Volume 08 · Issue 11 · 2016

The prevalence of diabetes in China has risen from less than 1% 30 years ago to 11.6% in the last report in 2013^[1]。 Diabetes is characterized by elevated plasma glucose, while the harm lies in complications. In 1921, Canadian doctors Banting et al. successfully isolated insulin from animal pancreas and began to use it for diabetes treatment. The occurrence and death of acute complications such as diabetic ketoacidosis and hyperosmolar syndrome suddenly decreased. With the significant prolongation of the life span of diabetic patients (especially type 1 diabetic patients), people have gradually found that the overall life span of diabetic patients is still lower than that of normal people, and their risk of chronic renal insufficiency, fundus vasculopathy, coronary heart disease, stroke and other diseases will be significantly higher than that of non-diabetic people. These diseases became known as chronic complications of diabetes. Among them, complications involving microvascular complications such as kidney and retina are called microvascular complications, while complications involving macrovascular complications such as heart, cerebrovascular and lower extremities are called macrovascular complications. Nowadays, chronic complications of diabetes have gradually become the main cause of disability and death in diabetic patients. Since elevated blood sugar can increase the risk of these chronic complications, can long-term blood sugar control effectively reduce these risks?

In recent years, the research field and drug development technology of type 2 diabetes (T2DM) have developed rapidly, and new hypoglycemic drugs have emerged in an endless stream. Among them, sodium-glucose co-transporter (SGLT) 2 inhibitors have emerged due to their unique renal sugar excretion mechanism. At present, there is more and more clinical research evidence on SGLT-2 inhibitors. The 2015 Empagliflozin Cardiovascular OUTCOME Study-EMPA-REG OUTCOME^®The release of the results has attracted much attention for empagliflozin. EMPA-REG OUTCOME^®A total of 7 020 patients with high-risk cardiovascular T2DM were randomized to receive empagliflozin 10 mg, 25 mg, or placebo once daily on top of conventional therapy, with a median follow-up of 3.1 years. The results showed that empagliflozin could significantly reduce the risk of cardiovascular disease in patients with high cardiovascular risk T2DM while effectively lowering glucose and weight^[1]。 Many new studies were published in 2016, especially at the European Diabetology Annual Meeting held in September this year, including the EMPA-REG OUTCOME^®The in-depth analysis of the study and other new studies of SGLT-2 inhibitors provide new evidence for us to further understand the efficacy and safety of SGLT-2 inhibitors in the treatment of patients with T2DM.

There is growing evidence that metformin can deliver multiple clinical benefits and improve outcomes in patients with diabetes. Nowadays, in the guidelines for the prevention and treatment of type 2 diabetes formulated by professional academic organizations at home and abroad, metformin is used as the first-line drug for hypoglycemic treatment. Metformin can be traced back to the 1920s. It is a guanidine substance extracted from a plant called "goat bean". In 1957, metformin was officially used in clinic. However, metformin was ill-fated. Because phenformin, which is also a biguanide drug, can cause lactic acidosis and was abandoned, metformin was also affected and withdrawn from the market in the United States. In 1998, the New England Journal of Medicine published the 20-year follow-up results of the United Kingdom Prospective Diabetes Study (UKPDS), which confirmed that the treatment of type 2 Diabetes with metformin not only reduces blood sugar, but also reduces chronic complications and death of Diabetes^[1]It provided very favorable evidence for the clinical application of metformin. Therefore, metformin was reborn, and it was relisted in the United States and Europe in 1995 and 2004. In recent years, with the deepening of research, it has been found that metformin also has multiple external benefits of hypoglycemic, which has become the focus of attention.

Dipeptidyl peptidase IV (DPP-4) inhibitors are a new class of oral hypoglycemic drugs, which exert hypoglycemic effects by inhibiting DPP-4 in vivo, increasing and prolonging the activity of endogenous glucagon-like peptide 1 (GLP-1)^[1]。 Since the first DPP-4 inhibitor (sitagliptin) was launched in 2006, there have been ten DPP-4 inhibitors on the market worldwide, namely saxagliptin, linagliptin, alogliptin and vildagliptin. Also newly launched are gemagliptin, ticagliptin, anagliptin, tropagliptin and ogliptin. In recent years, evidence-based medical evidence on the efficacy and safety of DPP-4 inhibitors has emerged, especially several prospective, multi-center large-scale safety studies carried out globally have been completed, which provides a reliable reference for us to further understand the efficacy and safety of various DPP-4 inhibitors.

