Volume 09 · Issue 03 · 2017

Diabetes has become a global disease, and the International Diabetes Federation predicts that by 2035, there will be 592 million people with diabetes worldwide^[1]The high prevalence of diabetes and the increase in young patients are major challenges that we have to deal with. Strict blood sugar control is also attracting more and more attention based on the requirements of reducing complications and improving prognosis. However, the resulting severe hypoglycemia, which is more dangerous than hyperglycemia to some extent, has not received due attention.

Diabetes is a major chronic non-communicable disease that threatens human health, and its prevalence is increasing year by year. China has now become the largest country with diabetes population. However, in contrast to the high prevalence rate, the blood glucose compliance rate of diabetic patients in China is still low, according to the Chinese glycated hemoglobin (HbA_1c) data of the monitoring network, when HbA_1c<When 7% is used as the compliance rate of blood glucose control target, the blood glucose compliance rates of diagnosed type 2 diabetes mellitus (T2DM) patients in China in 2009, 2010, 2011 and 2012 are only 35.28%, 32.33%, 31.77% and 30.15%, respectively^[1]。 It should be admitted that diabetes is a progressive disease, and it is also a disease closely related to lifestyle and behavior. There are many factors that affect patients' blood sugar control. It is the direction of our efforts to achieve the purpose of preventing and treating acute and chronic complications of diabetes by improving the blood sugar compliance rate. With the advent of the era of precision medicine, we have also focused on some "alternative" factors that affect patients' blood sugar control besides the classical factors that have been repeatedly emphasized, in the hope of arousing the attention and thinking of academic circles.

Hypoglycemia is a clinical syndrome caused by multiple etiologies and an obstacle to be crossed in the treatment of diabetes. For diabetic patients, hypoglycemia is defined as all abnormal reductions in plasma glucose concentrations that expose the patient to harm, whether symptomatic or not^[1]Its laboratory diagnostic criterion is ≤3.9 mmol/L (70 mg/dl). Hypoglycemia adversely affects the blood glucose level and prognosis of diabetic patients. Currently, the standard clinical treatment for severe hypoglycemia is intravenous glucose^[2]However, animal experiments and clinical studies have observed that the process of glucose reperfusion can further aggravate the original hypoglycemic injury. The timing and nodes of glucose input in reperfusion injury are still unclear, and the mechanism is also unclear.

To explore the diagnostic value of continuous glucose monitoring(CGM) in insulinoma.

Twenty-two insulinoma patients (insulinoma group) , 11 hypoglycemia patients without insulinoma (hypoglycemia group) , and 31 individuals with normal glucose regulation (control group) hospitalized in Chinese PLA General hospital from May 2011 to April 2014 were included. Blood biochemical markers including glucose metabolism markers were tested; CGM data were obtained. The EasyGV Version 9.0 software was used to analyze the CGMS data and to calculate the index of glucose variability. Statistics methods including t test, analysis of variance, and non-parametric test were used. Curve of receiver operating characteristic (ROC) and Youden Index were applied to determine the cut-off value.

(1)The fasting plasma glucose(FPG) and the lowest blood glucose(LBG) of insulinoma group were significantly lower than those of hypoglycemia group and control group (F=14.72, 9.74, P<0.05) . The fasting insulin (FINS), fasting C-peptide (FCP) and fasting insulin release index(FIRI) of insulinoma group were significantly higher than those of the other two groups (F=10.72, 5.07, 12.8, all P<0.05) ;(2) The continuous overall net glycemic action (CONGA) of insulinoma group was significantly lower than that of control group [3.98 (3.71, 4.63) vs 5.10 (4.78, 5.52) , Z=3.989, all P<0.05], whereas the low blood glucose index (LBGI) and M-value were higher than those of control group [7.38 (4.99, 11.92) vs 1.59 (0.73, 2.70) , 11.99 (8.45, 23.04) vs 1.68 (0.68, 3.27) , Z=2.780-5.163, all P<0.05]. Compared with hypoglycemia group, CONGA of insulinoma group was lower [3.98 (3.71, 4.63) vs 5.03 (4.40, 6.30) , Z=2.595, P<0.05], and LBGI, M-Value were higher[7.38 (4.99, 11.92) vs 1.89 (0.96, 4.02) , 11.99 (8.45, 23.04) vs 2.95 (1.05, 7.60) ; Z= 2.970, 2.526, all P<0.05]; (3)Results from the ROC curve and the Youden Index showed that the cut-off value of LBGI, M-value, CONGA was 4.06, 7.79 or 4.38, respectively. LBGI had the highest diagnostic power of insulinoma with 90.9% sensitivity and 81.8% specificity when using 4.06 as the cut-off point.

