Diabetes/Metabolism Research and Reviews

Published by Wiley
Online ISSN: 1520-7560
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Article
Insulin resistance is associated with low-grade inflammatory response. The probability that the acute-phase response is associated with enhanced erythrocyte adhesiveness/aggregation was not explored. The degree of erythrocyte adhesiveness/aggregation was evaluated by using a simple slide test. The insulin resistance was evaluated by insulin and glucose concentrations after a night of fasting. The inflammatory response was evaluated by variables of acute-phase response. A significant correlation (r = -0.2, p = 0.02) was noted between insulin resistance expressed as the HOMA index and the degree of erythrocyte adhesiveness/aggregation. This was probably due to the concomitant acute-phase response and the presence of increased amounts of inflammation-sensitive proteins that were found to correlate significantly with the degree of erythrocyte adhesiveness/aggregation. In the multiple linear regression analysis, erythrocyte sedimentation rate and fibrinogen concentration but not HOMA index were found to correlate significantly (p < 0.0001 and p = 0.0007 respectively) with the degree of red blood cell adhesiveness/aggregation. Insulin resistance is associated with an enhanced degree of erythrocyte adhesiveness/aggregation and this is related to the presence of enhanced inflammation-sensitive plasma proteins that are part of the acute-phase response. These findings might have hemorheological consequences and might contribute to the pathophysiology of the insulin-resistance syndrome.
 
Article
Epidemiological evidence has indicated that vitamin D deficiency increased the risk of insulin resistance in metabolic syndrome. The present study was conducted to test the hypothesis that 1,25-dihydroxyvitamin D may improve the free fatty-acid (FFA)-induced insulin resistance in muscle cells. The insulin resistance of muscle cell model was established by treatment of FFA in differentiated C2C12 cells. Glucose uptake of C2C12 myotubes was analysed by the 3H-labelled 2-deoxyglucose uptake assay. The diameter of myotubes was measured under the condition of glutaraldehyde-induced autofluorescense. Tyrosine phosphorylated insulin receptor substrate 1 (IRS-1) was measured by immunoprecipitation. Serine phosphorylated IRS-1 and protein kinase B (Akt), extracellular signal-related kinase (ERK), c-Jun amino-terminal kinases (JNK) as well as their phosphorylated form were analysed by Western blots. Compared with a vehicle-treated group, FFA treatment in myotubes was associated with 70.6% reduction in insulin-mediated uptake of glucose, a five-fold increase in serine phosphorylation of IRS-1, 76.9% decrease in tyrosine phosphorylation of IRS-1 and 81.8% decrease in phosphorylation of Akt. Supplement of 1,25-dihydroxyvitamin D improved the FFA-induced inhibition of glucose uptake in a dose- dependent (p < 0.001) and time-dependent manner (p < 0.01). This was accompanied by increase in tyrosine phosphorylation of IRS-1 and phosphorylated Akt and decrease in serine phosphorylation of IRS-1 (p < 0.001). 1,25-Dihydroxyvitamin D also inhibited the FFA-induced reduction in myotube diameter by 35.3% (p < 0.001). JNK phosphorylation was reduced by 126.7% with treatment of 1,25-dihydroxyvitamin D (p < 0.001). 1,25-Dihydroxyvitamin D had no effect on FFA-induced ERK phosphorylation (p = 0.84). 1,25-Dihydroxyvitamin D improved the FFA-induced insulin resistance in muscle cells.
 
Article
Differentiation and maturation of dendritic cells yield a cell type with the ability to prime immune responses towards defence and destruction. 1,25(OH)2D3, the active form of vitamin D3, fosters the development of tolerogenic dendritic cells. This study aimed to evaluate the effects of 1,25(OH)2D3 on murine dendritic cell behaviour in vitro and in vivo. Dendritic cells were differentiated from bone marrow cells of female C57Bl/6 mice in the presence or absence of 10(-8) M 1,25(OH)2D3 for 8 days (IL4 and GM-CSF). Maturation was induced for 48 h (IFNγ, LPS and BALB/C islet homogenate antigen). Bone marrow-derived dendritic cells displayed a different surface marker profile in the presence of 1,25(OH)2D3 with decreased MHC II, CD86 and CD80 and increased CCR5, DEC205, F4/80 and CD40, as well as lower IL6 and IL12 expression upon LPS/IFNγ stimulation. T-cell proliferation was significantly reduced when exposed to islet antigen-loaded 1,25D3-DCs as compared to control dendritic cells and IL4, IL10, TNFα and TGFβ levels were increased. In vivo, transfer of islet antigen-loaded control dendritic cells resulted in priming of the immune system and hyperacute islet allograft rejection (4/4), whereas this was prevented in 5/7 mice treated with islet antigen-loaded 1,25D3-DCs. We conclude that in vitro 1,25(OH)2D3 exposure alters dendritic cell behaviour, converting them into a cell type that drives T cells away from destruction towards a regulatory phenotype.
 
The characteristics of 1,5-anhydroglucitol (1,5-AG) levels in healthy adults. 1,5-AG concentrations in the control group were 28.44 ± 8.76 µg/mL. (a) when compared with different genders, concentrations of men (31.11 ± 8.91 µg/mL ) were higher than that of women (26.33 ± 8.05 µg/mL) ( p < 0.001); (b) when compared with different age groups, there was no significant difference ( 20–39 years old: 29.21 ± 8.54 µg/mL, 40–59 years old: 28.06 ± 8.46 µg/mL, >60 years old: 27.57 ± 9.62 µg/mL ) ( p = 0.176) and (c) 1,5-AG concentrations in the control group were significantly higher than in type 2 diabetes mellitus group 4.57 ± 3.71 µg/mL, (p < 0.001)
The correlations between 1,5-anhydroglucitol (1,5-AG) and blood glucose characteristics of patients with type 2 diabetes mellitus. 1,5-AG levels were negatively correlated with (a) mean blood glucose (MBG); (b) standard deviation of blood glucose (SDBG); (c) mean amplitude of glucose excursion (MAGE); (d) mean of daily differences (MODD); (f) area under the curve for blood glucose above 180 mg/dL-3rd day (AUC180 -3rd); (g) area under the curve for blood glucose above 180 mg/dL-4th day (AUC180-4th); (h) area under the curve for blood glucose above 180 mg/dL-7th day (AUC180-7th) and was not correlated with (e) low blood glucose M-value index (LBMI). Glycated haemoglobin levels were not correlated with MBG, SDBG, MAGE, MODD, LBMI, and AUC180-3rd, AUC180-4th, AUC180-7th (the figures were not shown)
Article
Blood glucose excursion is an important component of the glycaemic burden, but there are no indexes that can directly reflect them. The aim was to evaluate the values and significance of serum 1,5-anhydroglucitol (1,5-AG) in people with type 2 diabetes mellitus in China and to elucidate the relationship between 1,5-AG and traditional indexes of glycaemic excursions by continuous glucose monitoring. A total of 576 healthy adults and 292 patients were included, and their 1,5-AG, fasting blood glucose and postprandial blood glucose and glycated haemoglobin were measured. For the 34 patients, their mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion, mean of daily differences, low blood glucose M-value index and the area under the curve for blood glucose above 180 mg/dL were calculated by use of a continuous glucose monitoring system. Serum levels of 1,5-AG among healthy adults were 28.44 ± 8.76 µg/mL with a significant gender bias rather than age bias. The 1,5-AG levels in people with type 2 diabetes mellitus were 4.57 ± 3.71 µg/mL, which were lower than those seen in the healthy adults. There was a correlation between 1,5-AG and glycated haemoglobin, fasting blood glucose, and postprandial blood glucose (r = -0.251, -0.195 and -0.349, respectively; all had p < 0.05). The continuous glucose monitoring system demonstrated that 1,5-AG presents a negative correlation with mean blood glucose, standard deviation of blood glucose, mean amplitude of glucose excursion and mean of daily differences for 7 days and with the area under the curve for blood glucose above 180 mg/dL on the third, fourth and seventh days. 1,5-AG may serve as a marker of hyperglycaemia and 7-day hyperglycaemic excursions as well as being a useful adjunct to glycated haemoglobin for blood glucose monitoring in patients with diabetes.
 