The global prevalence of diabetes and obesity is increasing. According to the latest global diabetes report released by the World Health Organization in 2016, the global prevalence of diabetes is 8.5%, and the number of adult diabetic patients has reached 422 million^[1]。 China has become the number one diabetic country, with 110 million patients^[2]。 58.3% of the patients were combined with overweight or obesity [body mass index (BMI)>24 kg/m²]^[3]And compared with Europeans, Chinese people have a relatively higher visceral fat content at the same BMI^[4]。 In addition, 72% of Chinese patients with type 2 diabetes (T2DM) also have hypertension and/or hyperlipidemia, while the current comprehensive compliance rate of blood sugar, blood pressure and blood lipids is only 5.6%^[3]。 Therefore, the management of diabetes has changed from simple hypoglycemic treatment to comprehensive management of metabolic indicators such as blood sugar, blood pressure, blood lipids and body weight.

With the change of lifestyle and the acceleration of population aging, the prevalence of type 2 diabetes mellitus (T2DM) and obesity is on the rise rapidly and has become a global public health problem. An epidemiological survey of diabetes mellitus in China in 2010 [with hemoglobin A1c (HbA_1c) ≥6.5% as one of the diagnostic criteria] Data show that the prevalence of adult diabetes in China is as high as 11.6%, and the number of diabetic patients ranks first in the world^[1]。 Obesity and T2DM are closely related, and the prevalence of diabetes in overweight and obese people in China is 12.8% and 18.5%, respectively^[2]； Among diabetic patients, the proportion of overweight was 41%, the proportion of obesity was 24.3%, and the proportion of abdominal obesity [waist circumference ≥90 cm (men) or ≥85 cm (women)] was as high as 45.4%^[3]。 Compared with Caucasians, the degree of obesity in Chinese people is less, and the distribution of body fat tends to accumulate in the abdominal cavity, which is more likely to form abdominal obesity^[4]。

To analyze the efficacy and safety of octreotide treatment in patients with congenital hyperinsulinism(CHI).

Twenty-six patients with CHI hospitalized in Beijing Children's Hospital from February 2002 to January 2016 who received octreotide treatment were selected as the research subjects. The efficacy, side effects and prognosis of octreotide treatment of congenital hyperinsulinism in the 26 patients were analyzed retrospectively.

In 26 patients, 16 cases(61.4%) showed good response to octreotide and 5 patients(19.2%) were unresponsive to octreotide, and the effect of octreotide in the other 5 cases (19.2%) was not clear. Seven cases of 16 patients who were responsive to octreotide received detection of CHI-related genes, and six infants were found carrying ABCC8 gene mutations. Fourteen patients had tried diazoxide treatment, 1 case had good response and 8 cases showed no response, the efficacy in the other 5 cases was not clear. Four cases received ¹⁸F-L-Dopa-positron emission tomography(PET) scan of pancreas, and three of them were found with focal type CHI and were cured with partial pancreatectomy. After application of octreotide, varying degrees of side effects were recorded in 9 patients.

Octreotide has good therapeutic effect for poorly-controlled CHI with diazoxide. Children with CHI poorly-controlled with diazoxide should undergo the pancreas ¹⁸F-L-Dopa-PET scan to confirm the histological type of the CHI, and different levels of pancreatectomy should be performed when needed.

To evaluate the correlation between anthropometric indices and diabetes and dyslipidemia in Chinese adults.

A total of 14 336 participants with complete data from Shanghai Adults Diabetes Epidemiology Study during 2002 to 2003 were recruited. The correlation between body mass index(BMI), waist circumference, waist-hip ratio (WHR) and waist-height ratio (WHtR) and blood glucose and lipids were analyzed; receiver operating characteristic (ROC) curve analysis and the best cut-off point of the four indicators for diabetes and hyperlipidemia were compared; multi-variable logistic regression analysis was also conducted.

All anthropometric (BMI, waist circumference, WHR and WHtR) indices were closely correlated with blood glucose and lipid levels(partial correlation coefficient 0.034-0.261, P<0.01), which were not affected by gender and age. Compared with other anthropometric indicators, WHtR was found to have the largest area under the ROC curve (0.712 for diabetes and 0.642 for hyperlipidemia), and the best cut-off points of diabetes and hyperlipidemia were 0.51 and 0.49, respectively. Multi-variable logistic regression analysis showed WHtR had the highest degree of association with diabetes, hypertriglyceridemia and hypercholesterolemia (OR=1.67, 2.0 and 1.53).

