The paraoxonase-2-310 polymorphism is associated with the presence of microvascular complications in diabetes mellitus

OBJECTIVE: To investigate the paraoxonase-2 (PON 2)-C/S 310 polymorphism and its relationship to the presence of diabetic complications and glycaemic control. DESIGN: Case-control study. SETTING: One study centre at University hospital. MATERIALS AND METHODS: The subjects were people with type 2 diabetes (n=252), type 1 diabetes (n=152) and healthy controls (n=282). The PON 2-C/S 310 polymorphism was measured by restriction fragment length polymorphism analysis. Lipids and lipoproteins were measured by standard clinical chemistry methods. Diabetes and diabetic complications were defined by World Health Organization criteria. RESULTS: There was an over-representation of the C/C 310 genotype in those with diabetes and microvascular complications (type 2 diabetes P=0.043, type 1 diabetes P=0.052, both populations combined P=0.014). The PON 2-C/S 310 polymorphism was also associated with glycaemic control. C 310/C 310 homozygotes had the highest HbA(1c) concentration (P=0.020 type 2 diabetes, P=0.065 type 1 diabetes, P=0.035 both populations combined). There was no association between the PON 2-310 polymorphism and lipid and lipoprotein concentrations. CONCLUSIONS: PON 2 could be directly involved in protecting critical enzymes or organelles against oxidative damage; PON2 may thus predispose to the development of microvascular complications.     

Dry eye and its correlation to diabetes microvascular complications in people with type 2 diabetes mellitus

AimsThis study was performed to investigate the correlation between dry eye disease and diabetes microvascular complications.MethodsIn this study 243 people with type 2 diabetes were enrolled. Tear osmolarity was measured using tear lab osmolarity system. All of the participants were evaluated for diabetes microvascular complications. The Michigan neuropathy screening instrument was used for detection of peripheral neuropathy, and the albumin/creatinine ratio in a spot urine sample was considered to diagnose diabetic nephropathy.ResultsThe prevalence of dry eye disease was 27.7%. The mean value for tear osmolarity was 301.97 ± 13.52 mOsm/L. We found a significant correlation between dry eye disease and diabetic retinopathy (P = 0.01). However no significant correlation was found between dry eye disease, diabetic neuropathy, and diabetic nephropathy.Dry eye disease was more prevalent in people with proliferative diabetic retinopathy and/or clinically significant macular edema (0.006). In a binary logistic regression analysis model, there was a significant correlation between dry eye disease and retinopathy (OR = 2.29, CI = 1.16–4.52, P = 0.016). In addition, both dry eye and retinopathy had significant correlation with HbA1C.ConclusionsDry eye disease is common in people with type 2 diabetes, especially in those with diabetic retinopathy. In addition, it is more prevalent in people who suffer from advanced stages of diabetic retinopathy.     

Hypovitaminosis D in type 2 diabetes mellitus: Association with microvascular complications and type of treatment

The prevalence of hypovitaminosis D has been recently reevaluated, and diabetes is considered as a risk factor for osteoporosis. We studied the association of the prevalence of hypovitaminosis D with the clinical features of diabetes. We conducted the observational study in 581 Japanese patients with type 2 diabetes mellitus and 51 normal subjects, and analyzed the relationship between serum 25-hydroxyvitamin D (25-OHD) concentration and the clinical features associated with type 2 diabetes. Mean serum 25-OHD concentration in type 2 diabetes patients was 17.0 +/- 7.1 ng/ml (Mean +/- SD) in winter, and was not statistically different from normal population (17.5 +/- 3.6 ng/ml). The prevalence of hypovitaminosis D (<20 ng/ml) was 70.6%. Serum concentrations of 25-OHD were associated with HbA1c (P = 0.013), age (P = 0.070) and serum albumin (P < 0.001), but were not related to BMI or the duration of diabetes. The levels of 25-OHD were significantly lower in the population with apparent microvascular complications, although serum creatinine levels were below 2.0 mg/dl. Serum 25-OHD concentrations in the group treated with insulin (15.4 +/- 6.5 ng/ml) was lower than those in the patients treated with diet alone (20.8 +/- 7.6 ng/ml) and with oral hypoglycemic agents (17.3 +/- 7.0 ng/ml). Furthermore, the highest incidence of osteoporotic fracture and/or back deformity was observed in insulin-treated patients with hypovitaminosis D. In conclusion, these results suggest that microvascular complications and insulin treatment in type 2 diabetes patients are associated with the co-existence of hypovitaminosis D, and that hypovitaminosis D in insulin-treated patients is possibly related to the risk of osteoporotic fracture.     