Article
In the BIGPRO 1 trial, one year of treatment with metformin in non-diabetic obese subjects with a central fat distribution had no significant effect on fasting plasma triglyceride concentration or on blood pressure despite a decrease in weight, fasting plasma insulin and glucose concentrations. To re-evaluate the effect of metformin on fasting triglyceride concentration and on blood pressure, the BIGPRO 1.2 trial included non-diabetic men (n=168) with a fasting plasma triglyceride concentration > or =1.7 and < or =6.5 mmol/l, high blood pressure (systolic > or =140 and < or =180 and/or diastolic > or =90 and < or =105 mmHg, or treatment for hypertension) and a waist-to-hip ratio > or =0.95. A randomised double-blind trial comparing metformin treatment (850 mg bid) with placebo. Metformin had no significant effect either on blood pressure or plasma triglyceride concentration. In comparison with the placebo group, fasting plasma insulin (p<0.04), total cholesterol (p<0.05) and Apo B (p<0.008) concentrations decreased more in the metformin group in the BIGPRO 1. 2 trial, confirming most of the previous results of the BIGPRO 1 trial. Tissue plasminogen activator antigen concentration decreased significantly (p<0.01) only in the metformin group, but this was not significantly different from the placebo group (p<0.12); further, there were no significant differences in the change in plasminogen activator inhibitor 1. The consistency of the two BIGPRO trials supports the conclusion that metformin affects several cardiovascular risk factors favourably in non-diabetic subjects with a central fat distribution.
 
Article
Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia.
 
Article
Background: This study aimed to compare the metabolic and insulin secretory responses to dexamethasone with the metabolic responses observed at 10 years in normoglycaemic relatives of type 2 diabetic and healthy control subjects. Methods: Twenty relatives and 20 matched control subjects were studied twice at 0 year (pre- and post-dexamethasone) and at 10 years, employing a 75-g oral glucose tolerance test (OGTT), with serial measurements of glucose and insulin, for determination of glucose tolerance and calculations of acute insulin release (ΔI30 /ΔG30 ; insulinogenic index) and insulin sensitivity (SIHOMA ). Results: Following dexamethasone, the relatives group developed varying degrees of glucose intolerance, associated with reduced insulin sensitivity and insulinogenic index. By 10 years, fasting glucose and 2-h OGTT glucose were raised in the relatives group, especially in the relatives most metabolically affected by dexamethasone, including a reduced insulinogenic index. Multiple regression analysis of the data in relatives demonstrated that the 2-h OGTT glucose and fasting glucose values at 10 years depended on the 0-year post-dexamethasone 2-h OGTT glucose, post-dexamethasone fasting glucose and post-dexamethasone insulin sensitivity, r(2) adj = 56% (p < 0.001) and r(2) adj = 60% (p < 0.0001), respectively. No pre-dexamethasone metabolic or insulin secretory responses entered these models. Conclusions: In relatives, fasting and 2-h OGTT glucose concentrations and β-cell responses to acute dexamethasone-induced insulin resistance are similar to those observed at 10 years, especially in relatives who develop the most disturbed dexamethasone-induced glucose intolerance and impaired acute insulin secretion. The combined 0-year, post-dexamethasone fasting and 2-h OGTT glucose concentrations and insulin resistance, measured as SIHOMA , are the best predictors in relatives of future dysglycaemia.
 
Article
Adipose tissue and liver play important roles in mediating the metabolic actions of glucocorticoids. However, the effects of glucocorticoids on glucose and lipid metabolism in skeletal muscle are not understood completely. Intracellular glucocorticoid action is dependent on 11 beta-hydroxysteroid dehydrogenase 1 (HSD1), an enzyme that converts cortisone to active cortisol. We investigated the direct role of HSD1 in cultured primary human skeletal muscle cells using siRNA and pharmacological inhibitors of the enzyme. Primary human skeletal muscle cells were cultured in the presence of 0.5 microM cortisone or 0.5 microM cortisol for eight days. siRNA was utilized to reduce expression of either HSD1 or pyruvate dehydrogenase kinase (PDK) 4. Effects of pharmacological inhibitors of HSD1 were also studied. Exposure to cortisone or cortisol decreased basal glucose uptake and glucose incorporation into glycogen, but was without effect on the insulin-stimulated response. Glucocorticoid exposure increased palmitate oxidation, as well as the expression of PDK4. siRNA-mediated reduction or pharmacological inhibition of HSD1 prevented the effects of cortisone, but not cortisol, on metabolic responses. siRNA-mediated reduction of PDK4 prevented the effect of cortisol to attenuate glycogen synthesis. Targeted reduction or pharmacological inhibition of HSD1 in primary human skeletal muscle cells prevents the effects of cortisone, but not cortisol, on glucose metabolism and palmitate oxidation. Furthermore, the glucocorticoid-mediated reductions in glucose metabolism are dependent on PDK4.
 