Continuous glucose monitoring data can be used to diagnose insulinoma and fluctuation indicators of blood glucose such as LBGI, M-Value and CONGA might be useful to identify insulinoma. LBGI has the highest diagnostic power of insulinoma.

To investigate the effects of epigallocatechin-3-gallate (EGCG) on apoptosis, oxidative stress and inflammation induced by glucose reperfusion after hypoglycemia in hippocampus in rats.

A total of 56 male Wistar rats (SPF grade) at the age of 8-10 weeks and weighing 300-350 g were used. Finally, 40 rats were included in the study and were randomly divided into control group(A group, n=11), glucose reperfusion after hypoglycemia group (B group, n=10), glucose reperfusion after hypoglycemia+ low dose EGCG group (C group, n=9), and glucose reperfusion after hypoglycemia+ high dose EGCG group (D group, n=10). Apoptosis in hippocampus were monitored by TUNEL method. P47phox protein levels were detected by Western blotting. Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels were detected by ELISA. One-way analysis of variance was used for data analysis. Differences between the two groups were compared using t test.

(1) Compared with group A, the apoptosis, membrane p22phox protein expression, membrane/cytoplasmic p47phox protein expression, IL-6 and TNF-α levels in group B increased [10.1±2.5 vs 72.5±12.6; 0.42±0.05 vs 0.79±0.12; 0.44±0.09 vs 1.10±0.16; (50±10) vs (128±22) ng/L; (121±22) vs (248±39) ng/L;t=6.292-16.111, all P<0.05].(2) The apoptosis, membrane p22phox protein expression, membrane/cytoplasmic p47phox protein expression, IL-6 and TNF-α levels of group C were decreased compared with group B (t=2.247-3.858, all P<0.05). (3) The apoptosis, membrane p22phox protein expression, membrane/cytoplasmic p47phox protein expression, IL-6 and TNF-α levels of group D were lower than those in group C (t=2.836-7.225, all P<0.05).

EGCG alleviates the apoptosis induced by glucose reperfusion after hypoglycemia in hippocampus in rats, and the mechanism may be related to the amelioration of oxidative stress and inflammation.

To investigate the association of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) gene polymorphisms with metabolic syndrome (MS) and its related phenotypes in Han population in northwest China.

A case-control study was performed, which included 350 subjects with MS (MS group) and 304 subjects without MS (control group) selected with random number table from the epidemiological survey database of diabetes in Shannxi province form 2007 to 2008. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used as the genotyping method. rs4402960 and rs1470579 genotypes and allele frequencies between MS group and control group were analyzed. Logistic regression was used to analyze the associations of different genotypes of rs4402960 and rs1470579 with parameters of MS. Linear regression was used to analyze the relationship between IGF2BP2 gene rs4402960 and rs1470579 polymorphisms and parameters of MS.