Cochlear dysfunction and microvascular complications in patients with type 1 diabetes mellitus

Sensorineural hearing impairment has been associated with DM, and it is probably linked to the same pathophysiological mechanisms as well-established in microvascular diabetes complications. The study of otoacoustic emissions (OAEs) is useful to identify subclinical cochlear dysfunction. Therefore, the aim of this study was to evaluate the association between abnormal OAEs responses, diabetic kidney disease (DKD) and diabetic cardiac autonomic neuropathy (CAN). We performed a cross-sectional study with 37 type 1 DM patients without auditory symptoms, submitted to the study of Distortion Product Otoacoustic Emissions (DPOAEs) and screened for DKD and CAN. The otoacoustic emissions responses were considered abnormal in 27/37 (73%) patients. A correlation was found between abnormal OAEs responses and presence of DKD (r?=?0.36, p?<?0.05), and 14/16 (88%) patients with a lower amplitude of OAEs in 8 kHz frequency band presented DKD. Abnormal OAEs responses in the 6 kHz frequency band were correlated with the presence (r?=?0.41, p?=?0.01) and severity of CAN (r?=?0.44, p?<?0.001). Additionally, 7/9 (78%) patients with abnormal OAE responses in this frequency also presented abnormal CAN scores. Our results suggest that abnormal otoacoustic emissions responses in high frequency bands are associated with diabetes microvascular complications and could be a risk marker for DKD and CAN, presenting low sensitivity and high specificity. Therefore, assuming that hearing impairment is a pre-clinical stage of hearing loss, performing distortion product otoacoustic emissions in T1DM patients with microvascular complications could be useful to identify those who would be benefit with regular audiologic follow up and tighter diabetes control.     

老年糖尿病患者自由基与微血管并发症关系的探讨

目的　探讨老年糖尿病患者自由基和抗氧化能力的变化及其与微血管并发症的关系。　方法　测定 6 5例老年糖尿病患者和 6 5例健康老年对照者血浆或红细胞中脂质过氧化物 (LPO)、超氧化物岐化酶 (SOD)、过氧化氢酶 (CAT)、谷胱甘肽过氧化物酶 (GSH PX)、维生素C(VC)、维生素E(VE)、β 胡萝卜素 (β CAR)、谷胱甘肽 (GSH) ,同时测定患者的空腹血糖、餐后 2h血糖、糖化血红蛋白(HbA1c)、空腹和餐后 2hC肽、血脂、尿微量白蛋白排泄率、肌电图。　结果　老年糖尿病患者LPO(42 97± 6 99)nmol/g高于健康老年组 (31 5 9± 7 4 4 )nmol/g ,SOD(1712 4 4± 15 7 0 4 )U/L、CAT(2 17 0 1± 2 9 36 ) μg/g、GSH PX(2 1 0 1± 3 38)× 10 -10 U/RBC、VC(40 98± 10 5 1) μmol/L、VE(16 4 4± 2 4 5 ) μmol/L、β CAR(1 19± 0 2 3) μmol/L、GSH(0 98± 0 16 )nmol/L低于健康老年组〔分别为 (192 8 38± 14 3 4 4 )U/L、(2 6 4 4 0± 6 3 5 5 ) μg/g、(2 5 16± 6 4 1)× 10 -10 U/RBC、(5 2 2 3± 10 5 1) μmol/L、(2 3 0 4± 5 38) μmol/L、(1 6 3± 0 4 0 ) μmol/L、(1 2 5± 0 2 0 )nmol/L〕 ,合并糖尿病微血管并发症者变化更加明显 ,LPO和年龄呈正相关 (r=0 310 ,P <0 0 5 ) ,SOD、C     

Lower circulating irisin is associated with type 2 diabetes mellitus

AimsIrisin is a novel myokine secreted in response to PPAR-γ co-activator-1α (PGC-1α) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients.MethodsIn this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression.ResultsCirculating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204 ± 72 ng/ml vs. non-diabetic control 257 ± 24 ng/ml, p < 0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r = 0.398, p < 0.01), BMI (r = 0.387, p < 0.01), total cholesterol (r = 0.341, p < 0.01), total triglycerides (r = 0.299, p < 0.05), fasting blood glucose (r = 0.430, p < 0.01) and diastolic blood pressure (r = 0.306, p < 0.05). Multiple linear regression model revealed that BMI (β = 0.407, p = 0.012) and FBG (β = 0.315, p = 0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn’t reveal significant association between circulating irisin and major markers of metabolic phenotype.ConclusionsCirculating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.     