Article
In 2003, the American Diabetes Association (ADA) established a new cutoff for impaired fasting glucose (IFG) by reducing it from 110 to 100 mg/dL. This change was challenged as to its appropriateness. A few studies have examined the impact of the ADA(2003) threshold of IFG on metabolic and cardiovascular risk factors. We examined whether metabolic and cardiovascular risk factors, including inflammatory biomarkers, differ in subjects with the new ADA(2003) threshold of IFG (IGF100) as compared with subjects with the old ADA(1997) threshold of IFG (IFG110) in a cohort of 946 nondiabetic Italian Caucasians (fasting plasma glucose < 126 mg/dL). As compared with normal fasting glucose (NFG), subjects with IFG100 and IFG110 had higher body mass index (BMI), waist circumference, total and low density lipoprotein (LDL) cholesterol, triglyceride, fasting and 2-h post-challenge plasma glucose, fasting insulin, systolic blood pressure, and lower levels of high density lipoprotein (HDL) and insulin-like growth factor I (IGF-I). In a logistic regression analysis with adjustment for age and gender, IFG110 was associated with higher risk of post-challenge glucose intolerance as compared with IFG100. As compared with IFG100, subjects with IFG110 have significantly lower levels of circulating IGF-I. As compared with NFG, IFG110, but not IFG100, showed a significant association with increased levels of inflammatory markers including white blood cell count (WBCC), and C-reactive protein (CRP). Both CRP and WBCC were correlated with 2-h plasma glucose but not with fasting plasma glucose (FPG). The data show that IFG110 is associated with a worse metabolic and cardiovascular risk profile as compared with IFG100.
 
Article
Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the scavenging antioxidant system has been shown to be related to the pathogenesis of the disease. This, therefore suggests that genes encoding catalase and other antioxidant enzymes may implicate in the development of type 1 diabetes. Nine microsatellite markers that cover about 10 megabases around the catalase (CAT) gene on chromosome 11p13 were analyzed using polymerase chain reaction (PCR) and fluorescence-based genotyping on an automatic DNA sequencer. We also evaluated three single-nucleotide polymorphisms (SNP) within genes encoding catalase (T1667T and C(-262)T dimorphism) and ETS homologous factor (EHF) (C255T SNP) using a PCR-restriction fragment-length polymorphism approach. Multipont linkage analysis in 37 affected sibling pairs was performed using GENEHUNTER 2.1. We examined the markers for association with the disease by transmission disequilibrium tests in 57 discordant sibling pairs and by a case-control study in 258 unrelated healthy donors and 247 affected patients. We obtained close-to-suggestive evidence of linkage to type I diabetes, with the maximum linkage peak between markers D11S907 and D11S2008. Analysis of three SNPs at the CAT and EHF gene located within the region of maximum linkage showed that T1667T and C(-262)T markers of the CAT gene are strongly associated with the disease. Our findings support evidence of a new putative type 1 diabetes susceptibility locus on chromosome 11p13 and suggest that the CAT gene may play a role in conferring susceptibility to the disorder in Russian patients.
 
Article
Impairment of insulin-stimulated glucose transport is a characteristic of type 2 diabetes. A radioactive glucose analogue has been synthesized: [(125)I]-6-deoxy-6-iodo-D-glucose. Its biological behaviour in vitro is similar to that of 3-O-methyl-D-glucose, the reference tracer of glucose transport. The aim of the present study was to determine the ability of [(125)I]-6-deoxy-6-iodo-D-glucose to evaluate variations in glucose transport in vivo. Biodistributions of [(125)I]-6-deoxy-6-iodo-D-glucose were performed with or without exogenous insulin (iv injection of 1.5 IU/kg) in db/+ non-diabetic control mice and in db/db type 2 diabetic mice, exhibiting a severe insulin resistance characterized by a lack of increase in glucose uptake in response to insulin. In db/+ mice, insulin increased [(125)I]-6-deoxy-6-iodo-D-glucose transport by 30% in most insulin-sensitive tissues (heart, diaphragm and skeletal muscle, p < 0.05) and had no effect in other organs. In db/db mice, [(125)I]-6-deoxy-6-iodo-D-glucose transport in these organs was not modified by insulin. [(125)I]-6-deoxy-6-iodo-D-glucose is able to trace in vivo an increase in glucose transport with insulin in non-diabetic mice and a defect of glucose transport in type 2 diabetic mice. It is the first time that an iodinated analogue of glucose has shown such promising results after in vivo injection. The use of this tracer to assess glucose transport in vivo in humans via nuclear imaging warrants further investigation.
 
Article
Cyclosporin A (CyA) may induce acute nephrotoxicity. The question has been raised of the possible long-term unfavorable course of CyA-induced lesions. Advantage was taken of a large cohort of diabetic patients treated for several months using moderate CyA dosage to evaluate the long-term evolution of renal function in such patients. Two hundred and eighty five recently diagnosed type 1 diabetic patients having received CyA for a mean of 19.9 months were monitored for 13 years, in parallel with 100 similar patients treated with insulin alone. In the CyA-treated group, a transient increase in creatininemia levels occurred during the first 18 months of treatment associated with a transient increase in renal vascular resistance. Both effects disappeared later on: creatininemia levels then remained normal. Inulin and p-aminohippurate (PAH) clearances remained normal throughout follow-up. Neither permanent renal failure nor progressive deterioration of renal function occurred in either group or in individual patients. A 10 to 12% increase in inulin and PAH clearance was elicited by IV amino acid infusion at 7 to 10 years, a finding consistent with a normal renal functional reserve. Patients with moderate kidney lesions on biopsy at 1 year had normal and stable clearance values at 7 to 13 years. The prevalence of arterial hypertension and retinopathy was lower in the CyA-treated group than in the control group, possibly because of the tighter metabolic control obtained in the CyA group. These results suggest that low-dose CyA treatment combined with thorough monitoring does not result in long-term renal dysfunction.
 
Article
13-cis-Retinoic acid (Roaccutan) treatment is associated with disturbances in lipid and sometimes also in glucose metabolism. Thus, we investigated whether 13-cis-retinoic acid treatment decreases insulin sensitivity. We studied 11 men [aged 24+/-2 years (mean+/-SEM), body mass index (BMI) 22.1+/-0.9 kg/m(2)] who received Roaccutan treatment for acne for a period averaging 5 months but who were otherwise healthy. The insulin sensitivity of the subjects was measured before, during and 1-3 months after the end of treatment using the euglycaemic hyperinsulinaemic clamp technique. Treatment with 13-cis-retinoic acid reduced total (59+/-4 vs 55+/-4 micromol/kg/min, p<0.02), oxidative (25+/-1 vs 22+/-2 micromol/kg/min, p<0.05) and non-oxidative (36+/-3 vs 33+/-3 micromol/kg/min, p=0.05) glucose disposal rate, and there was a 4% increase in HbA(1c) (from 5.2+/-0.07 to 5.4+/-0.07%, p<0.02). After treatment cessation these values returned to baseline. 13-cis-Retinoic acid treatment also resulted in increased very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, increased VLDL triglyceride, and increased VLDL and LDL phospholipid concentrations. Treatment of acne with 13-cis-retinoic acid reduces insulin sensitivity and induces alterations in lipid metabolism resembling those of the insulin resistance syndrome.
 
