c and fatty acid synthase were notably decreased after 4-week metformin intervention (0.82±0.07 vs 0.59±0.03, 0.94±0.12 vs 0.42±0.10, 1.24±0.05 vs 1.56±0.08, 1.09±0.07 vs 1.42±0.06, t=-2.892, -3.463, 3.447, 3.507, all P<0.05).

Metformin might alleviate hepatic lipid accumulation in high-fat-diet-induced C57BL/6J mice via AMPK signaling pathway, it suggests that metformin can be a promising treatment for NAFLD.

To identify whether regulation of Cathepsin G (CatG) expression can influence CD₄⁺ T lymphocytes (T cells) activation in non-obese diabetic (NOD) mice, and to demonstrate the role of CatG inhibition in prevention and treatment for type 1 diabetes mellitus (T1DM).

A total of 36 female NOD mice (6 weeks old) were randomly divided into 3 groups according to the duration and blood glucose: normal control group, pre-diabetes (pre-DM) group, and diabetes (DM) group. CatG gene expression and CD₄⁺ T cells activation were examined in these three groups of NOD mice (12 mice in each group). After modelling, CatG small interfering RNA (siRNA) was administrated to treat the other pre-diabetic NOD mice, and CatG inhibitor was administrated to treat diabetic NOD mice (12 mice in each intervention group) . Also control groups (12 mice in each group) were respectively set. After 8 weeks, all the mice were executed and histological analysis were performed. The effect of CatG inhibitor was investigated in NOD mice on CD₄⁺ T cells activation, islet β cell function, and islet inflammation. Furthermore, NOD mice were injected with CatG siRNA in early stage to observe the effect of CatG knockdown on CD ₄⁺ T cells activation status and on diabetes progression. The data of three groups were analyzed with single factor analysis of variance, and the data of two groups were compared with independent samples t test.

(1) The gene level of CatG of the 3 groups was 0.42±0.21, 0.60±0.33, 0.94±0.45, respectively (F=12.89, P<0.05). The gene level of CatG in pre-DM group and DM group was significantly higher than that in normal control group. Meanwhile, compared with normal control group, the CD₄⁺ T cells in spleen and peripheral blood were gradually activated in pre-DM group and DM group, resulting in more T helper (Th)1 cells and fewer Th2 and regulatory T(Treg) cells (F=11.85-21.36, all P<0.01). (2) After administration with CatG inhibitor, the level of blood glucose was decreased (t=11.26-12.45, all P<0.01) and insulin was increased (t=11.89-13.78, all P<0.01);Meanwhile, the activation of CD₄⁺ T cells was decreased, and the difference was statistically significant (all P<0.05) . (3) Compared with the control group, after early application of CatG siRNA, the percentage of Th1 cells was decreased [peripheral blood: (5.1±1.4)% vs (2.4±0.3)%, spleen: (10.6±2.0) % vs (6.3±1.5) %, t=20.78, 27.96, all P<0.05]. The percentage of Th2 and Treg cells was increased (t=20.59-30.25, all P<0.05). Meanwhile, the mice could maintain in normal glucose status or pre-DM status, and the insulin level could be enhanced significantly in CatG siRNA group (t=31.69-33.98, all P<0.01).

CatG is the major effector protease in CD₄⁺ T cells activation in the pathogenesis of T1DM. Targeted inhibition of CatG may delay or block T1DM progression through alleviating CD₄⁺ T cells activation.

In order to improve physician's understanding of the clinical characteristics and molecular pathogenesis of this disease, we reported one case of primary renal glucosuria (PRG) and had literature reviewed.

Molecular genetic analysis of SLC5A2 gene was conducted in 1 patient with isolated glucosuria. Extensive laboratory test, physical and imaging examination were performed. We also analyzed of the clinical data of renal glucosuria reported in China since 1979 and summarized the SLC5A2 mutations in these Chinese patients with PRG.

The test results of the patient indicated that glucose metabolism was normal. A novel missense mutation (c.917 G>T, p.S306I) in exon 8 was detected. Review of literature reported in China, 85 cases of PRG were reported, involving 17 families and some sporadic cases. There were 52 males and 33 females with onset age from 7 to 73 years old (mean age 34.03 years). Most patients had no symptoms, 11 patients (12.9%) had different degrees of dry mouth, polydipsia, polyuria, weight loss, fatigue, and 3 cases with urinary tract infection. All of these patients met the diagnostic criteria for PRG. Their fasting blood sugar fluctuated at 2.8-6.6 mmol/L, and 61 patients were excluded diabetes by glucose tolerance test. Six patients were followed up for 4 months to 15 years and no obvious complications occurred.

The clinical manifestations of PRG patients are mostly benign, and SLC5A2 gene analysis is helpful for the etiological diagnosis of the disease.

In recent years, due to the abuse of antibiotics, the infection rate of fungi has also increased, especially in combination with immunocompromised diseases such as diabetes (especially in combination with ketoacidosis), malignant tumors, leukopenia or severe burns. According to previous literature^[1,2]It was reported that the main opportunistic fungal infections were Candida, Aspergillus, Cryptococcus neoformans, and Mucor was less common. The clinical manifestations, imaging characteristics, diagnosis and treatment of a case of diabetes mellitus complicated with naso-orbital cerebral mucormycosis infection were analyzed and summarized.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted by L cells in the distal ileum, colon, and rectum. It plays an important role in improving islet β cell function, promoting insulin secretion, and delaying complications in patients with type 2 diabetes. In recent years, the role of GLP-1 in cell proliferation and apoptosis and its mechanism of action have become a hot research topic. In this paper, the research progress of GLP-1 is reviewed from the relationship between GLP-1 and signal transduction pathway.