Elevation of serum thioredoxin levels in patients with type 2 diabetes.

To evaluate the clinical significance of thioredoxin in diabetic patients, serum thioredoxin levels measured with a recently established sandwich enzyme-linked immunosorbent assay kit were compared with clinical laboratory data and complications in 174 patients with Type 2 diabetes. Thioredoxin levels were significantly higher in diabetic patients (mean value, 38 ng/ml) than in healthy controls (21 ng/ml) (p < 0.05). Fasting blood sugar and hemoglobin A1c did not correlate with thioredoxin. Plasma non-esterified fatty acids levels were significantly higher in patients with higher thioredoxin levels (>or= 40 ng/ml) than in those with lower thioredoxin levels (< 40 ng/ml) (p < 0.001). There was a significant correlation both between thioredoxin and non-esterified fatty acids in patients with diet/exercise therapy (p < 0.01) and between thioredoxin and fasting immunoreactive insulin in those treated with diet/exercise or oral hypoglycemic agents (p < 0.05). Thioredoxin did not correlate with diabetic complications. In conclusion, serum thioredoxin levels may reflect the status of insulin resistance in Type 2 diabetic patients.     

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA₁c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA_IR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA_IR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.     

老年2型糖尿病患者的血清FGF21水平与临床参数的相关性研究

目的目的对老年糖尿病患者的空腹血浆成纤维细胞生长因子（Fibroblast growth factor21,FGF21）的水平与其临床参数进行相关性分析。方法对辽宁省沈阳市部分社区进行糖尿病普查,对78名65岁以上老年糖尿病患者的空腹血浆FGF21的水平与其临床参数进行相关性分析。其中包括腰围、体重指数（BMI）、血生化学指标、应用针对糖尿病,高血压和血脂异常治疗药物的情况等。结果在单变量分析中,2型糖尿病患者的FGF21水平与是否使用贝特类药物、甘油三酯水平、肌酐水平、腰围和BMI有独立相关性。经过校正年龄,性别和BMI之后进行多元线性回归分析发现,血清FGF21水平与贝特类药物的使用、TG水平、肌酐水平、LDL-C水平、胰高血糖素水平等独立相关。结论在老年2型糖尿病患者中,空腹血清FGF21水平与使用贝特类降脂药物,血脂水平,肾功等密切相关,说明FGF21水平在此类患者的糖脂代谢中占有重要地位。     

Identification of variables influencing resistin serum levels in patients with type 1 and type 2 diabetes mellitus.

BACKGROUND: Resistin, a peptide hormone, has been discussed controversially as a missing link between obesity and insulin resistance. In contrast to resistin mRNA expression in adipose tissue, data on human serum levels in obesity and diabetes mellitus is scarce. The physiological range of serum resistin levels, reference values or adjusted percentiles have not yet been determined, making the interpretation of serum resistin concentrations quite difficult. METHODS: Resistin serum concentrations were measured systematically by ELISA in 216 healthy controls, 555 patients with type 2 diabetes and 114 patients with type 1 diabetes. Mean values, median, and range were determined, and BMI-, gender-, and disease-adapted percentiles were calculated for all subgroups. RESULTS: Age and gender did not have any influence on resistin levels. BMI and resistin levels were positively correlated in healthy controls (p = 0.02), albeit with a weak correlation coefficient. This correlation was absent in patients with type 1 and type 2 diabetes. In both genders, healthy controls had significantly higher resistin levels than patients with type 1 and type 2 diabetes (7.9 +/- 0.2 ng/ml vs. 5.7 +/- 0.2 ng/ml and 5.5 +/- 0.1 ng/ml, respectively; p < 0.0001). There was no correlation between resistin levels and occurrence of diabetic retinopathy or nephropathy. CONCLUSIONS: Serum resistin levels can be measured by ELISA over a broad range from 0.6 ng/ml up to 27.7 ng/ml, suggesting that percentiles might be helpful in the interpretation of an individuals resistin value. While age and gender do not influence resistin levels, BMI and occurrence of diabetes have to be considered.     

Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes

Background

We recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resistance in the liver and skeletal muscle; however, it is unknown whether and, if so, how SeP acts on adipose tissue. The present study tested the hypothesis that SeP is related to hypoadiponectinemia in patients with type 2 diabetes.