Article
Background: The SLC38A4 gene is related to system 'A' activity, which seems to be related to impaired gluconeogenesis. The objective of this study was to determine whether the 292 C>T and 1304 G>A polymorphisms of SLC38A4 gene are associated with hyperglycaemia in humans. Methods: A total of 227 individuals were enrolled in a case-control study, in which hyperglycaemia was defined by plasma glucose levels ≥95 mg/dL. Genotyping was carried out by using real-time polymerase chain reaction. Results: The frequency of mutant alleles of SLC38A4 gene for single-nucleotide polymorphism (SNP) 1304 G>A was 23.6% and 30.2% for SNP 292 C>T. The frequency of allele T for the SNP 292 C>T in the case and control groups did not show significant differences, whereas the frequency of allele A for the SNP 1304 G>A was significantly higher in the case group than in the control group (p = 0.04). In the logistic regression analysis, the SNP 1304 G>A [odds ratio (OR) 1.78; 95%CI 1.04-3.05, p = 0.03] but not SNP 292 C>T (OR 1.41; 95%CI 0.80-2.47, p = 0.23) showed a significant association with hyperglycaemia. After adjusting by body mass index, waist circumference and triglycerides, the SNP 1304 G>A remained significantly associated with hyperglycaemia (OR 2.13; 95%CI 1.18-3.83, p = 0.03). Pair wise linkage disequilibrium showed correlation (D' > 0.82) between 292 C>T and 1304 G>A SNPs. Haplotype association with hyperglycaemia also showed significant association between both homozygous mutant alleles (A/T) and hyperglycaemia (OR 1.68; 95%CI 1.01-2.79, p = 0.048). Conclusions: Our results suggest that mutant allele A for SNP 1304 G>A of SLC38A4 gene is associated with hyperglycaemia.
 
Article
The results from the published studies on the association of fatty acid-binding protein 2 (FABP2) Ala54Thr polymorphism with insulin resistance and blood glucose are conflicting. In this meta-analysis, we investigated the association of the FABP2 Ala54Thr polymorphism with insulin resistance and blood glucose. We collected data on fasting blood glucose and fasting insulin, 2-h blood glucose (2-h BG) and 2-h insulin (2-h insulin), and homeostasis model assessment insulin resistance index. A dominant model was used for this meta-analysis. Thirty-one studies with 13 451 subjects were included in this meta-analysis. The carriers of Thr54 allele have significantly higher homeostasis model assessment insulin resistance index and marginally higher fasting insulin than the non-carriers: standardized mean difference (SMD) = 0.07, 95% confidence interval (CI, 0.02, 0.12), p = 0.007, p(heterogeneity) = 0.19 and SMD = 0.08, 95% CI (-0.01, 0.17), p = 0.07, p(heterogeneity) < 0.00001, respectively. A borderline significant association between the FABP2 Ala54Thr polymorphism and an increased 2-h BG was also detected under the dominant model: SMD = 0.10, 95% CI (0.00, 0.20), p = 0.05, p(heterogeneity) = 0.09. In addition, a borderline association between this polymorphism and an increased fasting blood glucose in populations of other ethnic origins was detected under the dominant model: SMD = 0.11, 95% CI (-0.00, 0.23), p = 0.06, p(heterogeneity) = 0.03. Our meta-analysis suggests that the Thr54 allele of the FABP2 Ala54Thr is weakly associated with a higher degree of insulin resistance, higher level of fasting insulin and higher level of 2-h BG. Our meta-analysis also suggests a weak association between this polymorphism and an increased fasting blood glucose in populations of other ethnic origins under the dominant model.
 
Article
Background: This experimental study explores a novel magnetic resonance imaging/spectroscopic (MRI/MRS) method that measures changes in renal metabolism in a diabetic rat model. This hyperpolarized metabolic MRI/MRS method allows monitoring of metabolic processes in seconds by >10 000-fold enhancement of the MR signal. The method has shown that the conversion of pyruvate to bicarbonate, i.e. pyruvate dehydrogenase (PDH) activity, is significantly altered in the myocardium already at the onset of diabetes, and the predominant Warburg effect is a valuable cancer maker via the lactate dehydrogenase (LDH) activity. We hypothesize that a similar change in PDH and LDH could be found in the early diabetic kidney. Methods: In a streptozotocin rat model of type 1 diabetes, hyperpolarized (13) C-MRI and blood oxygenation level-dependent (1) H-MRI was employed to investigate the changes in renal metabolism in the diabetic and the control kidneys in vivo. Results: The diabetic kidney showed a 149% increase in the lactate/pyruvate ratio compared with the control rat kidney, whereas the bicarbonate/pyruvate ratio was unchanged between the diabetic and the control rat kidneys, consistent with literature findings. These metabolic findings paralleled a reduced intrarenal oxygen availability as found by blood oxygenation level-dependent MRI. Discussion: Hyperpolarized (13) C-MRI shows promise in the diagnosis and monitoring of early renal changes associated with diabetes, with the pyruvate/lactate ratio as an imaging biomarker for regional renal changes.
 
Article
Persons with type 1 diabetes show electrophysiological abnormalities of the visual system which are revealed by methods such as flash electroretinogram (FERG), oscillatory potentials (OPs), pattern electroretinogram (PERG), focal electroretinogram (focal ERG), visual evoked potentials (VEP) in basal condition and after photostress. This review reports the changes in electrophysiological responses of the different structures composing the visual system observed in persons with type 1 diabetes before the development of the overt clinical retinopathy. In persons with type 1 diabetes without retinopathy (IDD), the earlier abnormal electrophysiological responses are recorded from the innermost retinal layers and postretinal visual pathways, as suggested by impaired PERGs and delayed retinocortical time (RCT). These are observed in IDD persons with a disease duration shorter than 6 months. Further electrophysiological changes are recorded from the macula (abnormal focal ERG and VEP after photostress) in IDD persons with disease duration greater than 1 year. Additional electrophysiological changes are recorded from the middle and outer retinal layers (impaired FERG and OPs) in IDD persons with a disease duration greater than 10 years. All the electrophysiological tests show a greater degree of abnormal responses in persons with type 1 diabetes when a background retinopathy is present.
 