Arm length is associated with type 2 diabetes mellitus in Japanese-Americans

Aims/hypothesis  

The aim of the study was to examine the association of type 2 diabetes mellitus with arm length as a marker for early life environment and development.     

Polymorphisms in the ghrelin gene are associated with serum high-density lipoprotein cholesterol level and not with type 2 diabetes mellitus in Koreans

CONTEXT: Ghrelin is known to play a role in glucose metabolism and in beta-cell function. There are controversies regarding the role of ghrelin polymorphisms in diabetes and diabetes-related phenotypes. OBJECTIVE: The objective of this study was to examine polymorphisms of the ghrelin gene in a Korean cohort and investigate associations between them and susceptibility to type 2 diabetes and its related phenotypes. DESIGN AND PATIENTS: The ghrelin gene was sequenced to identify polymorphisms in 24 DNA samples. Common variants were then genotyped in 760 type 2 diabetic patients and 641 nondiabetic subjects. Genetic associations with diabetes-related phenotypes were also analyzed. RESULTS: Nine polymorphisms were identified, and four common polymorphisms [g.-1500C>G, g.-1062G > C, g.-994C > T, g.+408C > A (Leu72Met)] were genotyped in a larger study. The genotype distributions of these four common polymorphisms in type 2 diabetes patients were similar to those of normal nondiabetic controls. However, these four common polymorphisms were variably associated with several diabetes-related phenotypes, such as high-density lipoprotein (HDL) cholesterol, fasting plasma glucose, and homeostasis model assessment of insulin resistance. In particular, subjects harboring g.-1062C were associated with a lower serum HDL cholesterol level after adjusting for other variables (P = 0.0004 or 0.01 after Bonferroni correction for 24 tests). CONCLUSION: The aforementioned four common polymorphisms in the ghrelin gene were not found to be significantly associated with susceptibility to type 2 diabetes mellitus in the Korean population. However, the common polymorphism g.-1062G > C in the promoter region of the ghrelin gene was found to be significantly associated with serum HDL cholesterol levels.     

Glimepiride increases high-density lipoprotein cholesterol via increasing adiponectin levels in type 2 diabetes mellitus

The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A_1c, and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 ± 4.5 vs 8.3 ± 4.5 μg/mL, P = .040) and HDL-c level increased significantly (50 ± 11 vs 53 ± 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 μg/mL), both plasma adiponectin level (4.5 ± 0.9 vs 5.9 ± 2.0 μg/mL, P = .004) and HDL-c level increased significantly (44 ± 8 vs 49 ± 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level ≥6 μg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (β = .574, P = .009, R² = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.     

Skin autofluorescence is associated with past glycaemic control and complications in type 1 diabetes mellitus

As skin autofluorescence (AF) can assess subcutaneous accumulation of fluorescent advanced glycation end-products (AGEs), this study aimed to investigate whether it was linked to glycaemic control and complications in patients with type 1 diabetes mellitus (T1DM). Using the AGE Reader™, AF was measured in T1DM patients referred to Haut-Levêque Hospital (Bordeaux, France); data on their HbA_1c levels measured every 6 months as far back as the last 5 years were also collected. The association of AF with the patients’ past glucose control, based on their latest HbA_1c values, and the means of the last five and 10 HbA_1c values, and with diabetic complications was also examined by linear regression analysis. The sample included 300 patients: 58% were male; the mean age was 49 (SD 17) years and the mean diabetes duration was 21 (SD 13) years. The median skin AF measurement was 2.0 [25th–75th percentiles: 1.7–2.4] arbitrary units (AU), and this was associated with age (β = 0.15 per 10 years, P < 0.001) and diabetes duration (β = 0.17 per 10 years, P < 0.001). After adjusting for age and estimated glomerular filtration rate (eGFR), the skin AF measurement was also related to the means of the last five and 10 HbA_1c values (β = 0.10 per 1% of HbA_1c, P = 0.005, and β = 0.13 per 1% of HbA_1c, P = 0.001, respectively). In addition, the skin AF was associated with retinopathy (P < 0.001), albuminuria (P < 0.001) and decreased eGFR (P < 0.001). In conclusion, the skin AF is related to the long-term glucose control and diabetic complications.     

