Biomarkers of oxidative stress and endothelial dysfunction in glucose intolerance and diabetes mellitus

Objectives: To evaluate biomarkers of endothelial dysfunction and oxidative stress in glucose intolerance (GI) compared to overt diabetes (DM2). Design and methods: 140 volunteers including 96 with DM2, 32 with GI and 12 controls (C) were Studied. NO metabolites, NO synthase inhibitors. thiols and N-acetyl-beta-glucosaminidase (NAGase) activity were analyzed by chemiluminescence, capillary electrophoresis, ELISA and colorimetric assay, respectively. Results: (center dot)NO metabolites were higher in GI (NOx: P=0.03 S-nitrosothiols: p=0.001) and DM2 (p=0.006; p=0.0006) groups in relation to group C, while nitrotyrosine was higher only in the DM2 group in comparison 10 the other groups. NAGase activity was elevated in GI (p=0.003) and DM2 (p=0.0004) groups in relation to group C, as well as, ADMA (p=0.01: p=0.003) and GSSG (p=0.01 p=0.002). Conclusions: (center dot)NO metabolites. (center dot)NO synthase inhibitors. thiols and NAGase are biomarkers Suitable to indicate endothelial dysfunction and oxidative stress in the early stages of impaired response to insulin. (c) 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Audit of maternal and fetal outcomes in women treated for glucose intolerance during pregnancy

Objective To determine whether one should aim for glycaemia that is statistically 'normal' or for levels of glycaemia low enough to prevent macrosomia (if such a threshold exists) when glucose intolerance is detected during pregnancy Design An audit of pregnancy outcomes in women with impaired glucose tolerance in pregnancy as compared to a local age-matched reference group with normal glucose tolerance. Results Our study suggests that for most patients, more intensive therapy would not have been justified. Maternal smoking appeared to convey some 'advantages' in terms of neonatal outcomes, with reduction in large-for-gestational-age (LGA) infants and jaundice in babies of impaired glucose tolerance (IGT) mothers. Conclusions These observations demonstrate the importance of considering risk factors other than GTT results in analysing pregnancy outcomes, while emphasising that 'normalisation' of fetal size should not be our only therapeutic endpoint. Our detailed outcome review allows us to reassure patients with GDM that with current treatment protocols, they should have every expectation of a positive pregnancy outcome.

Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice.

Insulin controls glucose homeostasis by regulating glucose use in peripheral tissues, and its own production and secretion in pancreatic beta cells. These responses are largely mediated downstream of the insulin receptor substrates, IRS-1 and IRS-2 (refs 4-8), through distinct signalling pathways. Although a number of effectors of these pathways have been identified, their roles in mediating glucose homeostasis are poorly defined. Here we show that mice deficient for S6 kinase 1, an effector of the phosphatidylinositide-3-OH kinase signalling pathway, are hypoinsulinaemic and glucose intolerant. Whereas insulin resistance is not observed in isolated muscle, such mice exhibit a sharp reduction in glucose-induced insulin secretion and in pancreatic insulin content. This is not due to a lesion in glucose sensing or insulin production, but to a reduction in pancreatic endocrine mass, which is accounted for by a selective decrease in beta-cell size. The observed phenotype closely parallels those of preclinical type 2 diabetes mellitus, in which malnutrition-induced hypoinsulinaemia predisposes individuals to glucose intolerance.

Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake

Different levels of insulin sensitivity have been described in several animal models of obesity as well as in humans. Monosodium glutamate (MSG)-obese mice were considered not to be insulin resistant from data obtained in oral glucose tolerance tests. To reevaluate insulin resistance by the intravenous glucose tolerance test (IVGTT) and by the clamp technique, newborn male Wistar rats (N = 20) were injected 5 times, every other day, with 4 g/kg MSG (N = 10) or saline (control; N = 10) during the first 10 days of age. At 3 months, the IVGTT was performed by injecting glucose (0.75 g/kg) through the jugular vein into freely moving rats. During euglycemic clamping plasma insulin levels were increased by infusing 3 mU . kg-1 . min-1 of regular insulin until a steady-state plateau was achieved. The basal blood glucose concentration did not differ between the two experimental groups. After the glucose load, increased values of glycemia (P<0.001) in MSG-obese rats occurred at minute 4 and from minute 16 to minute 32. These results indicate impaired glucose tolerance. Basal plasma insulin levels were 39.9 ± 4 µU/ml in control and 66.4 ± 5.3 µU/ml in MSG-obese rats. The mean post-glucose area increase of insulin was 111% higher in MSG-obese than in control rats. When insulinemia was clamped at 102 or 133 µU/ml in control and MSG rats, respectively, the corresponding glucose infusion rate necessary to maintain euglycemia was 17.3 ± 0.8 mg . kg-1 . min-1 for control rats while 2.1 ± 0.3 mg . kg-1 . min-1 was sufficient for MSG-obese rats. The 2-h integrated area for total glucose metabolized, in mg . min . dl-1, was 13.7 ± 2.3 vs 3.3 ± 0.5 for control and MSG rats, respectively. These data demonstrate that MSG-obese rats develop insulin resistance to peripheral glucose uptake

Risk factors for glucose intolerance in active acromegaly

In the present retrospective study we determined the frequency of glucose intolerance in active untreated acromegaly, and searched for risk factors possibly supporting the emergence of the diabetic condition. Among 43 patients, 8 (19%; 95% CI: 8-33%) had diabetes mellitus and 2 (5%; 1-16%) impaired glucose tolerance. No impaired fasting glycemia was demonstrable. The frequency of diabetes was on average 4.5 times higher than in the general Slovak population. Ten factors suspected to support progression to glucose intolerance were studied by comparing the frequency of glucose intolerance between patients with present and absent risk factors. A family history of diabetes and arterial hypertension proved to have a significant promoting effect (P<0.05, chi-square test). A significant association with female gender was demonstrated only after pooling our data with literature data. Concomitant prolactin hypersecretion had a nonsignificant promoting effect. In conclusion, the association of active untreated acromegaly with each of the three categories of glucose intolerance (including impaired fasting glycemia, not yet studied in this connection) was defined as a confidence interval, thus permitting a sound comparison with the findings of future studies. Besides a family history of diabetes, female gender and arterial hypertension were defined as additional, not yet described risk factors.

Variants of transcription factor 7-like 2 (TCF7L2) gene and incident glucose intolerance in Japanese-Brazilians

Common variants of the transcription factor 7-like 2 (TCF7L2) gene have been found to be associated with type 2 diabetes in different ethnic groups. The Japanese-Brazilian population has one of the highest prevalence rates of diabetes. Therefore, the aim of the present study was to assess whether two single-nucleotide polymorphisms (SNPs) of TCF7L2, rs7903146 and rs12255372, could predict the development of glucose intolerance in Japanese-Brazilians. In a population-based 7-year prospective study, we genotyped 222 individuals (72 males and 150 females, aged 56.2 ± 10.5 years) with normal glucose tolerance at baseline. In the study population, we found that the minor allele frequency was 0.05 for SNP rs7903146 and 0.03 for SNP rs12255372. No significant allele or genotype association with glucose intolerance incidence was found for either SNP. Haplotypes were constructed with these two SNPs and three haplotypes were defined: CG (frequency: 0.94), TT (frequency = 0.027) and TG (frequency = 0.026). None of the haplotypes provided evidence for association with the incidence of glucose intolerance. Despite no associations between incidence of glucose intolerance and SNPs of the TCF7L2 gene in Japanese-Brazilians, we found that carriers of the CT genotype for rs7903146 had significantly lower insulin levels 2 h after a 75-g glucose load than carriers of the CC genotype. In conclusion, in Japanese-Brazilians, a population with a high prevalence of type 2 diabetes, common TCF7L2 variants did not make major contributions to the incidence of glucose tolerance abnormalities.

