[IV. Management of diabetic neuropathy].
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Blood Glucose↗
Biomedical subjects
M Marre
Publications and source records attributed to M Marre.
Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse.
Diabetic nephropathy is a major risk factor for end-stage renal disease and cardiovascular diseases and has a marked genetic component. A common variant (D allele) of the angiotensin I-converting enzyme (ACE) gene, determining higher enzyme levels, has been associated with diabetic nephropathy. To address causality underlying this association, we induced diabetes in mice having one, two, or three copies of the gene, normal blood pressure, and an enzyme level range (65-162% of wild type) comparable to that seen in humans. Twelve weeks later, the three-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels is sufficient to cause nephropathy in diabetic mice.
Albuminuria↗
[Tissular toxicity of glucose and therapeutic perspectives].
Vascular endothelial cells are the main victims of chronic hyperglycaemia. In these cells glucose uptake is directly proportional to the glucose concentration in the medium. Excessive intracellular glucose concentration increases the production of free radicals. Free radicals directly activate 4 biochemical pathways which are involved in the pathogenesis of chronic diabetic complications: the hexosamine pathway, the polyol pathway, the advanced glycation endproducts pathway and the activation of protein kinase C. A precapillary vasodilatation is consequent to the developed pseudo-hypoxia, which provides a haemodynamic basis for diabetic microangiopathy. New specific inhibitors of each of these pathways are studied in clinical trials. Based on these pathophysiological observations, a new treatment strategy is proposed for diabetic microangiopathy.
Antioxidants↗
[Prediction, screening and treatment of renal complications of diabetes].
Diabetic nephropathy is a glomerular disease, which causes most of premature mortality observed in diabetic patients. The risk of diabetic nephropathy is not entirely accounted for by diabetes duration and control. Diagnosis has been improved by sensitive assays for urinary albumin (microalbuminuria). Treatment relies up on early and liberal use of several antihypertensive agents. Among them, angiotensin I converting enzyme inhibitors rank first, because of their efficacy.
Adult↗
Microalbuminuria and markers of the atherosclerotic process: the D.E. S.I.R. study.
The relationship between microalbuminuria and tissue-type plasminogen activator antigen (tPA-ag) and fibrinogen was evaluated in non-diabetic subjects. Subjects were participants of the D.E.S.I. R. (Data from an Epidemiological Study on the Insulin Resistance syndrome) Study. Analyses were carried out on 2248 women and 2402 men for fibrinogen and on 272 women and 284 men for tPA-ag. Microalbuminuria was defined as urinary albumin concentration greater than 20 mg/l. Men with microalbuminuria had a 6% higher fibrinogen concentration than those without (3.07 g/l (95% confidence interval: 2.99,3.15) vs. 2.89 g/l (2.87,2.91), adjusted for age and smoking). This relationship existed in hypertensive as well as non-hypertensive subjects. The association between microalbuminuria and tPA-ag existed only in hypertensive men, those with microalbuminuria having a 21% higher tPA-ag than those without (4.39 ng/ml (3.70,5.08) vs. 3.63 ng/ml (3.32,3.94), adjusted for age and smoking). Adjustment for other risk markers for cardiovascular disease did not change the results. There was no relationship between microalbuminuria and these haemostatic factors in women. The results of this study suggest that in non-diabetic men, microalbuminuria is associated with fibrinogen, but with tPA-ag only when concomitant with hypertension.
Adult↗
Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study.