Methodology/Principal Findings

We compared serum levels of SeP with those of adiponectin and other clinical parameters in 36 patients with type 2 diabetes. We also measured levels of blood adiponectin in SeP knockout mice. Circulating SeP levels were positively correlated with fasting plasma glucose (r = 0.35, P = 0.037) and negatively associated with both total and high-molecular adiponectin in patients with type 2 diabetes (r = −0.355, P = 0.034; r = −0.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (β = −0.343, P = 0.022; β = −0.357, P = 0.017). SeP knockout mice exhibited an increase in blood adiponectin levels when fed regular chow or a high sucrose, high fat diet.

Conclusions/Significance

These results suggest that overproduction of liver-derived secretory protein SeP is connected with hypoadiponectinemia in patients with type 2 diabetes.     

Effects of zinc supplementation in patients with type 1 diabetes

The purpose of this study was to identify the effect of oral zinc supplementation in patients with type 1 diabetes (T1DM) on metabolic control and zinc blood concentrations. The sample consisted of 20 patients with T1DM and a control group (n=17). Metabolic control was evaluated by glycemia at fast, 24 h glycosuria, and HbA1c. Zinc concentrations were measured in plasma and erythrocytes. After the first collection of biological material, oral zinc supplementation was initiated and continued for 4 mo in T1MD patients (T1). Daily dosages were established based on Dietary Recommended Intakes (DRIs), considering zinc intake based on data from other studies previously performed with this population. All analyses were repeated after supplementation (T2). Metabolic control was unsatisfactory, with an HbA1c increase at T2. There was no difference in zinc concentrations in plasma and erythrocytes between patients with T1DM and control. Zinc concentrations in plasma were within the normal range in T1MD before and after supplementation and the control. Zinc concentrations in erythrocyte presented lower than normal values for all groups. A zinc increase in erythrocyte after supplementation was observed in T1DM patients, although without statistical significance. More studies are needed to confirm oral zinc supplementation as nutritional management in diabetes.     

格列吡嗪对2型糖尿病患者血糖、血脂的影响

目的:探讨格列吡嗪对2型糖尿病患者血清血糖及血脂水平的影响.方法:2型糖尿病患者120例.两组年龄、性别匹配,按随机双盲法分为治疗组(60例)和安慰剂组(60例),干预治疗16周后比较其血清血糖和血脂水平,同时测血压、身高、体重等指标,计算体重指数(BMI).结果:经格列吡嗪治疗后,患者血糖、血脂水平明显降低(P＜0.05).结论:格列吡嗪可能通过降低血糖和血脂水平改善2型糖尿病患者胰岛素抵抗从而改善血糖及血脂水平.     

Analysis of glycated serum proteins in type 2 diabetes patients with nephropathy

The aim of this study was to screen for proteins that are susceptible to glycation under hyperglycemic conditions in patients with type 2 diabetic nephropathy. Serum proteins were analyzed by a proteomic approach using two-dimensional electrophoresis (2-DE) and ESI-Q-TOF MS/MS. Gels were stained with Pro-Q Emerald 488 to analyze the serum glycoproteome, followed by silver nitrate to examine the total serum proteome. Patient sera were divided into four groups according to their microalbuminuria index: type 2 diabetics with normoalbuminuria, microalbuminuria, and overt nephropathy, and healthy subjects. When the HbA1c levels of the diabetic groups were examined, groups with higher HbA1c exhibited higher fructosamine levels, suggesting that the loss of glycemic control affected the glycation of serum proteins. The proteins that became glycated under poor glycemic control were PEDF, apolipoprotein J precursor, hemopexin, immunoglobulin mu heavy chain, and immunoglobulin kappa chain. As albuminuria increased, a marker of kidney damage, the levels of glycated prekallikrein and complement factor C4B3 also increased. The glycated proteins identified in this study may provide the foundation for the development of novel markers of diabetes, hyperglycemia, and diabetic complications.     

Increased serum HSP70 levels are associated with the duration of diabetes

The evolutionary conserved family of heat shock proteins (HSP) is responsible for protecting cells against different types of stress, including oxidative stress. Although the levels of HSPs can be readily measured in blood serum, the levels of HSP70 in patients with different durations of diabetes have not been studied before. We quantified serum HSP70 levels in a healthy control group (n = 36) and two groups of type 2 diabetic patients, defined as newly diagnosed diabetes (n = 36) and patients with diabetes duration of more than 5 years (n = 37). The clinical characteristics and biochemical parameters were evaluated in the studied population. We found that serum HSP70 levels were significantly higher in patients with diabetes when compared with controls (p < 0.001) and it was higher in patients with disease for more than 5 years than in newly diagnosed patients (p < 0.001). Serum HSP70 was inversely correlated with fasting blood sugar in patients with diabetes for more than 5 years (r = −0.500, p = 0.002), positively correlated with the history of hypertension in newly diagnosed patients (p < 0.001), and positively correlated with age in patients with diabetes (r = 0.531, p = 0.001). Serum level of HSP70 is significantly higher in patients with diabetes and correlates with the duration of disease. Higher HSP70 in prolonged diabetes versus newly diagnosed diabetes may be an indicator of metabolic derangement in the course of diabetes.     