Thyroid dysfunction and its association with microvascular complications in patients with type 2 diabetes mellitus in south India

Background and aimsTo study the prevalence of thyroid disorders and their association with microvascular complications among adult type 2 diabetes mellitus (T2DM) patients from south-coastal Andhra Pradesh, IndiaMethodsThis cross-sectional study included 500 subjects with T2DM and was conducted in a tertiary health care center from south-coastal Andhra Pradesh. Participants previously diagnosed with thyroid disorders were excluded from the study.ResultsThyroid dysfunction was observed in 98 (19.6%) subjects of which subclinical hypothyroidism (n = 66, 13.2%) was the most common. Subclinical hypothyroidism (SCH) was more frequent in obese patients (16.2% vs 7.6%, p = 0.007) and metformin users (9.6% vs 18.7%, p = 0.0044). Diabetic retinopathy (27.3% vs 8.9%, p = 0.001) was significantly more frequent in SCH patients than euthyroid T2DM patients.ConclusionAmong T2DM patients from south-coastal Andhra Pradesh the prevalence of thyroid dysfunction, especially that of SCH was high; SCH was more frequent among obese and nonmetformin users and was associated was associated with increased risk of diabetic retinopathy.     

Common polymorphism in the cannabinoid type 1 receptor gene (CNR1) is associated with microvascular complications in type 2 diabetes

Endocannabinoids exert their biological effects via interaction with G-protein coupled cannabinoid receptors CB1 and CB2. Polymorphisms in the CNR1 gene (encoding CB1 receptor) were previously found to be associated with dyslipidemia and cardiovascular diseases. We investigated a role of the polymorphism in CNR1 gene in type 2 diabetes and its complications. The study involved 667 T2DM patients and 450 healthy individuals. All subjects were genotyped for G1359A polymorphism by PCR-RFLP procedure. Genotype frequencies did not differ significantly between patients and controls. The statistically significant differences were seen between T2DM patients with diabetic nephropathy (DN) and those without it (OR for risk allele 2.84, 95% CI 2.04–3.94, p < 0.0001). There were also differences between patients with diabetic retinopathy (DR) and those without DR (OR for risk allele 1.81, 95% CI 1.30–2.53, p = 0.0005). No differences were observed in diabetic neuropathy. The A allele was more frequent in patients with coexisting cardiovascular disease (CVD) compared to patients without CVD (p = 0.0044). The novel finding of our study is the association of the G1359A polymorphism with diabetic nephropathy and diabetic retinopathy in patients with T2DM. This polymorphism was also associated with cardiovascular disease in the patient group.     

Altered high-density lipoprotein composition is associated with risk for complications in type 2 diabetes mellitus in South Asian descendants: A cross-sectional,case-control study on lipoprotein subclass profiling

Background

Composition of high-density lipoproteins (HDL) is emerging as an important determinant in the development of microvascular complications in type 2 diabetes mellitus (T2DM). Dutch South Asian (DSA) individuals with T2DM display an increased risk of microvascular complications compared with Dutch white Caucasian (DwC) individuals with T2DM. In this study, we aimed to investigate whether changes in HDL composition associate with increased microvascular risk in this ethnic group and lead to new lipoprotein biomarkers.

Materials and Methods

Using ¹H nuclear magnetic resonance spectroscopy and Bruker IVDr Lipoprotein Subclass Analysis (B.I.LISA) software, plasma lipoprotein changes were determined in 51 healthy individuals (30 DwC, 21 DSA) and 92 individuals with T2DM (45 DwC, 47 DSA) in a cross-sectional, case-control study. Differential HDL subfractions were investigated using multinomial logistic regression analyses, adjusting for possible confounders including BMI and diabetes duration.

Results

We identified HDL compositional differences between healthy and diabetic individuals in both ethnic groups. Specifically, levels of apolipoprotein A2 and HDL-4 subfractions were lower in DSA compared with DwC with T2DM. Apolipoprotein A2 and HDL-4 subfractions also negatively correlated with waist circumference, waist-to-hip ratio, haemoglobin A1c, glucose levels and disease duration in DSA with T2DM, and associated with increased incidence of microvascular complications.

Conclusion

While HDL composition differed between controls and T2DM in both ethnic groups, the lower levels of lipid content in the smallest HDL subclass (HDL-4) in DSA with T2DM appeared to be more clinically relevant, with higher odds of having diabetes-related pan-microvascular complications such as retinopathy and neuropathy. These typical differences in HDL could be used as ethnicity-specific T2DM biomarkers.     

