Changes in placental adipocytokine gene expression associated with gestational diabetes mellitus

Leptin and adiponectin, two adipocytokines, may work together in regulating energy homeostasis and insulin action. Leptin gene expression has been investigated in term placental tissue complicated by gestational diabetes mellitus (GDM), but never in conjunction with all isoforms of the leptin receptor (LEPR A-D), or with adiponectin receptors (ADIPOR1 and 2). In this study we examined the association between changes in expression of these genes in placental tissue and GDM risk. We assessed placental gene expression of leptin, LEPR A-D and ADIPOR1 and 2 by real time PCR using mRNA from maternal and fetal biopsies. Tissues were collected from uncomplicated pregnancies (n=28) and those complicated by GDM (n=19). Gene expression was normalized to three endogenous housekeeping genes. Relative gene expression values were reported as fold change between groups. Adiponectin gene expression was out of the sensitive range of our assay. There were increases in leptin mRNA expression in GDM cases compared with controls for maternal-side (p=0.06), and fetal-side (p=0.09) placental biopsies. No significant changes were seen in GDM cases compared with controls in LEPR A-D or ADIPOR1 and 2. mRNA derived from maternal-side tissue was positively correlated with tissue from the fetal side for all genes studied (all p<0.01). Finally, we noted that absence or presence of GDM was a major factor in leptin mRNA expression after adjusting for maternal age, mode of delivery, parity and smoking status. In conclusion, increases in leptin mRNA expression in term placenta, but not that of its receptors, are associated with the diagnosis of GDM. Changes seen in the ligand, but not the receptor, of the leptin pathway in GDM-complicated pregnancies may also apply to the adiponectin pathway, as the ADIPOR1 and 2 mRNAs do not change with GDM diagnosis.     

Social and lifestyle factors associated with diabetes in the adult Bahraini population

This paper aimed to assess the prevalence of known diabetes among Bahraini adults, and to determine associated social and lifestyle factors. A community-based survey was carried out on 514 adults aged 30-79 years. The overall prevalence of known diabetes was 9%. Using multivariate analysis, the risk of diabetes was found to be higher among older (50-79 years), female, illiterate, currently married, non-smoking people, those who did not walk regularly, overweight and obese people (BMI > or = 25), those who had a history of hypertension and those who consumed fresh vegetables more than 3 times a week. However, only obesity was found to be significantly associated with diabetes (OR = 1.83, CI 1.48-4.15).     

Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action

Despite recent advances in understanding the pathophysiology of schizophrenia and the mechanisms of antipsychotic drug action, the development of biomarkers for diagnosis and therapeutic monitoring in schizophrenia remains challenging. Metabolomics provides a powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual's metabolic profile in response to pathophysiological stimuli or drug intervention. In this study, we performed gas chromatography-mass spectrometry based metabolomic profiling in serum of unmedicated schizophrenic patients before and after an 8-week risperidone monotherapy, to detect potential biomarkers associated with schizophrenia and risperidone treatment. Twenty-two marker metabolites contributing to the complete separation of schizophrenic patients from matched healthy controls were identified, with citrate, palmitic acid, myo-inositol, and allantoin exhibiting the best combined classification performance. Twenty marker metabolites contributing to the complete separation between posttreatment and pretreatment patients were identified, with myo-inositol, uric acid, and tryptophan showing the maximum combined classification performance. Metabolic pathways including energy metabolism, antioxidant defense systems, neurotransmitter metabolism, fatty acid biosynthesis, and phospholipid metabolism were found to be disturbed in schizophrenic patients and partially normalized following risperidone therapy. Further study of these metabolites may facilitate the development of noninvasive biomarkers and more efficient therapeutic strategies for schizophrenia.     