Insulin aspart (IAsp), is a rapid-acting analogue of human insulin (HI), for use in the meal related treatment of diabetes mellitus. The degree of glycaemic control achieved by IAsp in comparison with HI after algorithm-driven dose optimisation was tested over 3 months. The prospective, multicentre, randomised, open-label study with parallel groups was performed in 48 centres in 11 countries and included 423 basal-bolus treated patients with Type 1 diabetes. Main outcome measures were blood glucose control assessed by HbA1c, nine-point self-monitored blood glucose profiles, insulin dose, quality of life, hypoglycaemia and adverse events. An algorithm-driven increase occurred in the dose and number of daily injections of basal insulin, particularly in the IAsp group. After 12 weeks of treatment, HbA1c was significantly lower in IAsp compared to HI treated subjects by 0.17 (95% CI 0.30-0.04) (P<0.05). Comparison of the blood glucose profiles showed lower blood glucose levels with IAsp after breakfast (mean 8.4 vs 10.1 mmol/l; P<0.0001) and dinner (8.2 vs 9.3 mmol/l; P<0.01). There were no differences between treatments in the incidence of hypoglycaemic episodes or in the adverse event profiles. The WHO Diabetes Treatment Satisfaction Questionnaire score for perceived hyperglycaemia was lower with Iasp (P=0.005), and patients found the insulin aspart treatment more flexible (P=0.022). The current study underlines the need for optimising the basal insulin regimen in order to take full advantage of the pharmacodynamics of IAsp.
Adult↗
Is microalbuminuria an integrated risk marker for cardiovascular disease and insulin resistance in both men and women?
BACKGROUND: Microalbuminuria is associated with some cardiovascular risk factors. However, it is presently unclear whether microalbuminuria is associated with other cardiovascular risk factors and markers of insulin resistance in both men and women. DESIGN: The baseline parameters of the on-going prospective D.E.S.I.R. Study (Data from an Epidemiological Study on the Insulin Resistance syndrome) were analysed. METHODS: The subjects (n = 3878, age 30-64) had a medical and biological checkup including arterial pressure, ECG, lipids, haematocrit, leukocyte count, insulin and urinary albumin concentration. RESULTS: Arterial pressure was significantly higher in microalbuminuric than in normoalbuminuric men and women. The heart rate and the prevalence of smoking were higher in microalbuminuric than in normoalbuminuric men, but not in women. Total- and LDL-cholesterol, triglycerides, apolipoprotein-B, leukocyte count, uric acid, haematocrit, haemoglobin and red cell volume were greater in microalbuminuric than in normoalbuminuric men. Total- and HDL-cholesterol were lower whereas triglycerides and uric acid were significantly greater in microalbuminuric than in normoalbuminuric women. The 9-year calculated absolute cardiovascular risk was higher in microalbuminuric than in normoalbuminuric men (4.18% vs. 2.79%, respectively, P < 0.0001) but was similar in women (0.75% vs. 0.69%, respectively, NS). Fasting blood glucose and insulin were higher in microalbuminuric than in normoalbuminuric men, but not in women. A multiple regression showed that microalbuminuria was associated with systolic arterial pressure, fasting glucose, leukocyte count and haematocrit in men, and with systolic arterial pressure and triglycerides in women. CONCLUSIONS: Microalbuminuria is associated with most cardiovascular risk factors and markers of insulin resistance in men, but no consistent association is observed in women. The determinants of microalbuminuria appear different in men and women, suggesting a different pathophysiology and perhaps significance of microalbuminuria in men and women.
Adult↗
Interest of Clinitek Microalbumin in screening for microalbuminuria: results of a multicentre study in 302 diabetic patients.