Control of hsp70 RNA levels in human lymphocytes

The expression of a hsp70 gene in human cells has previously been shown to be related to the growth state of the cells. As an alternative to in vitro synchronization procedures, we have measured steady-state levels of the RNA for a heat-shock protein 70 (hsp70) in human peripheral blood mononuclear cells (PBMC) that are naturally quiescent in a G0 state. The probe used recognized, on RNA blots, one single band. The levels of this hsp70 RNA are elevated in circulating PBMC and decrease when the cells are incubated with serum, or phytohemagglutinin, or simply when they are incubated in culture medium. The levels of hsp70 RNA decrease within 30 min after in vitro culture, and are accompanied by an increase in the levels of c-fos RNA. These findings, together with other recent reports in the literature, suggest a possible role of the hsp70 proteins in the regulation of cell growth.     

The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes

Background

Experimental evidence suggests that heat shock proteins (HSP) and asymmetric dimethylarginine (ADMA) are induced in the state of chronic inflammation and stress conditions. They are both inhibitors of nitric oxide synthase (NOS). The aim of this study was to evaluate the correlation between ADMA and HSP70, in patients with type 2 diabetes with respect to serum levels of C reactive protein (CRP).

Methods

We quantified serum HSP70, ADMA and CRP in 80 newly-diagnosed patients with type 2 diabetes plus 80 age-, sex and BMI-matched healthy controls. The patients and controls were also stratified into groups of high and low CRP levels (cut-point: 2.5 mg/ml).

Results

Patients with type 2 diabetes had significantly higher serum HSP70 (0.52 [0.51–0.66] vs. 0.27 [0.26–0.36], p < 0.001), ADMA (0.86 [0.81–0.92] vs. 0.72 [0.71–0.85], p < 0.05) and CRP (2.9 [1.7–3.4] vs. 1.6[1.2–2.3], p < 0.05) compared with healthy controls. Serum HSP70 and ADMA levels were significantly correlated in patients with high CRP levels (r = 0.89, p < 0.01), whereas there were no correlation in patients with low CRP (r = − 0.37, p = 0.07) and controls. This correlation was significant (r = 0.77, p < 0.001) in patients with high CRP and also in patients with low CRP levels (r = − 0.51, p < 0.05), after multiple adjustments for LDL and HDL levels.

Discussion

We showed that, in a state of high inflammation; serum levels of ADMA parallel the HSP70 levels. However in low inflammation, they are negatively correlated. The duality in HSP70 and ADMA correlation may be related to the duality of NOS function in low and high CRP levels.     

Role of chromium supplementation in Indians with type 2 diabetes mellitus

Type 2 diabetes mellitus is a complex metabolic disorder with adverse cardiovascular risk. The role of micronutrients has not yet been well clarified in this condition, especially in India.THE OBJECTIVES OF THIS STUDY WERE TO: (1) evaluate chromium status in Indian subjects with type 2 diabetes mellitus, (2) assess the effect of chromium picolinate (200 &mgr;g trivalent chromium twice daily) administration on glycaemic control and lipid profile in these subjects and (3) comment on the possible mechanism of any beneficial effect noted above.Fifty subjects were studied in a double blind, placebo-controlled, crossover fashion, with each treatment arm (chromium/placebo) lasting 12 weeks and 4 weeks' wash-off period in between. 50 healthy age- and sex-matched volunteers served as controls. Serum chromium level appeared to be higher in the general population in our country compared to western countries (36.5-59.5 nmol/L as compared to 2.3-40.3 nmol/L) However, the local diabetics were found to have a lower serum chromium level than the healthy controls (32.3 nmol/L against 44.7 nmol/L; p < 0.0001) and a mean increase of 3.5 nmol/L was noted after 12 weeks of chromium supplementation that was, expectedly, not seen in the placebo phase (p < 0.0001).Significant improvement in glycaemic control was noted in the chromium-treated group (DeltaFasting serum glucose = 0.44 mmol/L, p < 0.001; DeltaPost-prandial serum glucose = 1.97 mmol/L, p < 0.001; Deltaglycated hemoglobin = 0.01; p = 0.04, in comparison to placebo) This was accompanied by a significant greater fall in fasting serum insulin in the chromium-treated group, p < 0.05.The change in lipid parameters (total serum cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) did not show significant difference between the chromium and placebo groups.Clinically significant hematological, renal or hepatic toxicity were excluded by routine hemogram, serum urea, creatinine, alanine amino transferase (ALT) and alkaline phosphatase estimations.In conclusion, chromium supplementation seems to improve glycaemic control in type 2 diabetic patients, which appears to be due to an increase in insulin action rather than stimulation of insulin secretion.     

Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients

Type 2 diabetic subjects have an increased propensity to premature atherosclerosis. Alpha tocopherol (AT), a potent antioxidant, has several anti-atherogenic effects. There is scanty data on AT supplementation on inflammation in Type 2 diabetic subjects. The aim of the study was to test the effect of RRR-AT supplementation (1200 IU/d) on plasma C-reactive protein (CRP) and interleukin-6 (IL-6) release from activated monocyte in Type 2 diabetic patients with and without macrovascular complications compared to matched controls. The volunteers comprised Type 2 diabetic subjects with macrovascular disease (DM2-MV, n = 23), Type 2 diabetic subjects without macrovascular complications (DM2, n = 24), and matched controls (C, n = 25). Plasma high sensitive CRP (Hs-CRP) and Monocyte IL-6 were assayed at baseline, following 3 months of supplementation and following a 2 month washout phase. DM2-MV subjects have elevated HsCRP and monocyte IL-6 compared to controls. AT supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6 in all three groups. In conclusion, AT therapy decreases inflammation in diabetic patients and controls and could be an adjunctive therapy in the prevention of atherosclerosis.     

Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus

Background:

Small cross-sectional studies have suggested that metformin, a first-line oral hypoglycemic agent, may lower thyroid-stimulating hormone (TSH) levels. Our objective was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with type 2 diabetes mellitus.

Methods:

Using the Clinical Practice Research Datalink, we identified patients who began receiving metformin or sulfonylurea monotherapy between Jan. 1, 1988, and Dec. 31, 2012. We assembled 2 subcohorts of patients with treated hypothyroidism or euthyroidism, and followed them until Mar. 31, 2013. We used Cox proportional hazards models to evaluate the association of low TSH levels with metformin monotherapy, compared with sulfonylurea monotherapy, in each subcohort.

Results:

A total of 5689 patients with treated hypothyroidism and 59 937 euthyroid patients were included in the subcohorts. Among patients with treated hypothyroidism, 495 events of low TSH levels were observed during follow-up (incidence rate 119.7/1000 person-years). In the euthyroid group, 322 events of low TSH levels were observed (incidence rate 4.5/1000 person-years). Compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (incidence rate 79.5/1000 person-years v. 125.2/1000 person-years, adjusted hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.09–2.20), with the highest risk in the 90–180 days after initiation (adjusted HR 2.30, 95% CI 1.00–5.29). No association was observed in euthyroid patients (adjusted HR 0.97, 95% CI 0.69–1.36).

Interpretation:

In this longitudinal population-based study, metformin use was associated with an increased incidence of low TSH levels in patients with treated hypothyroidism, but not in euthyroid patients. The clinical consequences of this need further investigation.Metformin, a first-line oral hypoglycemic agent for the treatment of type 2 diabetes mellitus, improves hepatic insulin resistance and reduces glucose production.¹ However, despite its excellent safety profile,² studies have suggested that its use may lower thyroid-stimulating hormone (TSH) levels in patients with diabetes and hypothyroidism.^3–9 In some studies, the use of metformin was associated with reductions in TSH levels below the reference range,^4–7 potentially exposing patients to the harmful consequences of subclinical hyperthyroidism (e.g., cardiovascular conditions and fractures¹⁰). In contrast, metformin was not associated with changes to TSH levels in euthyroid patients.¹¹ Given the methodologic shortcomings of the few studies conducted to date (i.e., small samples, cross-sectional designs and no active comparator), it remains uncertain whether the use of metformin is associated with an increased risk of low TSH levels in patients with hypothyroidism or euthyroidism and type 2 diabetes.Given the widespread use of metformin in patients with type 2 diabetes and the potential negative consequences of low TSH levels, there is a need to assess the incidence and magnitude of this biochemical event in the natural setting of clinical practice. Thus, the objective of this large population-based study was to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with treated hypothyroidism or euthyroidism and type 2 diabetes.     