No single nucleotide polymorphism was found to be associated with MS. The T allele frequencies of rs4402960 in MS group and control group were 28.6% and 27.3%, respectively (χ²=0.268, P=0.605). The C allele frequencies of rs1470579 in MS group and control group were 30.1% and 29.3%, respectively(χ²=0.117, P=0.732). With the linear regression analysis adjusted for age, gender, body mass index, smoking and physical exercise, a tendency toward association between rs4402960 and systolic pressure was observed under recessive model (t=2.068, P=0.04) and additive model(t=2.144, P=0.034).

IGF2BP2 rs4402960 and rs1470579 polymorphisms are not associated with MS in Han population in northwest China. However, IGF2BP2 may be related to increased systolic blood pressure.

To evaluate the value of blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) in the assessment of renal oxygenation of patients with type 2 diabetes mellitus (T2DM).

From April 2014 to October 2015, kidney scans were conducted in eighteen patients with T2DM and twenty-two healthy controls with a Philips 3.0T scanner by using a BOLD-MRI sequence. The medullary and cortical apparent relaxation rate(R2^*)values were measured in both groups. Paired samples t-test and independent samples t-test were used in data comparison within or between groups. The correlation between the renal glomerular filtration rate estimated using cystatin C(CysC-GFR) and the R2^* values was analyzed by Pearson correlation coefficient analysis.

The medullary R2^* values were significantly higher than those of cortex in both groups (t=21.5, 21.1, both P<0.01). The cortex R2^* values in patients with T2DM and healthy controls were (15.3±1.9) and (15.0±1.7) 1/s respectively, and there was no significant differences between two groups (t=0.7, P>0.05). The medullary R2^* values in the patients with T2DM and healthy controls were (38.1±4.1) and (29.6±2.7) 1/s respectively, it was significantly higher in the type 2 diabetic patients than that in healthy controls (t=8.0, P<0.01). Medullary R2^* value had a high sensitivity (83.33%) and specificity (100%) in identifying patients with T2DM with an area under the receiver operating characteristic curve of 0.965, and the best testing threshold was 34.1 1/s. The medullary R2^* value was found positively correlated with CysC-GFR level in patients with T2DM (r=0.7, P<0.01), but no correlation was found between the cortical R2^* value and CysC-GFR (r=0.1, P>0.05).

BOLD-MRI can detect and assess the renal medullary hypoxia in patients with T2DM at the early stage, and medullary R2^* value may reflect the changes of renal function.

To explore the role of interleukin-1 (IL-1) in human islet amyloid polypeptide (iAPP) related pancreatic islet cell toxicity.

Pancreatic islets were isolated from adult Wistar rats and the cell vitality was identified. The islets were divided into control islets (group A), 10 μmol/L iAPP incubated islets (group B), 10 μmol/L iAPP plus 10 mg/L IL-1 receptor blocker (IL-1Ra) co-incubated islets (group C) and incubated for 24 h. Annexin-V/propidium iodide (PI) double-staining was used to detect islet cell apoptosis. The expressions of inflammation-related and apoptosis-related genes Bax Bcl-2 mRNA were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Independent sample t test was used for comparison between two groups. LSD test was used to compare the differences among three groups.

(1) The apoptosis ratio and apoptosis-related gene expression: the apoptosis ratio in group B increased significantly than those in group A [(16.8±4.7)% vs (1.2±0.4)%]; while the apoptosis ratio in group C[(4.4±2.1)%] was significantly lower than those in group B (t=5.72, 4.17, respectively, both P<0.05). Consistently, the expression of Bax mRNA increased (2.28±0.46) times and Bcl-2 mRNA decreased (0.42±0.18) times in group B than those in group A (t=4.27, 3.10, respectively, both P<0.05). The expression of Bax mRNA decreased (0.48±0.17) times and the expression of Bcl-2 mRNA increased (1.93±0.25) times in group C than those in group B, respectively (t=3.41, 3.23, respectively, bothP<0.05). (2) The expressions of the inflammatory factors: the expressions of IL-1β and tumor necrosis factor increased by (4.25±1.64) times and (3.19±1.04) times in group B than those in group A, respectively (t=3.39, 3.49, respectively, both P<0.05); While they decreased by (0.32±0.11) times and (0.28±0.11) times in group C than those in group B, respectively (t=2.94, 3.65, respectively, both P<0.05).