Article
Type 2 diabetes is a heterogeneous and polygenic disorder resulting from interaction of genetic factors with environmental influences. Numerous candidate genes for insulin signaling proteins have been screened, but no single major susceptibility gene for type 2 diabetes has been identified. Due to its pivotal role in insulin action, the insulin receptor was considered a plausible candidate gene. The insulin receptor exists in two isoforms differing by the absence (Ex11(-)) or presence (Ex11(+)) of a 12 amino acid sequence in the COOH-terminus of the alpha-subunit, as a consequence of alternative splicing of exon 11. The Ex11(-) binds insulin with two-fold higher affinity than the Ex11(+). This difference is paralleled by a decreased sensitivity for metabolic actions of insulin. Some, but not all, studies have reported that expression of the low-affinity Ex11(+) is increased in target tissues from type 2 diabetic patients, thus suggesting that alterations in abundance of the two isoforms might contribute to insulin resistance. Insulin and type 1 IGF receptors have been shown to form hybrid receptors in tissues co-expressing both molecules. Hybrid receptors bind IGF-I, but not insulin, with high affinity, and behave as IGF-I holoreceptors, rather than insulin receptors, in terms of receptor autophosphorylation, and hormone internalization. It has been shown that the abundance of hybrid receptors is increased in skeletal muscle and adipose tissue from type 2 diabetic patients, and is negatively correlated with in vivo insulin sensitivity. Mutations in the insulin receptor gene have been identified in studies which examined an appropriately sized population of patients with type 2 diabetes. The prevalence of mutations in the insulin receptor gene ranged from 0.4%-7.8%. This review will focus on the structural and functional heterogeneity of the insulin receptor, and will discuss the pathogenetic role of insulin receptor variant forms and polymorphisms in the development of the common form of type 2 diabetes.
 
Article
STUDY OBJECTIVE AND SETTING: The aim of this study is to determine the incidence rate of type 1 diabetes in the metropolitan region of Santiago, Chile from 1 January 1986 to 31 December 2003. Population-based incidence study. Participants: A case must fulfill the following requirements to be included in this study: age at onset: 0 to 14 years, diagnosed with diabetes and placed on insulin, diagnosed within the defined time period, and to be a resident of the metropolitan region of Santiago at the time of the diagnosis. The population 'at risk' is the population less than 15 years of age. The overall rate of type 1 diabetes was estimated as 4.02 cases per 100 000 children per year (95% confidence interval: 2.98-4.83). The incidence of type 1 diabetes in Santiago, Chile has increased during the last years. This data are concordant with the observation that the incidence of type 1 diabetes is increasing in Latin America and worldwide.
 
Article
Glucose can be extracted through intact skin by electro-osmotic flow (a process called ‘reverse iontophoresis’) upon the application of a low-level electrical current. Recently we have combined iontophoretic extraction with an in situ glucose sensor in a device called the GlucoWatch® biographer. Clinical results with this device show close tracking of blood glucose over a range of 2.2 to 22.2 mmol/l for up to 12 h using a single blood glucose value as calibration. The biographer readings lag behind blood glucose values by an average of 18 min. An analysis of data from 92 diabetic subjects in a controlled clinical setting shows a linear relationship (r=0.88) between GlucoWatch biographer readings and blood glucose. The mean absolute relative difference between the two measurements was 15.6% and more than 96% of the data fell in the (A+B) regions of the Clarke error grid. Similar results have been obtained from subjects using the GlucoWatch biographer in an uncontrolled home environment. The automatic, frequent, and non-invasive measurements obtained with the GlucoWatch biographer provide substantially more information about glucose levels than do the current fingerstick methods. This information can be used for improved decisions about all aspects of diabetes management. Copyright
 
Article
Charcot's joint disease of the foot and ankle is a poorly understood and frequently overlooked complication of diabetes. Recognition of this condition, especially in its earliest stage, remains problematic, with many cases going misdiagnosed even today. Medical management of the Charcot foot remains the standard of care for the majority of patients, with surgical intervention reserved for the most difficult cases. This historical perspective began in the early nineteenth century with the first attempts to experimentally examine the spinal origin of rheumatism of the foot and ankle. J.-M. Charcot was the first to describe the arthropathies associated with tabes dorsalis. His early investigations into the tabetic arthropathies (1868) and his brilliant presentation, Demonstration of Arthropathic Affections of Locomotor Ataxy, at the 7th International Medical Congress (1881), established this disease as a distinct pathological entity. Charcot and Féré published the first observations of the tabetic foot (Pied tabétique) in the Archives de Neurologie in 1883. It was not until 1936, however, that W. R. Jordan established the association between neurogenic arthropathy of the foot/ankle and diabetes mellitus.
 
Article
The objective of this review was to revise the existing information regarding type 2 diabetes (T2D) prevalence in the Argentine population during the past 30 years and to see whether the available data and methodology of the studies conducted allow analysis of time trends. The PubMED and LILACS databases were searched using the search terms "diabetes prevalence" and "Argentina". A total of 301 studies were identified and 19 of them remained in the review after applying the inclusion and exclusion criteria. The studies reviewed covered a time period of 30 years (1979-2012). The studies conducted in Argentina during the last 30 years assessing the prevalence of T2D are very heterogeneous. The majority of the studies were conducted in the province of Buenos Aires. As the assessment of T2D varied between the studies in respect of diagnostic criteria and diagnostic tests for T2D, meaningful comparisons are difficult to make, not to mention an analysis of time trends. All in all, the T2D prevalence seems to be at least 10% in the Argentina population. However, the latest large population surveys conducted in Argentina is promising and may offer the most reliable estimates of the T2D prevalence even though the diagnosis of T2D was based on participant self-report. This article is protected by copyright. All rights reserved.
 
Article
The study aimed to describe the epidemiology of diabetes in minority children residing in Chicago, IL, USA, and to compare the demographic and clinical characteristics of those with type 1 to those with youth-onset type 2 diabetes. Medical records were obtained on 735 insulin-treated African-American and Latino children aged 0-17 years at onset, and diagnosed between 1985 and 1994; 195 of the children were interviewed. Subjects were presumed to have type 2 diabetes if they fitted specific criteria. Univariate and multivariate analyses were conducted and Poisson regression was used to analyze time trends. Ten-year average annual incidence of childhood diabetes for African-Americans [15.2/10(5), 95% confidence interval (CI): 13.5, 17.0] was significantly higher than for Latinos (10.7/10(5), 95% CI: 9.1, 12.6). The average annual incidence was 10.3/10(5) population for type 1 and 3.2/10(5) for those with presumed type 2 diabetes. Most patients (99.6% of type 1, 94.1% of type 2) exhibited more than one of the classic onset symptoms of type 1 diabetes. Mean age at diagnosis was older, 13.1 versus 10.5 years, and there were more females, 62.4%, versus 49.8%, among the type 2 patients; ethnicity was not an important distinguishing factor. The risk of childhood diabetes increased among African-Americans and Latinos between 1985 and 1994, driven by an increase in children with type 2 diabetes. This is likely related both to an increase in risk factors, i.e. obesity, and to changes in diagnostic practice.
 