Micronuclei in diabetes: Folate supplementation diminishes micronuclei in diabetic patients but not in an animal model

Diabetes mellitus (DM) is associated with a high risk of health complications, mainly due to excessive free radical (FRs) production that could result in an increased frequency of micronuclei. The consumption of antioxidants, like folic acid (FA), may mitigate the effects of the FRs. In the present study, micronucleated polychromatic erythrocyte (MNPCE) frequencies were determined in blood sampled weekly from the tails of pregnant female Wistar rats and pregnant Wistar rats with experimental diabetes that were given unsupplemented diets and diets supplemented with FA. At birth, the pups were sampled to analyze micronucleated erythrocyte (MNE) and MNPCE frequencies. Moreover micronucleated cells (MNCs) were evaluated in buccal mucosa samples taken from 81 healthy adult subjects, 48 patients with DM, and 30 DM patients who were sampled before and after FA treatment. Increases in MNPCE frequencies were significant only at the first sampling (P < 0.01 and P < 0.03) in pregnant rats with experimental diabetes. In addition, the pups from the diabetic group and from diabetic group treated with FA had higher frequencies of MNEs (P < 0.03 and P < 0.001, respectively) and MNPCEs (P < 0.009 and P < 0.05, respectively) than the controls. No differences were found in diabetic rats and newborn rats born to diabetic mothers treated with FA compared with untreated animals. Patients with DM had a higher frequency of MNCs compared with healthy subjects (P < 0.001). Also FA reduced the frequency of MNCs in DM patients (P < 0.001). The results of this study indicate that diabetes results in elevated frequencies of micronuclei, and that, at least in humans, FA can protect against the elevation.     

Plasma resistin levels in patients with type 1 and type 2 diabetes mellitus and in healthy controls.

Resistin is a recently discovered hormone that is exclusively expressed in adipose tissue. Its expression in rodents was reported to be elevated or suppressed in genetic and diet-induced obesity, respectively. Resistin treatment impaired glucose tolerance and insulin action. Immunoneutralization of resistin improved insulin sensitivity, while thiazolidinedione treatment reduced resistin expression. Therefore, resistin could play a critical role in the development of obesity and type 2 diabetes. In this study were determined resistin plasma levels in humans suffering from type 1 and type 2 diabetes and in healthy controls. Plasma levels of resistin in healthy controls were 38.78 ng/ml. They were not statistically different in individuals with a broad BMI range. Resistin plasma levels in type 2 diabetes were 38.7 ng/ml, and 39.4 ng/ml in type 1 diabetes. Thiazolidinedione treatment did not influence resistin plasma levels. We conclude from our data: 1. resistin can be detected in human plasma, 2. plasma resistin levels are not different in type 1 and type 2 diabetes.     

Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes

Low-volume high-intensity interval training (HIT) is emerging as a time-efficient exercise strategy for improving health and fitness. This form of exercise has not been tested in type 2 diabetes and thus we examined the effects of low-volume HIT on glucose regulation and skeletal muscle metabolic capacity in patients with type 2 diabetes. Eight patients with type 2 diabetes (63 ± 8 yr, body mass index 32 ± 6 kg/m(2), Hb(A1C) 6.9 ± 0.7%) volunteered to participate in this study. Participants performed six sessions of HIT (10 × 60-s cycling bouts eliciting ～90% maximal heart rate, interspersed with 60 s rest) over 2 wk. Before training and from ～48 to 72 h after the last training bout, glucose regulation was assessed using 24-h continuous glucose monitoring under standardized dietary conditions. Markers of skeletal muscle metabolic capacity were measured in biopsy samples (vastus lateralis) before and after (72 h) training. Average 24-h blood glucose concentration was reduced after training (7.6 ± 1.0 vs. 6.6 ± 0.7 mmol/l) as was the sum of the 3-h postprandial areas under the glucose curve for breakfast, lunch, and dinner (both P < 0.05). Training increased muscle mitochondrial capacity as evidenced by higher citrate synthase maximal activity (～20%) and protein content of Complex II 70 kDa subunit (～37%), Complex III Core 2 protein (～51%), and Complex IV subunit IV (～68%, all P < 0.05). Mitofusin 2 (～71%) and GLUT4 (～369%) protein content were also higher after training (both P < 0.05). Our findings indicate that low-volume HIT can rapidly improve glucose control and induce adaptations in skeletal muscle that are linked to improved metabolic health in patients with type 2 diabetes.