Hemoglobin Dallas (α97(G4)Asn→Lys):functional characterization of a high oxygen affinity natural mutant

Hemoglobin Dallas, an α-chain variant with a substitution of lysine for asparagine at position 97(G4), was found to have increased oxygen affinity ($\text{p}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 1}\text{mmHg at pH}\text{7.3}\text{and}\text{20°C), diminished cooperativity (0n,}\text{the Hill coefficient}\text{= 1.7}$) and reduced Bohr effect (about 50%). Addition of allosteric effectors (such as 2,3-diphosphoglycerate, inositol hexakisphosphate and bezafibrate) led to a decrease in oxygen affinity and increase in cooperative energy. Kinetic studies at pH 7.0 and 20°C revealed that (i), the overall rate of oxygen dissociation is 1.4-fold slower than that for HbA and (ii), the carbon monoxide dissociation rate is unaffected. The abnormal properties of this hemoglobin variant can be atttributed to a more ‘relaxed’ T-state.     

少年游泳运动员冬训期间HbA_2百分含量的规律性变化

 本研究用聚丙烯酰胺凝胶垂直板电泳,双波长扫描仪对少年游泳运动员的HbA_2百分含量进行测定。发现大运动量训练对HbA_2水平是有影响的。经六天训练(星期二、五为大运动量训练),星期日休息一天,次周的星期一晨HbA_2百分含量升高,星期二大运动量训练后的次日晨HbA_2百分含量显著下降。运动性贫血的运动员,其HbA_2百分含量一周中的变化趋势与正常运动员相似,但HbA_2百分含量比正常运动员高。     

The influence of blood glucose on neutrophil function in individuals without diabetes

We assessed the association of neutrophil function with glycated hemoglobin (HbA1c) levels in a Japanese general population. Participants were 809 males and females who were over 20 years old living in the Iwaki region in Aomori Prefecture located in northern Japan. Lifestyle parameters (smoking, alcohol consumption, and exercise habits), HbA1c and neutrophil function such as reactive oxygen species (ROS) production capability and phagocytic activity (PA) were measured. ROS production capability was measured before and after phagocytic stimulus to obtain basal ROS production and stimulated ROS production. Level of HbA1c had a positive correlation with basal ROS production (p=0.053), a negative correlation with stimulated ROS production (p=0.072) and PA (p=0.059) only in post‐menopausal groups, and not in pre‐menopausal groups. However, there were no correlations between levels of HbA1c and neutrophil functions in male. In conclusion, in the present study, despite the presence of diabetes, chronic hyperglycemia was found to cause an increase in daily basal ROS production of neutrophils, and increased susceptibility to infection caused by reduced neutrophilic reaction in females in their menopause. Therefore, from the oxidative point of view, strict glycemic control is necessary to prevent post‐menopausal females from developing diabetic complications in spite of the presence of diabetes.     

糖尿病肾病与非糖尿病肾病维持性血液透析患者血钙、血磷及甲状旁腺激素水平的分析

目的：探讨糖尿病肾病（diabtic nephropgthy,DN）与非糖尿病肾病（non-DN）维持性血液透析患者（maintenance hemodialysis,MHD）血钙、血磷、甲状旁腺激素（intact parathyroid hormone,iPTH）水平的差异;分析其血钙、血磷、iPTH和糖化血红蛋白（glycosylated hemoglobin,HbA1c）水平的相关性。方法：选择沈阳军区总医院血液透析中心收治的148例MHD患者,分为糖尿病组（58例）和非糖尿病组（90例）,比较两组间血钙、血磷、甲状旁腺激素水平的差异,并分析其血钙、血磷、iPTH、HbA1c水平的相关性。结果：糖尿病组iPTH、血磷水平均明显低于非糖尿病组（P〈0.05）,两组血钙水平比较无明显差异。在非DN组中,iPTH与血钙水平呈显著负相关（r=-0.320,P=0.036）,iPTH与血磷水平呈明显正相关（r=0.426,P=0.005）。在DN组中,iPTH与血钙、血磷无显著相关性,而iPTH与HbA1C水平呈显著负相关（r=-0.732,P=0.007）。结论：糖尿病肾病血液透析患者的iPTH水平和血磷水平明显低于非糖尿病肾病血液透析患者,HbA1c可能抑制iPTH的分泌。     

Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes

Genetic variants of IL-18 and IL-12B may be important in immunoregulatory abnormalities, observed in the patients with Type 1 diabetes mellitus (T1DM), that contribute to individual differences in response to a treatment. Therefore, we examined the significance of IL-18-137G/C, IL-18-607C/A, and IL-12B A/C polymorphisms in Croatians (187 patients, 236 controls), not only as factors that contribute to susceptibility to T1DM, but also as determinants of the clinical presentation of disease.     

