1,721,173 research outputs found
Sodium/hydrogen exchange activity in type 1 diabetes mellitus: the never-ending story.
No full textThe amiloride-sensitive Na+/H+ exchanger (NHE) mediates uphill H+ extrusion and thus causes intracellular alkalinization. The NHE plays a major role in pH homeostasis, Na+ absorption, cell volume regulation, and cell proliferation; it is activated by growth factors, mitogens, neurotransmitters, tumor promoters, and others. At intracellular pH (pHi)>7.2-7.4, the system is quiescent; when pHi falls, the rate of H+ - efflux increases in an allosteric manner to reach a maximum around pHi=6.0. The kinetics for external Na+ follows the Michaelis-Menten model with a single, binding site. The effect of intracellular H+ best fits an allosteric model with at least two binding sites. According to the postulate that erythrocyte sodium-lithium countertransport (NLCT) might be one mode of operation of the ubiquitous NHE, and following the trail of previous investigations of NLCT association with hypertension and diabetic nephropathy, several studies have confirmed elevated NHE activity in different cell types in patients with essential hypertension. However, the relation between NHE and either NLCT or hypertension remains unclear and the usefulness of NLCT activity as a risk marker for the development of essential hypertension has been now excluded. On the contrary, few publications have dealt with the physiologic NHE in diabetic nephropathy, and contrasting results have been reported. We have observed an accelerated NHE in essential hypertension and in Type 1 diabetes, however without any relationship with urinary albumin excretion rate. Furthermore, NHE activity increased in non-diabetic first-degree relatives of Type 1 diabetic patients, yet no difference could be observed between relatives of probands with diabetic nephropathy and relatives of probands with normoalbuminuria. Unlike erythrocyte NHE activity, abnormal albumin excretion was a distinctive feature of non-diabetic first-degree relatives of Type 1 diabetic patients with nephropathy. The lack of agreement among Authors, even using both the same cell and the same method, testifies to the difficulty in performing a correct patient selection and uniformly reproducible NHE measurement. We compare individual clinical characteristics among different study populations confirming previous conclusions regarding NLCT in essential hypertension: main determinant for the flux values of NHE seems to be patient selection rather than methodology. A common effort is advisable to collaborate, standardise, compare methodologies, and unify criteria of subject recruitment
Transmembrane electron transfer in diabetic nephropathy
No full textOBJECTIVE:
Erythrocytes (red blood cells [RBCs]) reduce extracellular ferricyanide by transmembrane transfer of reducing equivalents involving ascorbate recycling.
RESEARCH DESIGN AND METHODS:
Because ascorbate regeneration is glutathione (GSH) dependent and cells may be depleted of GSH in diabetes, we measured RBC GSH, plasma sulfhydryl (SH) groups, and RBC-mediated ferricyanide reduction in 30 type 1 diabetic patients (age 34 +/- 10 years, disease duration 20 +/- 8 years; no complications, n = 10; retinopathy, n = 10; nephropathy, n = 10), their 36 siblings (age 39 +/- 13 years), and matched healthy volunteers.
RESULTS:
Fasting plasma glucose was 15 +/- 7 mmol/l (vs. 5 +/- 1 in control subjects, P < 0.001), HbA1c 8.4 +/- 1.5% (vs. 5.4 +/- 0.3, P < 0.001), GSH 0.76 +/- 0.12 mg/ml packed RBCs (vs. 0.88 +/- 0.18, P < 0.01), SH groups 401 +/- 72 micromol/l (vs. 444 +/- 56, P < 0.05), and ferrocyanide generation 15 +/- 5 micromol/ml RBC per h (vs. 13 +/- 5, NS). In comparison with 10 normoalbuminuric diabetic subjects with retinopathy, 10 patients with diabetic nephropathy had similar fasting plasma glucose, HbA1c, and SH groups; lower RBC GSH (0.73 +/- 0.08 vs. 0.85 +/- 0.11, P < 0.05); and higher ferrocyanide generation (18 +/- 4 vs. 14 +/- 5, P < 0.05). The 10 patients without complications differed from the 10 healthy volunteers in glycemic control and RBC GSH. RBC electron transfer correlated with plasma lactate (r = 0.8, P = 0.01) only in the uncomplicated group. No difference was detected between siblings and healthy control subjects or between siblings of subjects in the nephropathy and retinopathy groups. Among diabetic patients, the rate of ferrocyanide generation was associated with urinary albumin excretion, plasma creatinine, and SH groups (multiple r = 0.6, P < 0.01).