Article
Argentina has a longstanding tradition of diabetes research, beginning with the seminal work of Prof. Bernardo A. Houssay, who was awarded the first Nobel Prize in Medical Sciences for his studies on the relationship between diabetes and pituitary function. Prof. Luis F. Leloir, who was also awarded the Nobel Prize for his work in carbohydrate metabolism, also inspired younger generations of biologists to work in the field of diabetes research. The aim of this paper is to provide a review of the contributions of Argentine researchers during the 1990s. This manuscript includes only reports of Argentine researchers working on diabetes in local laboratories and quoted in Medline. Thus, important contributions not reported in journals included in Medline or produced by Argentine researchers working abroad may have been omitted. The material consists of a brief description of clinical research (epidemiology and costs, metabolic control, associated risk factors, immunological aspects, and other clinical studies) and basic research (animal model with spontaneous diabetes, islet morphology and function in normal and pathological conditions, insulin action, metabolic disorders related to diabetes, and some miscellaneous effects related to drug-induced diabetes). Altogether, a broad idea of the continuous contribution of our national research to the international field of diabetes is provided, as well as a list of Argentine researchers and research centers devoted to the study of diabetes.
 
Article
Background: In Caucasians, a small number of Type 1 diabetic patients do not show evidence of humoral islet autoimmunity at disease onset, at least with common screening procedures. In African- and Hispanic-American diabetic children at time of diagnosis, many show no evidence of autoimmunity but have an atypical clinical form of the disease. According to the recent American Diabetes Association classification, this subgroup of autoantibody negative patients is referred to as Type 1b diabetic subjects. In the present study, a homogeneous Caucasian Type 1 diabetic clinic-based cohort has been evaluated at diagnosis using a large panel of diabetes-related antibodies and then characterized for various genetic features in order to identify newly diagnosed Type 1 diabetics who are potentially autoantibody negative, i.e. possibly referrable to as idiopathic Type 1b diabetes. Methods: Newly diagnosed Type 1 diabetic patients of Italian origin (n=141, mean age 12.0+/-7.6 years) were tested for anti-islet cell, anti-insulin, anti-65 kDa isoform of glutamic acid decarboxylase and anti-amino acid residues 256-979 of the tyrosine-phosphatase IA-2 molecule autoantibodies (Step 1). Only those patients found to be autoantibody negative were tested for anti-disialo-ganglioside GD3, anti-thyroid peroxidase, anti-thyroglobulin, anti-21-OH hydroxylase, anti-gastric parietal cell and anti-transglutaminase antibodies (Step 2). Sera negative for the presence of these six autoantibodies as well were characterized in terms of HLA DRB1, DQB1 and CTLA-4. Results: Six out of 141 subjects (3.5%) were autoantibody negative in the first step of the study and five out of six in the second. These five autoantibody negative patients underwent genetic analysis. Three of them had at least one Type 1 diabetes-related high risk HLA haplotype (3/141, 2.1%) while the remaining two cases showed neutral (DR5-DQB1*0301/DR5-DQB1*0301) or strongly protective (DR2-DQB1*0602/DR2-DQB1*0602) HLA genotypes, respectively (2/141, 1. 4%). Conclusions: Clinically defined Type 1 diabetic patients with no sign of autoimmunity do exist in a Caucasian population. These patients (2 out of 141) that cannot be classified as Type 1a diabetic patients lack clinical characteristics of Type 1b diabetes and have to be reconsidered for a more appropriate ADA classification. These data suggest the need of further large population-based studies to understand if Type 1b diabetes really occurs in a Caucasian population. The patient with a strongly protective HLA genotype is particularly interesting considering that among Caucasians only a few sporadic cases with Type 1 diabetes and DQB1*0602, have been reported, none of whom was homozygous at DQB1 locus.
 
Article
To describe a screening programme to detect undiagnosed diabetes in high-risk ethnic groups in New Zealand and determine the specificity and sensitivity of HbA(1c) to detect fasting hyperglycaemia. HbA(1c) was offered to subjects over 20 years of age participating in a screening programme for hepatitis B that was targeted at non-European populations. Two hundred and forty-four predominantly Maori subjects, with HbA(1c) levels 5 to 7.9% and who were not known to have diabetes, were tested with an oral glucose tolerance test. Comparison was made with fasting and 2-h samples. Fifty thousand eight hundred and nineteen subjects were screened using HbA(1c). 12% had HbA(1c) levels of 6.1% or more, and in 4% of the population HbA(1c) was 7.1% or more. Maori, Pacific Island people, and Indians had particularly high rates of elevated HbA(1c). HbA(1c) levels of 6.1% and greater were 94% sensitive and 77% specific in detecting the 32 subjects who had a fasting glucose of 7.0 mmol/L or more, and 90% sensitive and 73% specific for 20 subjects with a 2-h glucose of 11.1 mmol/L or more. Rates of elevated HbA(1c) levels in non-Europeans in New Zealand are very high, particularly in Maori, Pacific Island Peoples', and Indians, reflecting their high risk of diabetes and vascular disease. HbA(1c) can be used as an opportunistic screening test for diabetes and glucose intolerance, but a high level should be followed by an oral glucose tolerance test.
 
Article
To improve diabetes screening efforts, the American Diabetes Association now recommends haemoglobin A(1c) (HbA(1c) ) as a diagnostic test, increasing access to patients found in acute care environments. However, the influence of acute illness and care on HbA(1c) levels has not been well studied. To address this, we evaluated for intra-patient differences in HbA(1c) assessed in the emergency department (ED) and after recovery from the acute illness. Adult patients with no known history of diabetes were tested for HbA(1c) during an ED and scheduled follow-up visit. HbA(1c) differences between the two visits were compared using limits of agreement with 95% confidence intervals. The frequency of individuals who changed diagnostic categories (using ≥6.5% to classify newly diagnosed diabetes) from ED to follow-up was determined. A total of 589 patients were included with a mean age of 50 years, and 57/589 (9.7%) had an ED HbA(1c)  ≥ 6.5% with the average follow-up visit 45 days after the ED visit. The mean ED HbA(1c) was 5.67% (±0.86), and the follow-up HbA(1c) was 5.65% (±0.89), (difference -0.0129%, 95% limits of agreement -0.740, 0.714). The ED and follow-up HbA(1c) was highly correlated (r² = 0.829). Although on follow-up almost all patients were classified in the same diagnostic category as in the ED, 17 patients had an HbA(1c)  ≥ 6.5% in the ED and an HbA(1c)  < 6.5%. On follow-up most patients (14/17) still fell in an abnormal range (6.0-6.5%). The HbA(1c) value is not substantially affected by acute illness and is feasible as a screening assay for diabetes in the acute care setting such as an ED. Copyright © 2012 John Wiley & Sons, Ltd.
 