Unraveling Seasonality in Population Averages: An Examination of Seasonal Variation in Glucose Levels in Diabetes Patients Using a Large Population-based Data Set

It has been shown that the population average blood glucose level of diabetes patients shows seasonal variation, with higher levels in the winter than summer. However, seasonality in the population averages could be due to a tendency in the individual to seasonal variation, or alternatively due to occasional high winter readings (spiking), with different individuals showing this increase in different winters. A method was developed to rule out spiking as the dominant pattern underlying the seasonal variation in the population averages. Three years of data from three community-serving laboratories in Israel were retrieved. Diabetes patients (N?=?3243) with a blood glucose result every winter and summer over the study period were selected. For each individual, the following were calculated: seasonal average glucose for all winters and summers over the period of study (2006–2009), winter-summer difference for each adjacent winter-summer pair, and average of these five differences, an index of the degree of spikiness in the pattern of the six seasonal levels, and number of times out of five that each winter-summer difference was positive. Seasonal population averages were examined. The distribution of the individual's differences between adjacent seasons (winter minus summer) was examined and compared between subgroups. Seasonal population averages were reexamined in groups divided according to the index of the degree of spikiness in the individual's glucose pattern over the series of seasons. Seasonal population averages showed higher winter than summer levels. The overall median winter-summer difference on the individual level was 8?mg/dL (0.4?mmol/L). In 16.9% (95% confidence interval [CI]: 15.6–18.2%) of the population, all five winter-summer differences were positive versus 3.6% (95% CI: 3.0–4.2%) where all five winter-summer differences were negative. Seasonal variation in the population averages was not attenuated in the group having the lowest spikiness index; comparison of the distributions of the winter-summer differences in the high-, medium-, and low-spikiness groups showed no significant difference (p?=?.213). Therefore, seasonality in the population average blood glucose in diabetes patients is not just the result of occasional high measurements in different individuals in different winters, but presumably reflects a general periodic tendency in individuals for winter glucose levels to be higher than summer levels. (Author correspondence: anneke@clalit.org.il)     

Effect of nitric oxide on the transport and release of oxygen in fetal blood

It is well known that nitric oxide (NO), the most important vasodilator agent, plays an important role in lowering vascular resistance in the human umbilical-placental circulation and that its deficiency is related to the pathogenesis of pre-eclamptic disorder. Besides it has recently been demonstrated that human hemoglobin (HbA) is able to transport nitric oxide, as S-nitrosohemoglobin (SNO-Hb), from the arterial to the venous blood. In the present study we examine the functional properties of the adult and fetal nitrosated hemoglobins to see if the double transport of oxygen and NO may influence the fetal oxygenation and the relation between maternal and fetal blood. Our results show that S-nitrosation significantly increases the oxygen affinity of the adult Hb (HbA) with respect to native protein (no-nitrosated) while the functional properties of HbF are less influenced. The oxygen affinity modification, found for SNO-HbA, was ascribed to the nitrosation of cysteine beta 93: really, the same residue is also present in the gamma chains of fetal hemoglobin, while the increase of affinity is less evidenced; hence, it is probable that the 39 aminoacidic substitutions between beta and gamma chains allay the effects of S-nitrosation. As regards the physiological modulators (protons, chloride ions, 2,3-diphosphoglyceric acid, and temperature), they influence the oxygen affinity of the two hemoglobins S-nitrosated, in equal mode with respect to the native forms determining the same variation on the oxygen affinity. Hence, our results evidence the fact that the NO release by SNO-HbA "in vivo" would be limited to regions of extremely low oxygen tension (such as hypoxic regions), while in fetus, SNO-HbF would unload nitric oxide and oxygen at pressure values close to normal.     

The SGLT2 inhibitor dapagliflozin promotes systemic FFA mobilization,enhances hepatic β-oxidation,and induces ketosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to increase ketone bodies in patients with type 2 diabetes; however, the underlying mechanisms have not been fully elucidated. Here we examined the effect of the SGLT2 inhibitor dapagliflozin (1 mg/kg/day, formulated in a water, PEG400, ethanol, propylene glycol solution, 4 weeks) on lipid metabolism in obese Zucker rats. Fasting FFA metabolism was assessed in the anesthetized state using a [9,10-³H(N)]-palmitic acid tracer by estimating rates of plasma FFA appearance (R_a), whole-body FFA oxidation (R_ox), and nonoxidative disposal (R_st). In the liver, clearance (K_β-ox) and flux (R_β-ox) of FFA into β-oxidation were estimated using [9,10-³H]-(R)-bromopalmitate/[U-¹⁴C]palmitate tracers. As expected, dapagliflozin induced glycosuria and a robust antidiabetic effect; treatment reduced fasting plasma glucose and insulin, lowered glycated hemoglobin, and increased pancreatic insulin content compared with vehicle controls. Dapagliflozin also increased plasma FFA, R_a, R_ox, and R_st with enhanced channeling toward oxidation versus storage. In the liver, there was also enhanced channeling of FFA to β-oxidation, with increased K_β-ox, R_β-ox and tissue acetyl-CoA, compared with controls. Finally, dapagliflozin increased hepatic HMG-CoA and plasma β-hydroxybutyrate, consistent with a specific enhancement of ketogenesis. Since ketogenesis has not been directly measured, we cannot exclude an additional contribution of impaired ketone body clearance to the ketosis. In conclusion, this study provides evidence that the dapagliflozin-induced increase in plasma ketone bodies is driven by the combined action of FFA mobilization from adipose tissue and diversion of hepatic FFA toward β-oxidation.