CONCLUSIONS:
Transmembrane electron transfer is selectively increased in diabetic nephropathy, where RBC GSH is also depleted. The abnormality is peculiar to the nephropathy group and not contributed by familial or hereditary components because the electron flow was normal in siblings. The close relationship between cytosolic NADH and RBC electron transfer observed in diabetic patients without complications seems to be lost in the microangiopathic patients. Whereas patients with retinopathy alone still had normal activity of the RBC-reducing system, patients with nephropathy showed significantly increased activity, unrelated to metabolic parameters or plasma lactate concentration and correlated with renal function parameters and plasma thiols
Dipeptidyl peptidase-4 (CD26): knowing the function before inhibiting the enzyme
No full textDipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions are largely unknown. Protein dimerisation should be required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturation-differentiation is well-established. Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offers a new potential therapeutic approach for type 2 diabetes mellitus, as monotherapy and adjunct therapy to other oral agents. The clinical use of presently available orally active inhibitors of DPP4, however, has been associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Indeed, it is noteworthy that CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder. All-cause infections were increased after sitagliptin treatment. It is noteworthy that the effects of DPP4 inhibition on the immune system have not been extensively investigated. So far, only routine laboratory safety variables have been measured in published randomised controlled trials. The review summarises present knowledge in the field and suggests some potential directions of future research
The Winding Road to Health of People with Diabetes
No full textHealth statistics influences policies and resource allocation on the basis of health needs and system performance. The evaluation of the outcomes of health care is now based not only on changes in the morbidity and mortality of the population, but on a more comprehensive assessment of the trends in health. Demand for high-quality and timely data for reporting on country progress has led to proliferation of indicators (either clinical or performance), i.e. measurable aspects of care provided for which there is evidence that they represent quality on the grounds of scientific research or consensus among expert. Is time to develop a coherent system of data collection, analysis and use that meet country and international needs. Both individual characteristics (age, gender, income, education, occupational status, and social network) and societal features (gross domestic product per capita) influence health. Self-reported health covers physical, mental, and social aspects of health; it has proven to be a powerful predictor of morbidity and mortality and to be associated with the number of contacts with physician per year. The European Social Survey evaluated both individual- and country-level factors in examining health differences between 21 European countries.
Guidelines for diabetes provide evidence-based recommendations for management of diabetes in adults (control of haemoglobin A1c, blood pressure and lipid levels) whose goals are to improve quality of care, decrease morbidity, mortality, and costs by reducing complications, and improve quality of life for diabetic people. Diabetes quality indicators based on diabetes guidelines have been developed which were focused on process measures or on risk factor levels reported one at a time. Glycaemic, blood pressure, and lipid control are the principal specific indicators; other evaluation recommended include annual foot examination, annual tests for diabetic nephropathy, retinopathy, and neuropathy as well as smoking cessation counselling. Indicators may be examined separately; yet a summary measure of “diabetes risk factor control” should be useful for quality measurements. Quality-adjusted life years (QALYs) has been used as a composite measure of the clinical value attributable to better control of the three major risk factors: haemoglobin A1c, low-density lipoprotein-cholesterol and systolic blood pressure. Moreover, several quality initiatives are trying to establish an incentive for improved diabetes care. Achieving and documenting guidelines goals requires an organised system of diabetes care delivered by a multidisciplinary diabetes care team. However, some questions need special attention. First, how many countries have ideally organised health systems where diabetes care is delivered by multidisciplinary teams? Second, risk factor differences estimated by quality measured should be sustained over time to effectively prevent diabetic complications. Thus, examination surveys have to be done regularly. Third, both perceived health and quality of life have not been included among diabetes quality measures. Quality measurement remains prerogative of health care providers while diabetic people continue to be not actively involved in the care provided and in its evaluation
Il point-of-care testing in diabetologia
No full textIn diabetic patients glucose, haemoglobin A1c, ketones, lipids, and urinary albumin monitoring allows prevention, early detection, and treatment of diabetes-related acute and chronic complications.Thepoint-of-caretesting(PoCT)technologyoffersconvenientaspects,aslongas pre-analytical, analytical, and post-analytical errors are minimised.The overview summarises the current state-of-the-art of PoCT in diabetes care
Erythrocyte sodium-hydrogen antiport activity is not a predictor of diabetic nephropathy.