Metabolomic profiling of biomarkers of liver X receptor-induced toxicity in mouse liver tissue

Methods based on matrix-assisted laser desorption/ionisation mass spectrometry (MALDI-MS), liquid chromatography coupled to an LTQ-Orbitrap mass spectrometer (LC-MS) and gas chromatography-mass spectrometry (GC-MS) were used to investigate changes in the small molecule profiles of mouse liver in response to administration of an LXR agonist. Mice were treated with either 0.3 mg/kg, 1 mg/kg, 10 mg/kg, 30 mg/kg or 60 mg/kg of an LXR test compound or saline (control) once daily, over a 5 day period, to investigate the effects of the drug on metabolism in the liver. It was possible to detect triacylglycerol accumulation in the livers of animals treated with the drug, even at the lowest concentrations using, in the first instance, MALDI MS. There was also an increase in the relative degree of triacylglycerol saturation in the drug-treated samples. Changes in the profiles of phosphatidylcholine lipids were also observed. The changes in lipid profiles were also confirmed by LC-MS and GC-MS, the latter revealing a large increase in the level of the free fatty acid oleic acid (C18:1) in the treated samples. All of the changes were dose-related. Polar metabolites in the samples were analysed by hydrophilic interaction (HILIC) chromatography in combination with an LTQ-Orbitrap mass spectrometer. There were many changes in the metabolite profiles, some of which might simply be related to generalised toxicity. The clearest marker compounds, which showed very marked changes with dose, were methylglutaryl carnitine (MGC) and hydroxymethylglutaryl carnitine (HMGC). Another marker of some interest was uridine diphosphate N-acetylglucosamine (UNGA).     

Metabolomic and genetic analysis of biomarkers for peroxisome proliferator-activated receptor alpha expression and activation

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor with manifold effects on intermediary metabolism. To define a set of urinary biomarkers that could be used to determine the efficacy of PPARalpha agonists, a metabolomic investigation was undertaken in wild-type and Pparalpha-null mice fed for 2 wk either a regular diet or a diet containing the PPARalpha ligand Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid), and their urine was analyzed by ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry. Principal components analysis of 6393 accurate mass positive ions revealed clustering as a single phenotype of the treated and untreated Pparalpha (-/-) mice plus two additional discrete phenotypes for the treated and untreated Pparalpha (+/+) mice. Biomarkers of PPARalpha activation were identified from their accurate masses and confirmed by tandem mass spectrometry of authentic compounds. Biomarkers were quantitated from raw chromatographic data using appropriate calibration curves. PPARalpha urinary biomarkers highly statistically significantly elevated by Wy-14,643 treatment included 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (>3700-fold), 11beta,20-dihydroxy-3-oxopregn-4-en-21-oic acid (50-fold), nicotinamide (>2-fold), nicotinamide 1-oxide (5-fold), 1-methylnicotinamide (1.5-fold), hippuric acid (2-fold), and 2,8-dihydroxyquinoline-beta-d-glucuronide (3-fold). PPARalpha urinary biomarkers highly statistically significantly attenuated by Wy-14,643 treatment included xanthurenic acid (1.3-fold), hexanoylglycine (20-fold), phenylpropionylglycine (4-fold), and cinnamoylglycine (9-fold). These biomarkers arise from PPARalpha effects on tryptophan, corticosterone, and fatty acid metabolism and on glucuronidation. This study underscores the power of mass spectrometry-based metabolomics combined with genetically modified mice in the definition of monogenic metabolic phenotypes.     

Influence of dietary capsaicin and onion on the metabolic abnormalities associated with streptozotocin induced diabetes mellitus