Skin autofluorescence is associated with vascular complications in patients with type 2 diabetes

Aims

Tissue accumulatedadvanced glycation end products (AGEs) can be evaluated non-invasively by an autofluorescence reader as skin autofluorescence (skin AF)·The present study investigated whether skin AF is associated with diabetic micro- and macroangiopathies in Japanese patients with type 2 diabetes mellitus (T2DM).

Thiazolidinediones-benefits on microvascular complications of type 2 diabetes

Type 2 diabetes is associated with serious microvascular complications, such as nephropathy, retinopathy, and neuropathy, which have a significant impact on patients' quality of life, morbidity, and mortality. Type 2 diabetes management strategies to reduce the risk of microvascular complications include treatment of hyperglycaemia, hypertension, and other vascular risk factors. The importance of glycaemic control in reducing the risk of microvascular complications of diabetes is well established. However, many antihyperglycaemic therapies fail to provide adequate glycaemic control and do not prevent complications in the long term. The thiazolidinediones (TZDs) are a class of agents that provide sustained glycaemic control, mediated primarily by reductions in insulin resistance. Evidence reviewed suggests that the TZDs may have the potential to reduce microvascular complications through benefits that go beyond glycaemic control. Insulin resistance underlies a range of metabolic abnormalities, collectively known as the metabolic syndrome (MS), which are cardiovascular (CV) risk factors. Components include visceral obesity, hyperglycaemia, hypertension, dyslipidaemia, low-grade inflammation and microalbuminuria (an early manifestation of target organ damage). Reducing insulin resistance, therefore, has the potential to reduce both microvascular and macrovascular complications.     

Effect of glycemic control on microvascular complications in patients with type I diabetes mellitus

The relation between the control of blood glucose levels and the progression of early diabetic retinopathy and the width of skeletal muscle capillary basement membrane was studied in 54 insulin-dependent diabetic patients. After initial ophthalmologic evaluation including seven-field fundus photography and fluorescein angiography and measurement of levels of glycosylated hemoglobin and width of skeletal muscle capillary basement membrane, the patients were divided into two groups: an experimental group of 30 patients who were treated with continuous subcutaneous insulin infusion and a control group of 24 patients who continued to receive conventional treatment--usually two injections of insulin daily. After a mean follow-up period of 31.4 months, the experimental group had a significant decrease in glycosylated hemoglobin levels as compared with baseline values (mean +/- SEM, 7.2 +/- 0.3 percent versus 10.1 +/- 0.4 percent), reflecting improved control of blood glucose levels. The conventional treatment group had no change in glycosylated hemoglobin levels after a mean of 33.5 months of follow-up. With use of either a modified Early Treatment Diabetic Retinopathy Study grading system or macular microaneurysm counts, the experimental treatment group showed significantly less progression of retinopathy (p less than 0.05). The skeletal muscle capillary basement membrane width was significantly reduced only in the experimental treatment group with stable or improved retinopathy and was unchanged in the control group. There was a tendency for skeletal muscle capillary basement membrane width to increase in thickness over time in those patients whose retinopathy worsened irrespective of treatment. It is concluded that meticulous diabetic control may slow the progression of early diabetic retinopathy. Changes in skeletal muscle capillary basement membrane width may reflect the course of diabetic retinopathy.     

Reverse cholesterol transport in type 2 diabetes mellitus

High-density lipoprotein (HDL) plays an important protective role against atherosclerosis, and the anti-atherogenic properties of HDL include the promotion of cellular cholesterol efflux and reverse cholesterol transport (RCT), as well as antioxidant, anti-inflammatory and anticoagulant effects. RCT is a complex pathway, which transports cholesterol from peripheral cells and tissues to the liver for its metabolism and biliary excretion. The major steps in the RCT pathway include the efflux of free cholesterol mediated by cholesterol transporters from cells to the main extracellular acceptor HDL, the conversion of free cholesterol to cholesteryl esters and the subsequent removal of cholesteryl ester in HDL by the liver. The efficiency of RCT is influenced by the mobilization of cellular lipids for efflux and the intravascular remodelling and kinetics of HDL metabolism. Despite the increased cardiovascular risk in people with type 2 diabetes, current knowledge on RCT in diabetes is limited. In this article, abnormalities in RCT in type 2 diabetes mellitus and therapeutic strategies targeting HDL and RCT will be reviewed.