A prospective survey was performed in 302 consecutive diabetic outpatients from 3 French diabetic centres to study the sensitivity and specificity of screening for microalbuminuria using Clinitek Microalbumin. Urinary samples with positive (at least one +) proteinuria, hematuria, leucocyturia, or nitrates using the Multistix strip were excluded from the study. Results obtained with Clinitek Microalbumin were compared to those observed with the reference method of the biological laboratory of the centre on the same urinary sample. A positive result was defined as an albumin-to-creatinine ratio > or =30 mg/g. Results were described in terms of sensitivity, specificity, positive and negative predictive values and likelihood ratio. Agreement rates were compared with the Kappa test. In the study population, 48 patients (17%) had a positive microalbuminuria with reference assay. However, different rates were found in each site (25%, 11%, and 15%, respectively, p<0.001). Using the Clinitek Microalbumin, a positive result was found among 86 patients (29%), (39%, 26%, and 23%, respectively). A good agreement was observed in the population as a whole (81%, K=0.47 +/- 0.06) and in each site (77%, 81%, 84%, respectively). Sensitivity was 79% (82%, 80%, 75%), specificity 81% (76%, 81%, 85%), positive predictive value 46% (53%, 35%, 46%), negative predictive value 95% (93%, 97%, 95%), and positive likelihood ratio 4.2 (3.4, 4.3, 5.0, respectively). Due to the excellent negative predictive value, these results suggest that Clinitek Microalbumin is a good screening test for microalbuminuria. Positive results should be confirmed using a reference assay.
Albuminuria↗
[Insulin sensitivity, blood pressure and cardiovascular diseases].
Essential hypertension is one of the main components of the insulin resistance syndrome. Blood pressure levels are especially critical for the cardiovascular prognosis of patients with diabetes. However, whether the relationship between blood pressure levels and insulin sensitivity is causal, or just an association, remains debatable. In this study, this relationship is explored through the data of currently available clinical trials.
Blood Pressure↗
[Is it necessary to systematically treat diabetics with ACE inhibitors?].
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Angiotensin-Converting Enzyme Inhibitors↗
[Management of diabetic nephropathy before and during pregnancy].
Congenital malformations represent the major risk of pregnancy in diabetic women. Prevention needs strict glycemic control before and during pregnancy. The risk of maternal and foetal complications is particularly high among patients with diabetic nephropathy, and a multidisciplinary approach is necessary. Before pregnancy, nephropathy is evaluated on serum creatinine and 24 hour urinary albumin and protein excretions. We discuss the interactions between diabetic nephropathy and pregnancy: the care of the other diabetic complications, the course of renal function during and after pregnancy, the influence of nephropathy on maternal and foetal complications and prevention of the latter by strict control of blood pressure and glycaemia before and during pregnancy. All these elements should be taken into account when discussing pregnancy with diabetic women with nephropathy wishing to become pregnant. The need to take preventive measures should be emphasised but the practice of systematically discouraging pregnancy without careful evaluation should be avoided.
Congenital Abnormalities↗
The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril (DIABHYCAR) study: design, organization, and patient recruitment. DIABHYCAR Study Group.
The non-insulin-dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CARdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, prospective, double-blind, placebo-controlled, multicenter international trial of the ACE inhibitor ramipril (1.25 mg/day) in patients with type II diabetes and micro- or macroalbuminuria. The main outcome of the study is the time to first occurrence of either death from a cardiovascular origin, including sudden death, nonfatal myocardial infarction, stroke, or congestive heart failure, or requirement of hemodialysis or renal transplantation. The study was launched in France in early 1995 with the participation of general practitioners only, but had to be extended to 15 other countries in 1997 due to difficulties in recruitment. Since 2.5 years after the beginning of the trial the observed event rate was much less than anticipated, it was decided to increase recruitment and follow-up duration and to include congestive heart failure in the definition of the main outcome to keep the study power at a satisfactory level. Recruitment ended on April 1, 1998 with 4937 randomized patients. Following the early discontinuation for efficacy of another study of ramipril in high cardiovascular risk patients, the Heart Outcomes Prevention Evaluation study (HOPE), the second interim analysis of DIABHYCAR was performed early (when 406 instead of 500 patients presented a main outcome) and the Data Safety and Monitoring Board recommended that the study continue. Follow-up is planned to end on March 31, 2001.
Aged↗
Association between high von willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group.