The apoptosis of iAPP is associated with inflammation and IL-1 may play an important role in the pathogenesis of iAPP related pancreatic islet cell toxicity.

To explore the pathophysiological characteristics of myocardial injury model in type 2 diabetes mellitus (T2DM) induced by streptozotocin (STZ) injection after high-fat and high-sucrose feeding.

A total of 60 SD rats aged at 8-12 weeks and weighing 180-220 g were divided into normal (Nor) group (n=20), T2DM group (n=20) and insulin group (Ins, n=20) by random number table method. STZ was administrated to rats after 4 weeks of high fat and high sucrose diet or normal diet and followed by another 4 weeks of feeding with the same diet. Blood glucose and insulin levels were monitored, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Hemodynamic parameters were measured using an isolated cardiac perfusion model. The changes of mitochondrial structure were observed with transmission electron microscope. Mitochondrial respiratory function, activity of key enzymes in respiratory chain and ATP content were measured. One way ANOVA was used for statistical analysis.

A total of 50 SD rats were finally enrolled in Nor group (n=20), T2DM group (n=15) or Ins group (n=15). The HOMA-IR index of T2DM and Ins group were higher than that of Nor group (4.2±0.4, 3.9±0.4, 1.4±0.3, respectively, F=312.3, P<0.01). The +dp/dt max of left ventricle [(3 599±215), (3 123±239), (3 084±200) mmHg/s, F=31.02, P<0.01] and left ventricular development pressure [(102±8), (89±6), (90±7) mmHg, F=14.19, P<0.01, 1 mmHg=0.133 kPa] were superior to those in T2DM group and Ins group. The mitochondrial respiration State 3, respiration control ratio and respiratory chain enzyme activity of Nor group were superior to those of Ins group and T2DM group (F=11.12-505.50, P<0.05); Nor group had more ATP production compared to the other two groups (P<0.01).

The modeling method used in this study provides the pathophysiologic characteristics of diabetes related myocardial, damages such as cardiac ventricular malfunction, mitochondrial dysfunction, energy metabolism abnormality, as well as hyperglycemia and insulin resistance, which can be used for the studies of cardioprotection of diabetic cardiomyopathy.

Diabetic nephropathy (DKD) is one of the important causes of end-stage renal disease. microalbuminuria (MAU) is considered to be an early diagnostic index of DKD, which is related to the high risk of cardiovascular and cerebrovascular diseases^[1]。 Therefore, if the risk factors of MAU can be clarified, it can effectively prevent DKD and other cardiovascular and cerebrovascular events. Previous studies have suggested that hyperglycemia and hypertension are important risk factors for DKD^[2]However, both are not the only determinants of the development of DKD, because even if blood glucose and blood pressure control are achieved in patients with type 2 diabetes mellitus (T2DM), the residual risk of DKD is still high^[3]It suggests that other genetic, metabolic and environmental factors are also involved in its pathogenesis. Patients with T2DM typically develop lower levels of high-density lipoprotein cholesterol (HDL-C)^[4]HDL-C has reverse cholesterol transport, anti-inflammatory and antioxidant effects. Studies have shown that lower levels of HDL-C promote the development of MAU and DKD^[5,6]However, the sample size is small, and there are differences between subjects' ethnicities, and the results are inconsistent between studies. Therefore, we used a retrospective study to analyze the clinical data of 624 patients with T2DM hospitalized in the Department of Endocrinology of Qingdao University Affiliated Hospital from 2014 to 2015, aiming to explore the relationship between serum HDL-C levels and MAU in Chinese patients with T2DM.

To evaluate the characteristics of glucose metabolism and the possible mechanisms of glucose metabolism disorder in patients with Klinefelter's syndrome (KS).