There is a close relationship between anthropometric indices and diabetes and lipid metabolic disorder in adult population of Shanghai. WHtR can serve as an important indicator of screening assessment.

To investigate the role of Calcium/calmodulin-dependent serine protein kinase (CASK) in insulin granules secretion.

Interference or overexpression of CASK in combination with forskolin or nifidipine treatment were applied to explore the role of CASK in insulin granules secretion in pancreatic β-cell line (INS-1 cells). The anchoring and number of insulin granules were detected using electro microscope after CASK interference in primary islets. The t test was used for pairwise comparison, and differences among groups were compared by analysis of variance.

(1) Knockdown of CASK suppressed the effect of forskolin mediated insulin secretion [(4.5 ± 0.4)% vs (2.7 ± 0.6)%, t=6.019, P<0.01]. (2) The decrease of insulin secretion with nifidipine treatment was not reversed by overexpression of CASK [(1.4 ± 0.1)% vs (1.5 ± 0.3)%, t=0.40, P>0.05]. (3) The anchoring of insulin granules to cell member was dramatically attenuated after CASK interference, while the total number of insulin granules was not statistically different between groups [(140 ± 30) vs (123 ± 45), t=0.44, P>0.05].

CASK is involved in foskoline induced insulin secretion. CASK may play a role in the downstream of calcium channel. CASK is probably involved in the anchoring of insulin granules.

To investigate the inhibiting effect and mechanism of adiponectin on high glucose - induced mouse mesangial cells proliferation through microRNA221(miR-221)/tissue inhibitor of metalloproteinase 3(Timp3) pathway.

Mouse mesangial cells cultured in vitro were divided into the following groups: normal control group, high glucose group, high glucose + adiponectin group, high glucose+adiponectin+miR-221 inhibitor transfected group and control group, small interfering RNA-Timp3 (Si-Timp3) transfected group and control group, miR-221 mimic transfected group and control group, high glucose + adiponectin + miR - 221 mimic transfected group and control group. Mouse mesangial cells proliferation was measured by MTT assay. The level of miR-221 and Timp3 mRNA expressions were measured by quantitative real-time polymerase chain reaction (qRT-PCR); Western blotting was performed to detect the expression of Timp3 protein. Dual luciferase reporter assay was used to confirm the activity of 3'-UTR in Timp3. Differences between two groups were compared by LSD-t test.

High glucose could significantly promote the proliferation of mouse mesangial cells, up - regulate the expression of miR-221 and inhibit Timp3 (3.20±0.28vs1, 0.67±0.07vs1, t=13.69, 8.35, all P<0.05). Adiponectin could reverse the effect (t=7.60, 4.12, all P<0.05) . Compared to high glucose+ adiponectin+ miR-221 inhibitor transfected control group, miR-221 inhibitor up-regulated the mRNA expression of Timp3 (0.78 ± 0.03 vs 0.38 ± 0.04, t=14.57, P<0.05) . The cell proliferation was increased significantly in Si-Timp3 transfected group (1.72±0.06 vs 1.04±0.12, t=8.76, P<0.05) . The mRNA level of Timp3 was down-regulated in high glucose+adiponectin+miR-221 mimic transfected group compared to control group (0.72±0.09 vs 1.40±0.06, t=10.93, P<0.05) .

The findings suggest that high glucose is the important factor to improve mouse mesangial cells growth, up-regulate miR-221 but down-regulate Timp3. Adiponectin can reverse the effect through miR-221 and Timp3 pathway by negatively regulates Timp3 expression in high glucose-induced mouse mesangial cells.

To investigate the association between RhoA and cardiomyopathy in type 2 diabetic rats and the intervention effect of fasudil.