BACKGROUND: A genetic susceptibility for diabetic kidney disease is suspected since diabetic nephropathy occurs in only 30 to 40% of type I diabetic patients. As elevated von Willebrand factor (vWF) plasma concentrations have been reported to precede the development of microalbuminuria in type I diabetes, we addressed a possible implication of vWF as a genetic determinant for diabetic nephropathy. METHODS: Three known vWF gene polymorphisms were genotyped in a group of 493 type I diabetic subjects, all showing proliferative retinopathy, but with various stages of renal involvement, which ranged from no microalbuminuria, despite a mean duration of diabetes of 31 years, to advanced nephropathy (GENEDIAB Study): Thr789Ala (Rsa I), M-/M+ (Msp I) (intron 19), and Ala1381Thr (Hph I). Plasma vWF and factor VIII (F VIII) levels were also measured in this population. RESULTS: Plasma vWF and F VIII levels were increased in diabetic subjects with nephropathy (P < 0.001) or with coronary heart disease (CHD; P < 0.001), but there was no interaction of both conditions on plasma levels. The Msp I polymorphism (M-/M+) was weakly associated with nephropathy (P = 0. 04), but this association was not more significant when other risk factors were used in a logistic regression analysis. The vWF Thr789Ala polymorphism was associated with CHD (P = 0.002) and with plasma vWF levels. Logistic regression analysis indicated an independent and codominant effect of the Thr789Ala polymorphism on CHD, but not on nephropathy, with a maximal risk for Ala/Ala homozygotes (OR = 4.2, 95% CI, 1.8 to 9.9, P = 0.0008). CONCLUSION: It is unlikely that polymorphisms in the vWF gene contribute to the risk for nephropathy in type I diabetic patients. However, the Thr789Ala polymorphism might affect the risk for CHD in this population through modulation of plasma vWF levels.
Adolescent↗
Lack of relationship in long-term type 1 diabetic patients between diabetic nephropathy and polymorphisms in apolipoprotein epsilon, lipoprotein lipase and cholesteryl ester transfer protein. Genétique de la Nephropathie Diabétique Study Group. Données Epidémiologiques sur le Syndrome d'Insulino-Résistance Study Group.
BACKGROUND: Genetic susceptibility contributes to the risk of diabetic nephropathy. Lipid disorders may favour diabetic nephropathy. Thus polymorphisms in lipid metabolism are candidates for the genetic component of risk for diabetic nephropathy. METHODS: We searched for a contribution of the genetic polymorphisms of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and apolipoprotein epsilon (Apo E) to the development of diabetic nephropathy by studying 494 type 1 diabetic patients with proliferative retinopathy and various stages of diabetic nephropathy (GENEDIAB Study). The selection process ensured that all patients had expressed their risk of chronic complications due to uncontrolled diabetes. Thus the nephropathy stages were largely influenced by genetic background. The lipid profile included fasting plasma total cholesterol (TC), triglycerides (TG), apolipoprotein A1 (Apo A1) and B (Apo B), and lipoprotein (a) (Lp(a)). Genetic polymorphisms were determined by PCR-based detection of Apo epsilon (e2/e3/e4), LPL (mutation Asn 291 Ser) and CETP (TAQ:IB B1/B2). RESULTS: One hundred and fifty-seven patients (32%) had no nephropathy, 104 (21%) incipient nephropathy, 126 (25%) established nephropathy and 107 (22%) advanced nephropathy. There was a significant relationship between the stages of diabetic nephropathy and TC (P=0.002), TG (P<0.0001), Apo B (P=0.0007) or Lp(a) (P=0. 038), but not Apo A1. However the genetic polymorphism distributions of LPL, CETP and Apo epsilon did not differ in terms of renal complications. The study power to reject the null hypothesis was 58% for the Apo epsilon genotypes. CONCLUSION: These results support no or only marginal effects of a genetic basis for lipid disturbances encountered in diabetic nephropathy.
Adult↗
Normal and abnormal day-to-day variability of urinary albumin excretion in control and diabetic subjects.