Effect of feeding 15 mg% capsaicin diet or 3% freeze dried onion powder containing diet were examined in albino rats rendered diabetic with streptozotocin injection. Diabetic rats maintained on onion diet for 8 weeks excreted comparatively less amounts of albumin, urea, creatinine and inorganic phosphorus. Dietary onion also partially reversed the abnormalities in plasma albumin, urea, creatinine and inorganic phosphorus in diabetic animals. Onion also produced a significant reduction in hyperglycemic status of diabetic animals. Diabetic rats maintained on onion diet had a lowered relative liver weight at the end of the study compared to diabetic control group. Diabetic rats fed onion diet also exhibited lowered lipid peroxides in circulation and in urine when compared to diabetic control group. Blood cholesterol was lowered significantly by dietary onion in diabetic animals. Cholesterol decrease was exclusively from LDL-VLDL fraction. Significant decrease in blood phospholipids and tr iglycerides also brought about by dietary onion. Hepatic cholesterol, triglycerides, phospholipids which were elevated under diabetic condition were countered significantly by dietary onion. Dietary capsaicin did not have any significant influence on any of the parameters tested in diabetic rats. Thus, the study reveals that onion feeding improves the metabolic status in diabetic condition, probably because of its hypoglycemic as well as hypocholesterolemic effect. (Mol Cell Biochem 175: 49–57, 1997)     

Prolactin and lactation as modifiers of diabetes risk in gestational diabetes

Pregnancy and puerperium are periods of intense hormonal changes. Maternal metabolism adapts to spare the mother from harm on behalf of her developing offspring and major alterations maintain normal glucose tolerance. Insulin secretion increases during a normal pregnancy to compensate for pregnancy-induced insulin resistance and maintain euglycemia. Women at risk for gestational diabetes have insulin resistance before conception. Gestational diabetes develops when a woman at risk is unable to meet the insulin secretory demands imposed by the additional insulin resistance characteristic of pregnancy. The lactogens, human placental lactogen and prolactin, are major stimuli for the adaptation of the endocrine pancreas during gestation. This review discusses the role of lactogens on glucose homeostasis during pregnancy and proposes a mechanism by which the hormonal control of lactation, led by prolactin, may regulate adipocyte biology, glucose and lipid metabolism, and guard postpartum women against type 2 diabetes.     

Circulating monocyte chemoattractant protein-1 in women with gestational diabetes

Monocyte chemoattractant protein 1 (MCP-1) has been implicated as a key factor in the recruitment and activation of peripheral blood leukocytes in atherosclerotic lesions and adipose tissue. Elevated levels of circulating MCP-1 have been found in patients with type 1 and type 2 diabetes, as well as with coronary artery disease. In this study we compared serum MCP-1 concentrations between pregnant women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and non-pregnant healthy women. The group studied consisted of 62 patients with GDM (mean age 30.1 +/- 5.0 years) at 29.0 +/- 3.5 week of gestation, 64 pregnant women with NGT (mean age 30.0 +/- 4.7 years) at 29.2 +/- 2.9 week of gestation and 34 non-pregnant healthy women (mean age 29.8 +/- 4.7 years). Serum MCP-1 concentration was measured using an enzyme - linked immunosorbent assay. Median MCP-1 concentrations did not differ significantly between women with GDM (median 342.3 [interquartile range 267.9-424.4] pg/ml) and NGT (338.0 [274.7-408.2] pg/ml), but were markedly lower than those found in non-pregnant women (485.2 [409.6-642.4] pg/ml, p<0.0001). After adjusting for glucose, the difference between pregnant and non-pregnant women remained highly significant (p<0.0001). In GDM patients MCP-1 levels correlated significantly with fasting glucose (r=0.2665, p=0.0363), insulin (r=0.4330, p=0.0004), HOMA-IR (r=0.4402, p=0.0003), ISQUICKI (r=-0.4402, p=0.0003), HbA1c (r=0.2724, p=0.0322), as well as with prepregnancy and current BMI (r=0.3501, p=0.0057 and r=0.3250, p=0.0106, respectively). Multiple regression analysis revealed that MCP1 concentrations were significantly predicted only by plasma glucose ( beta=0.3489, p=0.00004). Our results suggest that MCP1 levels are decreased in pregnant women, irrespective of their glucose tolerance status.     

Circulating pro- and anti-inflammatory cytokines in Polish women with gestational diabetes.