Article
There is abundant evidence that glucotoxicity and lipotoxicity contribute to impaired β-cell function in type 2 diabetes. Interestingly, amino acid (AA) derangement is also a characteristic part of the diabetic state. The acute effects of AA on pancreatic β-cell function have been widely explored; however, to our knowledge, the chronic effects of AA, e.g. proline (Pro), homocysteine (Hcy), and leucine (Leu), on pancreatic β-cell function and integrity have not yet been studied. We aimed to investigate global alterations in β-cell gene expression after long-term exposure of clonal INS-1E cells to elevated level of specific AA in vitro. Global gene expression profiling was performed to characterize genes differently modified by Pro, Hcy, and Leu, respectively, in INS-1E cells. Gene expression profiling revealed significant changes in INS-1E cell mRNAs involved in the control of several aspects of β-cell function, e.g. epigenetic regulation of gene expression, metabolism, innate and adaptive immune responses, cellular signalling, protein synthesis, apoptosis, and cellular stress response. After 72 h, INS-1E cells were differentially regulated (≥1.5- or ≤ -1.5-fold) by Pro (295 transcripts), Hcy (301 transcripts), and Leu (701 transcripts). It appears that Hcy effects changes opposite to those induced by Leu and/or Pro. AA appears to participate in and to influence many physiological processes including those involved in cholesterol metabolism, immune responses, and oxidative phosphorylation. Whether such events promote the β-cell dysfunction and the β-cell failure in diabetes remains to be elucidated. Our data strongly indicate that AA elevation may take part in the progressive development of type 2 diabetes.
 
Article
There are a number of medical conditions such as growth failure in children, pregnancy, lipid abnormalities, and early complications that are improved by the meticulous glycemic control that can be achieved with insulin pump therapy (CSII). By using an insulin pump, many patients with severe hypoglycemia, the dawn phenomenon, extremes of glycemic excursion, recurrent diabetic ketoacidosis (DKA) and hypoglycemia unawareness have amelioration of these problems. However, pump therapy involves problems such as weight gain, recurrent ketosis due to pump failure, infections, and risk of hypoglycemia. Owing to many developmental issues, young children may not be able to wear the pump without parental supervision. We have used the pump at night time only in these patients. This has allowed children of 7-10 years of age to benefit from improved nocturnal glycemia without the risk of pump therapy when they are without an adult to help. We have also used the pump in subjects with recurrent DKA and in our general patient population (mean age 13.6+/-3.9 years). In our pump cohort, CSII led to improvement in quality of life, knowledge, adherence, and responsibility. A reduction in hypoglycemia, DKA rate and mean HbA(1c) was associated with pump usage. For this to occur, however, pump education must be geared to the pediatric subject and his/her family. Education materials and tools help in learning how to use the pump and how to deal with the intricacies of basal and bolus dosing, and the effect of exercise, food and illness on diabetes management. The pump has improved since it was first introduced and these modifications have made it easier, more painless and less hazardous. With the development of continuous glucose sensors and implantable pumps, the next century will see pump therapy lead to the artificial pancreas.
 
Article
Over the last 20 years, there has been considerable progress in the care of the diabetic foot. The increased limb survival rate in patients attending multi-disciplinary clinics has resulted from advances in the care of the neuropathic foot, the neuro-ischaemic foot and from advances in the management of infection. However, significant concerns still remain, requiring a call to action.
 
Article
Interest in mitogenic and potentially carcinogenic effects of insulin and insulin analogues has been renewed by several recent publications that have examined the relationship between cancer and insulin analogues. Actions mediated through the insulin-like growth factor-I receptor in a hyperinsulinaemic state have been implicated mechanistically. Both type 2 diabetes and endogenously elevated insulin-like growth factor-I have been epidemiologically linked to malignancies. Therefore, in vitro mitogenic effects and binding affinities of the various analogues have been analysed. A recent publication by Weinstein et al. studied the in vitro mitogenic and anti-apoptotic activities of insulin analogues, and their conclusion asserts that insulins glargine, detemir, and lispro displayed proliferative and anti-apoptotic effects in a number of malignant cell lines. However, their conclusions are not supported by the data which are not complete and lack clear statistical significance. This data should be interpreted cautiously in light of all other presently available scientific evidence. Prospective, randomized clinical trials will best address any direct relationship between insulin analogues and cancer. Until those studies are designed and completed, clinicians should consider the demonstrated strong benefit of glycaemic control in balance with any alleged risk.
 
Article
For cost-effective population-based diabetes prediction and confirmation, islet autoantibody assays must be made more economical. We evaluated glutamic acid decarboxylase (GAD)-Ruc (renilla luciferase) and IA2ic (also known as ICA512ic)-Ruc (renilla luciferase) fusion protein constructs in high-throughput islet antibody assay formats. Antigen production via transfection onto COS cells in 100 mm culture dishes yielded sufficient antigen to assay 375 and 535 serum samples for GAD and IA2ic per dish, respectively. Antigen was usably stable after -80 °C storage for 40-80 days after which luciferase activity decreased. The mean signal-to-noise ratios for luciferase-based immunoprecitation system (LIPS) GAD and LIPS IA2ic were 88±24 and 219±89, respectively, comparing favourably to radio-binding assays (RBA) in the same format. However, the coefficient of variation among triplicate wells was higher for IA2ic than for GAD in LIPS, similar to findings in RBA format. Correlation coefficients between autoantibody indices determined from the RBA and LIPS methods were only R2=0.79 and R2=0.75 for GAD and IA2ic, respectively, raising the possibility that different epitopes were favoured in the two different assay formats. Nevertheless, overall concordance for the two assay types was high, at 228/240=95.0% for GAD and 494/521=94.8% for IA2ic. Using optimal cutoffs, Diabetes Autoantibody Standardization Program (DASP) 2010 sensitivity/specificity was 80/99% for GAD RBA, 80/99% for GAD LIPS, 70/98% for IA2 RBA, and 72/99% for IA2 LIPS. The LIPS assays for islet autoantibodies to GAD and IA2ic performed as well as RBA in DASP 2010. With further refinements in expression and storage, these assays may be more economical than current methods to measure islet autoantibodies in type 1 diabetes.
 
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Article
Foot complications are among the most serious and costly complications of diabetes mellitus. Amputation of the lower extremity or part of it is usually preceded by a foot ulcer. A strategy that includes prevention, patient and staff education, multidisciplinary treatment of foot ulcers, and close monitoring can reduce amputation rates by 49–85%. Therefore, several countries and organizations, such as the World Health Organization and the International Diabetes Federation, have set goals to reduce the rate of amputations by up to 50%. The basic principles of prevention and treatment described in these guidelines are based on the International Consensus on the Diabetic Foot. Depending on local circumstances, these principles have to be translated for local use, taking into account regional differences in socio-economics, accessibility to health care, and cultural factors. These practical guidelines are aimed at healthcare workers involved in the care of people with diabetes. For more details and information on treatment by specialists in foot care, the reader is referred to the International Consensus document.
 
Article
In 1999 the International Consensus on the Diabetic Foot was published by a group of independent experts. The consensus process is described in this article together with the Practical Guidelines which were part of the consensus document.
 