This was a retrospective clinical research. The following data were collected and analyzed: the general condition, gonadotropic and gonadal hormone levels, lipid and glucose profiles, glucose and insulin levels after a 75 g oral glucose tolerance test, and homeostasis model assessment of insulin resistance (HOMA-IR) in 19 patients with KS alone, 9 patients with both KS and DM, 18 DM patients without KS; all were hospitalized in PLA General Hospital since 1990. Independent sample t test was used for comparison betneen two groups.

(1) The incidence of DM in KS patients was 32.1% (9/28); in patients with 47, XXY karyotype and 48, XXYY karyotype the incidence were 30.7% (8/26) and 50% (1/2), respectively; (2) Compared with simple KS patients, patients with both KS and DM was significantly older, while the testosterone (T) level was significantly lower[ (28±8) vs (22±4) year, (2.0±1.3) vs (5.4±4.3) nmol/L, t=3.044, -2.249; all P<0.05]; Although they had similiar fasting insulin level and area under the curve of insulin, KS patients complicated with DM presented a much higher insulin resistance index (6.5±3.4 vs 1.2±2.1, t=3.234, P<0.05) ; (3) KS patients complicated with DM were much higher and heavier than simple DM patients[(178±12)vs(170±6) cm, (91±23)vs(80±14)kg, t=0.750, 3.866; P<0.05]. The low-density lipoprotein concentration in patients with both KS and DM were lower than that of the patients with KS alone [(2.13±0.93)vs(2.85±0.50) mmol/L, t=-2.681; P<0.05], but their glucose and insulin levels during an oral glucose load were not different between two groups; (4) The estradiol-to-testosterone ratio of KS patients complicated with DM was significantly higher than that of simple KS patients as well as simple DM patients (t=2.302, 2.748; P<0.05) .

(1) KS patients tend to develop late-onset DM; (2) The possible risk factors of glucose metabolism disorder in KS patients are age, testosterone level, insulin resistance, high estradiol-to-testosterone ratio and abnormalities of X chromosome.

Bone metabolism includes two processes: bone formation and bone resorption, which maintain dynamic balance at all times to maintain normal bone structure and function. If this balance is disrupted, the structural function of bone will be impaired. If bone resorption exceeds bone formation, it will lead to osteopenia or even osteoporosis. Diabetic patients are prone to osteoporosis and have an increased risk of fracture^[1]While some hypoglycemic drugs such as thiazolidinediones have been shown to have osteopenic effects^[2]Therefore, it is also necessary to consider its effect on bone metabolism in the selection of hypoglycemic drugs. Recent studies have found that incretin can promote bone formation, inhibit bone resorption and exert osteogenic effects, and is expected to become a new choice for the treatment of type 2 diabetes mellitus (T2DM) complicated with osteoporosis. Incretins include glucagon-like peptide (GLP) 1, GLP-2, and glucose-dependent insulin-secreting polypeptide (GIP), named for their secretion by small intestinal cells and their ability to promote insulin release. The effects of GLP-1, GLP-2, and GIP on bone metabolism will be described below.

The concept of mitochondrial autophagy has developed rapidly since it was formally proposed in 2005. From yeasts to mammals and plants, research on mitochondrial autophagy continues to deepen. The important role that mitophagy plays in the mechanism of human diseases has received great attention and has also contributed to the development of this frontier field. In this paper, we will review the relationship and progress of mitophagy with diabetes mellitus and diabetic complications.

Recently, the American Diabetes Society issued the "Position Statement on Diabetic Neuropathy" (referred to as the Statement)^[1]。 The authors of the statement are leading experts in the field of diabetic neuropathy (DN) from the United States, the United Kingdom and Germany, all with rich clinical experience and strong scientific research capabilities. The statement is 18 pages long, but the key points are identified with blacked out sections in recommended form and highlighted.