No full textErythrocyte sodium-hydrogen antiport activity was measured by Orlov's method in 36 healthy volunteers (18 with negative, 18 with positive family history of hypertension) and 52 subjects with type 1 insulin-dependent diabetes mellitus: 29 patients were without known diabetic complications, 23 patients with microangiopathy (10 with diabetic retinopathy, 13 with 'incipient' diabetic nephropathy). Normotensive healthy adults had similar antiport activities independently of a positive or negative family history of hypertension (6.45 +/- 2.61 vs. 5.80 +/- 3.07 mmol/l of cells per h, respectively). Sodium-hydrogen antiport resulted 8.38 +/- 3.91 mmol/l of cells per h in the 29 uncomplicated diabetic patients, significantly higher (p < 0.05) compared to healthy subjects, both without and with family hypertension. Complicated diabetics confirmed to have an exchange rate higher than healthy controls (8.18 +/- 2.50 mmol/l of cells per h, p < 0.01): patients with retinopathy showed the highest antiport activity (8.96 +/- 2.95 mmol/l of cells per h, p < 0.01), while patients with nephropathy had milder antiport overactivity (7.58 +/- 2.02 mmol/l of cells per h), not significantly different from either uncomplicated diabetics or healthy controls. Thus, an increased sodium-hydrogen exchange rate in peripheral erythrocytes does not seem to be an early indicator of diabetic nephropathy
Activity of erythrocyte sodium-hydrogen exchange in normal pregnancy.
No full text1. Pregnancy is associated with a 30-50% rise in cardiac output and a 50% increase in blood volume. The contribution of changes in the activity of primary and secondary active transporters to these haemodynamic adaptations remains unknown. For the first time, we measured sodium-hydrogen exchange activity over the course of normal pregnancy. 2. Eighteen healthy pregnant women were studied at 14, 24 and 33 weeks of gestation and compared with 18 non-pregnant healthy women. None of the pregnancies was complicated by hypertension. At each antenatal visit, body weight and blood pressure were recorded, blood and 24 h-urine samples were taken to control renal function and metabolic equilibrium, maternal glucose tolerance was evaluated by oral glucose test and glycated haemoglobin testing, and erythrocyte sodium-hydrogen antiport was also measured. 3. Erythrocyte antiport activity values were 10.0 +/- 3.0, 9.6 +/- 2.9 and 8.4 +/- 3.5 mmol h-1 (litre of cells)-1 in the three gestational trimesters respectively, significantly higher at each trimester than in control women [6.8 +/- 2.5 mmol h-1 (litre of cells)-1]. The clearances of urea and creatinine were constantly elevated in pregnant women; at each trimester their serum concentrations were lower than in non-pregnant women. Serum potassium significantly decreased during pregnancy. Serum total cholesterol and triacylglycerol levels, already above the normal range from the first trimester, further increased until the third trimester. The area under the glycaemic curve became larger during pregnancy, and the area under the insulinaemic curve increased to a lesser extent. There was a significant association between antiport activity and serum triacylglycerol levels. 4. The observed hyperactivity of the transporter, peaking at the fourteenth week of gestation, may be a contributing factor to the haemodynamic adjustments attending upon normal pregnancy
Statin intolerance: Why and What to do - With a Focus on Diabetic People.
No full textThe standards of medical care in diabetes recommend that statin therapy is added to lifestyle therapy for diabetic patients with overt cardiovascular disease (LDL cholesterol goal <70 mg/dl), or without CVD who are over the age of 40 years and who have one or more other cardiovascular disease risk factors (LDL cholesterol goal <100 mg/dl). In order to reach strict LDL targets, high doses of statins may be required. However, the frequency of statin-associated adverse effects and statin intolerance in clinical practice is high (up to 10-15% of statin users) especially at muscle level. The review overviews: 1) the known or hypothesised mechanisms through which causal and contributing factors are associated with adverse effects in diabetic people, and 2) the rationale of strategies for managing statin intolerant patients
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