In this study we measured serum concentrations of proinflammatory interleukin-6, interleukin-8, and interleukin-18 as well as anti-inflammatory interleukin-10 in 30 pregnant women with normal glucose tolerance, in 32 women with abnormal results of a 50-g glucose challenge test, and in 57 patients with gestational diabetes mellitus. Patients with gestational diabetes had significantly higher IL-6 (median 1.0 [0.7-1.5] vs. 0.7 [0.4-0.8] pg/ml, p=0.001), IL-8 (2.1 [1.1-4.2] pg/ml vs. 0.7 [0.4-0.9] pg/ml, p<0.0001), and IL-18 (249.3 [188.5-318.7] pg/ml vs. 186.7 [139.9-243.9] pg/ml, p=0.005) as well as lower IL-10 levels than healthy pregnant women (0.6 [0.5-1.5] pg/ml vs. 2.9 [1.8-3.2] pg/ml, p<0.0001). After adjusting for glucose, insulin, and BMI values, the differences in IL-8 and IL-18 became insignificant, whereas the differences in IL-6 and IL-10 levels remained highly significant (p<0.0001). The subjects with abnormal glucose challenge test results had higher IL-6 levels (0.9 [0.7-1.3] pg/ml, p=0.005) and similar levels of other cytokines as compared with the women with normal glucose tolerance. Our results suggest an impaired balance between circulating pro- and anti-inflammatory cytokines in patients with gestational diabetes; however, a significant contribution of maternal obesity to the increased levels of IL-8 and IL-18 should be underlined.     

Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes

Emerging data indicate that gut-derived endotoxin (metabolic endotoxemia) may contribute to low-grade systemic inflammation in insulin-resistant states. Specific gut bacteria seem to serve as lipopolysaccharide (LPS) sources and several reports claim a role for increased intestinal permeability in the genesis of metabolic disorders. Therefore, we investigated the serum levels of LPS and zonulin (ZO-1, a marker of gut permeability) along with systemic levels of tumor necrosis factor-α (TNF-α) and Interleukin-6 (IL-6) in patients with type 2 diabetes mellitus (T2DM) compared to control subjects. Study subjects were recruited from the Chennai Urban Rural Epidemiology Study [CURES], Chennai, India. Study group (n = 45 each) comprised of a) subjects with normal glucose tolerance (NGT) and (b) patients with T2DM. LPS, ZO-1, TNF-α, and IL-6 levels were measured by ELISA. Serum levels of LPS [p < 0.05], LPS activity [p < 0.001], ZO-1 [p < 0.001], TNFα [p < 0.001], and IL-6 [p < 0.001] were significantly increased in patients with T2DM compared to control subjects. Pearson correlation analysis revealed that LPS activity was significantly and positively correlated with ZO-1, fasting plasma glucose, 2 h post glucose, HbA1c, serum triglycerides, TNF-α, IL-6, and negatively correlated with HDL cholesterol. Regression analysis showed that increased LPS levels were significantly associated with type 2 diabetes [odds ratio (OR) 13.43, 95 % CI 1.998–18.9; p = 0.003]. In Asian Indians who are considered highly insulin resistant, the circulatory LPS levels, LPS activity, and ZO-1 were significantly increased in patients with type 2 diabetes and showed positive correlation with inflammatory markers and poor glycemic/lipid control.     

Aberrant glycosylation associated with enzymes as cancer biomarkers

Background  

One of the new roles for enzymes in personalized medicine builds on a rational approach to cancer biomarker discovery using enzyme-associated aberrant glycosylation. A hallmark of cancer, aberrant glycosylation is associated with differential expressions of enzymes such as glycosyltransferase and glycosidases. The aberrant expressions of the enzymes in turn cause cancer cells to produce glycoproteins with specific cancer-associated aberrations in glycan structures.     