Article
Diabetic foot ulcers are the source of major suffering and very large costs for both the patient and the health-care system, and every 30 s, a leg is lost somewhere in the world. Investing in a diabetic foot care guideline can therefore be one of the most cost-effective forms of health-care expenditure, provided the guideline is goal focused and properly implemented. The objective of the International Working Group on the Diabetic Foot (IWGDF) is to develop guidelines that will reduce the effect of diabetic foot disease through cost-effective and quality health care, based on the principles of evidence-based medicine. These guidelines are produced by working groups of experts in the field and are endorsed by the more than 100 country representatives of the IWGDF. In 2009, the IWGDF invited again three working groups to write consensus guidelines on peripheral arterial disease, infection, and wound healing. New texts were produced according to a systematic review of the literature in order to inform protocols for routine care and to highlight areas that should be considered for further study. During a meeting of the members of the IWGDF in May 2011, the new set of guidelines was approved and is published in this journal.
 
Article
Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed 100 billion US dollars annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The 'Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications.
 
Glycated haemoglobin levels over 24 weeks of treatment with lixisenatide versus placebo (mITT population). (A) Mean HbA1c by visit from baseline to week 24. (B) HbA1c LS mean change from baseline at week 24. (C) Percentage of patients reaching HbA1c targets of ≤6.5% and <7% at week 24. mITT, modified intent-to-treat; HbA1c, glycated haemoglobin; LS, least squares; SE, standard error; LOCF, last observation carried forward; CI, confidence interval
Change from baseline in post-breakfast PPG parameters and fasting plasma glucose levels at week 24 with lixisenatide treatment versus placebo (mITT population). LS mean change from baseline in (A) 2-h PPG, (B) 2-h glucose excursion and (C) FPG at week 24. LS, least squares; mITT, modified intent-to-treat; PPG, postprandial plasma glucose; FPG, fasting plasma glucose; SE, standard error; CI, confidence interval
Article
This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin ± sulfonylurea. In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to Week 24. 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference:-0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-hour postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001), and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported. In Asian patients with T2DM insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study. This article is protected by copyright. All rights reserved.
 
Article
Patients with diabetes may undergo an approximately 24-h fast for a voluntary religious observance or in preparation for a medical procedure. Commonly, patients will manage their diabetes before and during such fasting without guidelines from their doctors, often because they did not ask for advice. The physician should therefore take the lead in advising patients how to fast safely, in order to avoid the situation wherein the patient manages medication changes on his/her own. Furthermore, it sends a message to the patient that having diabetes does not preclude living a reasonably 'normal' life, even when it comes to religious observances.
 
Article
Background: Our objective was to identify potentially modifiable risk factors and outcomes for gestational diabetes and impaired glucose tolerance in a contemporary American teen population. Methods: We conducted a retrospective cohort analysis of all teenage deliveries (≤18 years old) at one institution over a 4-year period with documented oral glucose tolerance testing. All cases of gestational diabetes and impaired glucose tolerance were identified using the Carpenter and Coustan diagnostic criteria and compared with teenage mothers with normal glucose tolerance testing. Results: Of the 670 included teen deliveries, 668 were either African American or Hispanic/Latino; 31 (5%) were diagnosed with gestational diabetes (n = 5) or impaired glucose tolerance (n = 26). Higher maternal prepregnancy body mass index (34.3 ± 7.8 vs 30.3 ± 6.4, p = 0.001) and morbid obesity (body mass index ≥ 35 kg/m(2) , RR 2.0, 95% CI 1.1-3.6) were associated with gestational diabetes and impaired glucose tolerance. There was no association with weight gain above the Institute of Medicine recommended levels (RR 1.6, 95% CI 0.77-3.4). On postpregnancy follow up, three of the five (60%) teens with gestational diabetes and none of the 26 (0%) teens with impaired glucose tolerance were diagnosed with diabetes mellitus. Conclusions: Higher prepregnancy body mass index, especially morbid obesity, places the gravid teen at higher risk for development of gestational diabetes and impaired glucose tolerance in pregnancy. The potentially modifiable nature of these risk factors coupled with the emerging teen obesity epidemic underscores the need for increased public health focus on this problem.
 
Article
Adenosine receptors (ARs) denoted A1 , A2A , A2B , and A3 and encoded by ADORA1, ADORA2A, ADORA2B, and ADORA3 genes, respectively, are adenosine-activated G-protein coupled receptors that play an important role in obesity and type 2 diabetes mellitus (T2DM). However, little is known about their significance in gestational diabetes mellitus (GDM). The purpose of this study was to investigate whether there are changes in leukocyte ARs expression in GDM patients and whether these alterations are linked to well-known diabetic genes. Leukocytes were isolated from the blood of normal glucose tolerant (NGT) (n = 35) and GDM (n = 82) pregnant women and ARs expression was determined by a semi-quantitative PCR. Univariate correlation analysis was performed to investigate associations between ARs expression and anthropometric and metabolic parameters of patients. Furthermore, the identification of diabetic genes linked to significantly differentiated leukocyte ARs expression in GDM women was also carried out with the use of the human diabetes RT(2) Profiler PCR arrays. ADORA2B mRNA expression was significantly higher in GDM versus NGT women (P < 0.05) and it positively correlated with the glucose level at 1 h 75 g oral glucose tolerance test (OGTT) (r = 0.21, P = 0.044). Nineteen diabetic genes linked to leukocyte ADORA2B overexpression associated with hyperglycemia in GDM women were also identified. Maternal leukocyte ADORA2B overexpression is associated with hyperglycemia in GDM subjects and it is accompanied by complex alterations in the expression of diabetes-related genes involved in insulin action, carbohydrate and lipid metabolism as well as oxidative stress and inflammation. This article is protected by copyright. All rights reserved.
 
Article
Several Type 1 diabetes susceptibility loci have been located to chromosome 2q12-21. However, results have not always been consistent and this may reflect study design and the population analysed. We have used a family-based design to look for an association between Type 1 diabetes and markers located to 2q12-21. Ninety-one South Indian families consisting of subjects with Type 1 diabetes and their parents were genotyped for eight polymorphic markers localised to 2q12-21, which includes the interleukin-1 gene cluster. Radiation hybrid mapping was used to localise the map position of D2S308 and D2S363 on 2q12-21. The extended transmission disequilibrium test was used for statistical analysis. No associations were found between Type 1 diabetes and markers located in and around the interleukin-1 gene cluster or the interleukin-1 Type 1 receptor. In contrast, a suggestive association was found between Type 1 diabetes and two closely-linked markers telomeric of the interleukin-1 gene cluster (D2S308 and D2S363, separated by 3.3 cR) (p=0.004 and p=0.002, respectively). This preliminary study suggests that a locus close to D2S308 and D2S363 is involved in the aetiology of Type 1 diabetes in the South Indian population.
 
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Jan Apelqvist
  • Skåne University Hospital
Solomon Tesfaye
  • Sheffield Teaching Hospitals NHS Foundation Trust
Karel Bakker
Nicolaas Schaper
  • Maastricht University
Benjamin Alan Lipsky
  • University of Washington; University of Oxford