The type 2 diabetic SD rat models were established by feeding with high-fat, high-sucrose diet and intraperitoneal injection of low-dose streptozotocin (30 mg/kg). The type 2 diabetic rats (n=30) were randomly divided into two groups: diabetic group (n=15) and fasudil group (n=15). In addition, 10 SD rats were set as normal control. The rats in fasudil group received fasudil at a dosage of 10 mg · kg^-1· d^-1 by intraperitoneal injection for 4 weeks. The rats in diabetic group and control group were given injection of saline simultaneously. At the end of the study, the weight of heart was measured and the heart/body weight index (HWI) was calculated. The histological changes in left ventricle were observed by light microscope and electron microscope. The protein and mRNA expression of RhoA in myocardium were examined by immunohistochemistry staining and reverse transcription-polymerase chain reaction (RT-PCR), respectively. The comparison of data between the groups were done with t or t' test.

HWI of diabetic group was higher than that of control group(0.006 0± 0.000 4 vs 0.003 0±0.000 3, t=-21.121, P=0.005). HWI of fasudil group(0.005 0±0.000 4) was lower than that of diabetic group(t=4.523, P=0.008). The histological changes of myocardium in diabetic group were severe and changes of those in fasudil group were moderate. The protein expression of RhoA in the diabetic group (70±10) was 2.89 times of that in the control group (24±3), and it was (53±6) in fasudil group. The expression level of RhoA mRNA in diabetic group was significantly higher than that in control group (1.43± 0.16 vs 0.42±0.06, t=-33.437, P=0.012). And the expression of RhoA mRNA in fasudil group (0.73±0.13) was significantly lower than that in diabetic group(t=8.145, P=0.038). The expression level of RhoA protein and mRNA were both positively correlated with HWI(r=0.94, 0.85, both P<0.05).

RhoA involves in the pathogenesis and progression of diabetic cardiomyopathy. Fasudil protects the diabetic myocardium by lowering the expression of RhoA.

Glucagonoma is a kind of neuroendocrine tumor mainly originating from alpha cells of the pancreas. It is relatively rare, and its incidence is about 1/20 million^[1]It is mainly caused by the spontaneous secretion of a large amount of glucagon by the tumor. Clinically, the main manifestations are recurrent skin necrosis, erythema migrans, angular stomatitis, glossitis, weight loss, abnormal glucose tolerance or diabetes, anemia, hepatic steatosis, etc. Following Becker's first report of this disease in 1942, Mcgavran et al.^[2]It was confirmed by electron microscopy and radioimmunoassay that there were a large number of pancreatic islet alpha cell granules and glucagon in the tumor tissues of patients with this disease, and people were aware of this disease. The data of 4 cases of glucagonoma diagnosed in the endocrinology department of our hospital in recent years are retrospectively analyzed and reported as follows.

Metformin is currently the first-line drug for the treatment of type 2 diabetes, and it is also the most widely used oral antidiabetic drug. Metformin and its similar drugs phenformin and butformin were used in the treatment of diabetes in the 1950s, but the latter two were quickly withdrawn from the market due to the higher risk of lactic acidosis. Metformin is still used today due to its superior hypoglycemic effect, good tolerance and high safety.

A sedentary lifestyle and excessive energy intake led to a marked increase in obesity. Meta analysis shows that the obesity problem faced by human society is becoming increasingly prominent. The number of obese people in the world has risen from 105 million in 1975 to 641 million in 2014. However, the disease situation in China is even more severe, and it has become the world's largest obese country^[1]。 Obesity is associated with a series of diseases such as coronary heart disease, hyperlipidemia, type 2 diabetes, hypertension, cancer, etc., creating a huge health burden. At present, domestic and foreign guidelines on the treatment of obesity mainly focus on diet, exercise, weight loss drugs and weight loss surgery, which are relatively limited. Therefore, exploring new intervention strategies is extremely necessary for the prevention and treatment of obesity and its associated metabolic diseases. In recent years, immune intervention therapy is expected to become a new direction of obesity treatment, which has been paid more and more attention by scholars. This paper mainly summarizes the progress in this aspect.

sodium-glucose co-transporter (SGLT) 2 inhibitor (SGLT-2 inhibitor, SGLT-2i) is a new class of oral hypoglycemic drugs. This drug acts on the proximal renal tubule SGLT, inhibits glucose reabsorption and promotes glucose excretion from urine, thereby achieving the purpose of lowering blood sugar. In 2012, the first SGLT-2i dapagliflozin was launched in Europe. Up to now, it has 4 years of clinical use experience, and a large number of clinical studies have also confirmed its efficacy and safety. However, with the continuous expansion of clinical practice, some special safety issues have also attracted much attention. This article will make a review of the safety issues that are currently concerned.