Effects of exercise and metformin on the prevention of glucose intolerance: a comparative study

We aimed to evaluate the effects of aerobic exercise training (4 days) and metformin exposure on acute glucose intolerance after dexamethasone treatment in rats. Forty-two adult male Wistar rats (8 weeks old) were divided randomly into four groups: sedentary control (SCT), sedentary dexamethasone-treated (SDX), training dexamethasone-treated (DPE), and dexamethasone and metformin treated group (DMT). Glucose tolerance tests and in situ liver perfusion were undertaken on fasting rats to obtain glucose profiles. The DPE group displayed a significant decrease in glucose values compared with the SDX group. Average glucose levels in the DPE group did not differ from those of the DMT group, so we suggest that exercise training corrects dexamethasone-induced glucose intolerance and improves glucose profiles in a similar manner to that observed with metformin. These data suggest that exercise may prevent the development of glucose intolerance induced by dexamethasone in rats to a similar magnitude to that observed after metformin treatment.

Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance

Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings. We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity. Short-term calorie restriction and intermittent feeding presented similar results relative to glucose tolerance. Surprisingly, long-term intermittent feeding promoted glucose intolerance, without a loss in insulin receptor phosphorylation. Intermittent feeding substantially increased insulin receptor nitration in both intra-abdominal adipose tissue and muscle, a modification associated with receptor inactivation. All restricted diets enhanced nitric oxide synthase levels in the insulin-responsive adipose tissue and skeletal muscle. However, whereas calorie restriction improved tissue redox state, food restriction and intermittent feedings did not. In fact, long-term intermittent feeding resulted in largely enhanced tissue release of oxidants. Overall, our results show that restricted diets are significantly different in their effects on glucose tolerance and redox state when adopted long-term. Furthermore, we show that intermittent feeding can lead to oxidative insulin receptor inactivation and glucose intolerance. (C) 2011 Elsevier Inc. All rights reserved.

Association Between Insulin Resistance, Glucose Intolerance, and Hypertension in Pregnancy

There is an association between insulin resistance, glucose intolerance, and essential hypertension, but the relation between insulin resistance, glucose intolerance, and hypertension diagnosed during pregnancy is not well understood. Transient hypertension of pregnancy, the new-onset nonproteinuric hypertension of late pregnancy, is associated with a high risk of later essential hypertension and glucose intolerance; thus, these conditions may have a similar pathophysiology. To assess the association between insulin resistance, glucose intolerance, essential hypertension, and subsequent development of proteinuric and nonproteinuric hypertension in pregnancy in women without underlying essential hypertension, we performed a prospective study comparing glucose (fasting, I and 2 hours postglucose load), insulin, glycosylated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), and triglycerides levels on routine screening for gestational diabetes mellitus. Women who developed hypertension in pregnancy (n = 37) had higher glycemic levels (fasting, 1 and 2 hours postglucose load) on a 100-gram oral glucose loading test, although only the fasting values showed a statistical significance (p < 0.05), and a significantly higher frequency of abnormal glucose loading tests, two hours after glucose load (>= 140 mg/dL) (p < 0.05) than women who remained normotensive (n = 180). Glucose intolerance was common in women who developed both subtypes of hypertension, particularly preeclampsia. Women who developed hypertension had greater prepregnancy body mass index (p < 0.0001), higher frequency and intensity of acanthosis nigricans (p < 0.0001), and higher baseline systolic and diastolic blood pressures (p <= 0.0001 for both), although all subjects were normotensive at baseline by study design; they also presented lower levels of HDL-C (p < 0.05). However, after adjustment for these and other potential confounders, an abnormal glucose loading test remained a significant predictor of development of hypertension (p < 0.05) and, specifically, preeclampsia (p < 0.01). There was a trend toward higher insulin and homeostasis model assessment-insulin resistance (HOMA-IR) levels in women developing any type of hypertension. When comparing women that remained normotensive to term with those with transient hypertension and preeclampsia, the preeclamptic women were born with lower weight (p < 0.05) and shorter length (p < 0.005); at screening they were older (p < 0.005), showed higher frequency and intensity of acanthosis nigricans (p < 0.0001), had higher prepregnancy BMI (p < 0.0005), as well as higher baseline systolic and diastolic blood pressures (p <= 0.0001 for both). They also showed higher HOMA-IR levels that did not show a statistical significance. When glucose tolerance status was taken in account, an association was found between increasing indexes of hypertension (p < 0.05) and of HOMA-IR (p < 0.05) with the worsening of glucose tolerance. These results suggest that insulin resistance and relative glucose intolerance are associated with an increased risk of new-onset hypertension in pregnancy, particularly preeclampsia, and support the hypothesis that insulin resistance may play a role in the pathogenesis of this disorder.