Urinary albumin excretion (UAE) is very variable from day to day. This variability, more or less potent, might by itself have a patho-physiological significance. We analyzed day-to-day UAE in 207 elderly (60-75 years) inpatients (134 with and 73 without diabetes mellitus) attending the department of internal medicine of the Angers University hospital. Twenty-four-hour urine was collected 3 times during a 5-10 day hospitalization period. One-hundred-fifty-one patients (73%) displayed normoalbuminuria (UAE<30 mg/24 h in 2 or 3 measures) while 56 patients (27%) had microalbuminuria (UAE within 30-300 mg/24 h in 2 or 3 measures). As the raw data of UAE was not normally distributed, we transformed UAE into the variable z=log (log (k + UAE)) where k is an integer and looked for a k value for which z might be normally distributed. We found that z was actually normally distributed for k=2. Mean value and coefficient of variation of z in the 3 measurements were used to define the level and the temporal intra-individual variability of UAE. Expressed in term of z, the day-to-day intra-individual variability of UAE showed a potent change (from large variability to small variability) at the particular level z=1.25, corresponding to UAE=30.8 mg/24 h. This value is precisely the level currently used to define microalbuminuria in diabetic subjects. It is remarkable that the day-to-day variability of UAE collapses when UAE crosses the level which has been used to define microalbuminuria.
Aged↗
Determinants of elevated urinary albumin in the 4,937 type 2 diabetic subjects recruited for the DIABHYCAR Study in Western Europe and North Africa.
OBJECTIVE: Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients. RESEARCH DESIGN AND METHODS: The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account. RESULTS: There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another. CONCLUSIONS: The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study.
Africa, Northern↗
Efficacy of diuretics and beta-blockers in diabetic hypertensive patients. Results from a meta-analysis. The INDANA Steering Committee.
OBJECTIVE: To review the effectiveness of diuretic or beta-blocker-based treatment of hypertension in diabetic patients. RESEARCH DESIGN AND METHODS: A meta-analysis on individual patient data was performed on four trials of the treatment of hypertension in which diabetic patients were included and treated with first-line diuretics or beta-blockers. The main outcomes were the relative risk of death, fatal or nonfatal stroke, fatal or nonfatal coronary events, and major cardiovascular events. RESULTS: There were 92 diabetic patients who received first-line beta-blockers and 1,008 who received diuretics. In the control groups, diabetic patients had nearly twice the risk of any outcome when compared with nondiabetic patients. The same blood pressure reduction was achieved under treatment in the diabetic and nondiabetic patients, except for systolic pressure, which decreased more in the nondiabetic patients at 1 year. In the 15,843 nondiabetic patients, the risk of all four outcomes was reduced significantly in the treated group. In the 2,254 diabetic patients, the risk reduction was significant only for fatal and nonfatal stroke (36%, P = 0.011) and major cardiovascular events (20%, P = 0.032), but not for death (5%, P = 0.65) and fatal or nonfatal coronary events (15%, P = 0.23). However, no heterogeneity was detected between diabetic patients and nondiabetic patients for any outcome. The numbers of outcomes avoided for 1,000 patients treated for 5 years were higher in diabetic patients (e.g., 38 major cardiovascular events) than with nondiabetic patients (e.g., 28 major cardiovascular events). CONCLUSIONS: These results show that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion can be drawn for beta-blockers, owing to the small sample size.
Adrenergic beta-Antagonists↗
Hereditary factors in the development of diabetic renal disease.
The role of genetics in diabetic renal disease has been suspected on the basis of follow-up and familial studies. Barely half of Type 1 patients who develop a diabetic retinopathy also develop nephropathy, and the relative risk of nephropathy for a diabetic proband is around 3 if a sib is affected. Candidate genes for diabetic nephropathy can be divided into two categories: those affecting glucose metabolism in target organs of diabetic microangiopathy, and those affecting renal changes in response to hyperglycaemia. The role of angiotensin-I-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been suspected for several years. Evidence of its possible role in the development and progression of diabetic renal disease is presented here.
Diabetes Mellitus, Type 1↗