Changes of serum selenium in pregnant women with gestational diabetes mellitus

Gestational diabetes is one of the most common diseases in pregnancy. In the present work, the possible relationship between serum selenium concentration and gestational diabetes was investigated. Blood samples of 234 pregnant women were collected, including 98 subjects with impaired glucose tolerance (IGT), 46 subjects with gestational diabetes mellitus (GDM), and 90 normal pregnant women (NPW). An additional 17 samples of normal women of fertile age (NW) were collected for comparison. The hydride generation atomic fluorescence spectrometry was used for selenium determination. The mean serum selenium levels obtained for each group were 0.0741±0.0167 mg/L for NPW, 0.0631±0.0132 mg/L for IGT, 0.0635±0.0120 mg/L for GDM, and 0.108±0.0170 mg/L for NW. Serum selenium levels were significantly lower in pregnant woman with IGT (p<0.001) and GDM (p<0.001) than in NPW. Furthermore, an inverse correlation between the serum selenium concentration and the gestational period was also observed. Selenium supplementation during gestation for pregnant women, especially with IGT and GDM, should be considered.     

Elemental contents in serum of pregnant women with gestational diabetes mellitus

Diabetes mellitus is characterized by hyperglycemia and is closely related to trace elements. Quite a few pregnant women suffer from impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM). Investigation of the changes of elemental contents in serum of the pregnant women with IGT and GDM is significant in the etiological research and cure of the diseases. In the present work, the elements Cu, Zn, Ca, Sr, Mg, P, Fe, and Al in the serum of pregnant women were determined. The elemental contents in different experimental groups were compared. Also, the correlation between elemental contents and gestational period was observed. The results showed that compared with normal pregnant women, the Cu contents in serum of pregnant women with GDM increased, but Zn contents had a decreasing trend. In addition, for all pregnant women, the Ca contents in serum had an obvious inverse correlation with gestational period.     

Identification and management of GCK-MODY complicating pregnancy in Chinese patients with gestational diabetes

Molecular and Cellular Biochemistry - Precise differentiation of glucokinase (GCK) monogenic diabetes from gestational diabetes mellitus (GDM) is critical for accurate management of the pregnancy...     

Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease ultimately leading to destruction of insulin secreting β-cells in the pancreas. Genetic susceptibility plays an important role in T1D etiology, but even mono-zygotic twins only have a concordance rate of around 50%, underlining that other factors than purely genetic are involved in disease development. Here we review the influence of dietary and environmental factors on T1D development in humans as well as animal models. Even though data are still inconclusive, there are strong indications that gut microbiota dysbiosis plays an important role in T1D development and evidence from animal models suggests that gut microbiota manipulation might prove valuable in future prevention of T1D in genetically susceptible individuals.     

Cardiomyopathy associated with noninsulin-dependent diabetes

Summary Cardiovascular disease represents the major cause of morbidity and mortality in noninsulin-dependent diabetic patients. While it was once thought that atherosclerotic vascular disease was responsible for all of these adverse effects, recent studies support the notion that one of the major adverse complications of diabetes is the development of a diabetic cardiomyopathy characterized by defects in both diastolic and systolic function. Contributing to the development of the cardiomyopathy is a shift in myosin isozyme content in favor of the least active V₃ form. Also defective in the noninsulin-dependent diabetic heart is regulation of calcium homeostasis. While transport of calcium by the sarcolemmal and sarcoplasmic reticular calcium pumps are minimally affected by noninsulin-dependent diabetes, significant impairment occurs in sarcolemmal Na⁺-Ca²⁺ exchanger activity. This defect limits the ability of the diabetic heart to extrude calcium, contributing to an elevation in [Ca²⁺]_i. Also promoting the accumulation of calcium by the diabetic cell is a decrease in Na⁺, K⁺ ATPase activity, which is known to increase [Ca²⁺]_i secondary to a rise in [Na⁺]_i. In addition, calcium influx via the calcium channel is stimulated. Although the molecular mechanisms underlying these defects are presently unknown, the possibility that they may be related to aberrations in glucose or lipid metabolism are considered. The evidence suggests that classical theories of glucose toxicity, such as excessive polyol production or glycosylation, appear to be insignificant factors in heart. Also insignificant are defects in lipid metabolism leading to accumulation of toxic lipid amphiphiles or triacylglycerol. Rather, the major defects involve membrane changes, such as phosphatidylethanolamine N-methylation and protein phosphorylation, which can be attributed to the state of insulin resistance.