Exercise training in the aerobic/anaerobic metabolic transition prevents glucose intolerance in alloxan-treated rats

Background: Ninety percent of cases of diabetes are of the slowly evolving non-insulin-dependent type, or Type 2 diabetes. Lack of exercise is regarded as one of the main causes of this disorder. In this study we analyzed the effects of physical exercise on glucose homeostasis in adult rats with type 2 diabetes induced by a neonatal injection of alloxan. Methods: Female Wistar rats aged 6 days were injected with either 250 mg/ kg of body weight of alloxan or citrate buffer 0.01 M (controls). After weaning, half of the animals in each group were subjected to physical training adjusted to meet the aerobic-anaerobic metabolic transition by swimming 1 h/day for 5 days a week with weight overloads. The necessary overload used was set and periodically readjusted for each rat through effort tests based on the maximal lactate steady state procedure. When aged 28, 60, 90, and 120 days, the rats underwent glucose tolerance tests (GTT) and their peripheral insulin sensitivity was evaluated using the HOMA index. Results: The area under the serum glucose curve obtained through GTT was always higher in alloxan-treated animals than in controls. A decrease in this area was observed in trained alloxan-treated rats at 90 and 120 days old compared with non-trained animals. At 90 days old the trained controls showed lower HOMA indices than the non-trained controls. Conclusion: Neonatal administration of alloxan induced a persistent glucose intolerance in all injected rats, which was successfully counteracted by physical training in the aerobic/anaerobic metabolic transition. © 2008 Mota et al; licensee BioMed Central Ltd.

Plasma kinetics of an LDL-like nanoemulsion and lipid transfer to HDL in subjects with glucose intolerance

OBJECTIVE: Glucose intolerance is frequently associated with an altered plasma lipid profile and increased cardiovascular disease risk. Nonetheless, lipid metabolism is scarcely studied in normolipidemic glucose-intolerant patients. The aim of this study was to investigate whether important lipid metabolic parameters, such as the kinetics of LDL free and esterified cholesterol and the transfer of lipids to HDL, are altered in glucose-intolerant patients with normal plasma lipids. METHODS: Fourteen glucose-intolerant patients and 15 control patients were studied; none of the patients had cardiovascular disease manifestations, and they were paired for age, sex, race and co-morbidities. A nanoemulsion resembling a LDL lipid composition (LDE) labeled with C-14-cholesteryl ester and H-3-free cholesterol was intravenously injected, and blood samples were collected over a 24-h period to determine the fractional clearance rate of the labels by compartmental analysis. The transfer of free and esterified cholesterol, triglycerides and phospholipids from the LDE to HDL was measured by the incubation of the LDE with plasma and radioactivity counting of the supernatant after chemical precipitation of non-HDL fractions. RESULTS: The levels of LDL, non-HDL and HDL cholesterol, triglycerides, apo A1 and apo B were equal in both groups. The 14 C-esterified cholesterol fractional clearance rate was not different between glucose-intolerant and control patients, but the H-3-free- cholesterol fractional clearance rate was greater in glucose-intolerant patients than in control patients. The lipid transfer to HDL was equal in both groups. CONCLUSION: In these glucose-intolerant patients with normal plasma lipids, a faster removal of LDE free cholesterol was the only lipid metabolic alteration detected in our study. This finding suggests that the dissociation of free cholesterol from lipoprotein particles occurs in normolipidemic glucose intolerance and may participate in atherogenic signaling.