In addition to von Willebrand factor and urinary albumin excretion, plasma endothelin is an indicator of endothelial dysfunction in diabetes mellitus

Diabetologia, May 1993

I. Vermes, C. D. A. Stehouwer

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In addition to von Willebrand factor and urinary albumin excretion, plasma endothelin is an indicator of endothelial dysfunction in diabetes mellitus

Environmentalinfluences on twins apparent at birth. A preliminarystudy. Biol Neonate 0 Dr. J. Tuomilehto Department of Epidemiology and Health Promotion National Public Health Institute EIimiienkatu25 A , 6th Floor SF-00510 Helsinki Finland 1 J Kaprio , J Tuomilehto, M Koskenvuo, K Romanov, A Reunanen, J Eriksson, J Stengfird, and YA Kes5niemi 2 Dr. D. I. W.Phillips Metabolic Programming Group MRC EnvironmentalEpidemiologyUnit Southampton General Hospital Tremona Road Southampton SO9 4XY UK R e s p o n s e f r o m t h e authors In addition to v o n Willebrand factor and urinary a l b u m i n e x c r e t i o n , p l a s m a e n d o t h e l i n is an indicator o f e n d o t h e l i a l d y s f u n c t i o n in diabetes m e l l i t u s Dear Sir, Stehouwer et al. [1] demonstrated the increased concentrations of yon Wiltebrand factor (vWF) in patients with Type 1 (insulin-dependent) diabetes mellitus independent of the presence or absence of retinopathy. Recently Stehouwer et al. [2] described in Type 2 (non-insulin-dependent) diabetes that an increase in urinary albumin excretion in patients with an increased baseline level of von Table 1. Immunoreactive endothelin (ETi) and von Willebrandfactor antigen (vWFi) blood concentrations in normal controI subjects and in diabetic patients with microvascular complications Group Control Microalbuminuria Macroalbuminuria Retinopathy Dear Sir, We thank Drs. Phillips, Hales and Barker for their comments on our paper [ 1 ].They suggest that fetal nutritionmay play a role in the aetiology of Type 2 (non-insulin-dependent)diabetes mellitus. They suggest that as monozygotic (MZ) twins have lower mean birthweight than dizygotic (DZ) twins, an increased concordance for Type 2 diabetes in MZ twins could be due to fetal and not genetic factors. In our study the rate of Type 2 diabetes in MZ twins was not significantlyincreased compared to DZ twins, and we are not aware of other population-based twin studies finding such differences. Because our data was derived from multiple medical registers, we cannot know at present the true prevalence of Type 2 diabetes in the twin population without testing all twins in the population. Phillips, Hales and Barker imply that a higher rate of low birthweight among MZ twins would result in greater concordance of Type2 diabetes. At birth, the pairwise correlation of weight (r = 0.62, 95 % CI 0.51-0.71) of MZ twins is no greater than that of like-sexed DZ pairs (r = 0.66, 95 % CI 0.53-0.76) or even opposite sex D Z pairs (r = 0.68, 95 % CI 0.53-0.79) according to the longitudinal data from the Louisville Twin Study [ 2 ]. Only after the age of 6 months is there higher concordance for weight in MZ pairs compared to DZ pairs [ 2 ]. In Aberdeen, Fraser and Nylander [ 3 ] found little evidence to substantiate the claim that the heavier twins will go on to grow taller than their lighter co-twins. They suggest that the birthweight of a twin is not on. its own an indicationof the quality of the prenatal environment,but has to be viewed in relation to that of its co-twin [ 3 ].Thus, the special prenatal environmentof twins would suggest that birthweights of twins cannot be compared directly to birthweights of singletons. Should an increased prevalence of Type 2 diabetes in MZ twins compared to DZ twins be observed, this may be due to many other factors than prenatal nutritional factors. MZ twins tend to have more contact with each other than D Z twins in adulthood [4], which may result in greater similarity for behaviour relevant to the aetiology of Type 2 diabetes, for example dietary habits or physical activity patterns. Also, as we have speculated elsewhere [5, 6] a higher prevalenceof disease in MZ pairs could be due to infectiousmechanisms. While we acknowledge the importance of the fetal period (maybe not only nutrition) for the development of various diseases, includingdiabetes, later in life, we would like to stress the strong influence of genetic factors in the aetiology of Type 2 diabetes. Without clustering of susceptibilitygenes there will be no familialclustering of diabetes. Before having a better understanding about the genetic susceptibility, it may be of little value to argue about the usefulness of different study designs in genetics of diabetes which all have their limitations. We believe that twin studies offer a good potential to sort out the unsolved questions related to genetic-environmental interaction in the development of Type 2 diabetes although the actual birth weights may be more difficult to interpret among twins than singletons. Sincerelyyours, J Kaprio, J Tuomilehto, M Koskenvuo, K Romanov, A Reunanen, J Eriksson, J Stengfird, and YA Kes5niemi 10 10 8 14 ap < 0.05 VScontrol group Results are mean + SD HbAlc (%) vWFi (%) ETi (pg/ml) 5.5 + 0.7 8.7 -+1,0 8.1 -+1.0 8.1 -+1.8 Willebrand factor during follow-up is associated with an increased risk of developing cardiovascular disease. We report here some observations about vWF endothelin levels in seven Type i and 25 Type 2 diabetic patients, which demonstrate that endothelin may be a more sensitiveindicator of endothelial damage than vWF in patients with diabetes. We measured in 10 control subjects and in 32 patients with diabetes under standardized conditions the urinary albumin excretion, HbAI~, and the plasma levels of vWF and endothelin. The patients are subdivided in three groups: A) 10 with microalbuminuria, B) 8 with macroalbuminuria,C) 14 with diabetic retinopathy, without nephropathy. Six patients in group A and one patient in group B had Type 1, the other 25 patients had Type 2 diabetes. Endothelin appeared significantlyelevated in group B patients with diabetic nephropathy. Other parameters such as HbAI0 and vWF were not significantly different between the three patient groups (Table 1). Although these data represent results in a small group of patients with no follow-up, we conclude that plasma endothelin should be taken into consideration as a sensitive indicator of endothelial damage in patients with diabetes. Yours sincerely, I. Vermes, R E M. J. Spooren, E. M. Kalsbeek-Batenburg and C. Haanen sensitive indicator of endothelial damage than yon Wiltebrand factor (vWF) - is very speculative at present. First, there is no gold standard for endothelial damage with which either vWF or endothelin can be compared; therefore, estimates of endothelial damage are by necessityindirect. Second, the levels ofvWF observed by Vermes et al. in patients with microalbuminuria are in fact similar to those we found, although we found lower levels in patients with normal albumin excretion [ 1 ]. Thus, the difference appears to be in the control group rather than the microalbuminuria group.As vWF levels may be influencedby the blood samplingprocedure, smoking habits, age, and the presence of atherosclerosis, there are many possible explanations for the difference between our data and those reported by Dr. Vermes. Finally, from the data presented by Dr. Verrues, it appears premature to conclude that plasma endothelin levels may be influencedby gender [ 2 ], atherosclerosis and renal function; in addition, it may be relevant to distinguish between Type i (insulin-dependent) and Type 2 (non-insulin-dependent)diabetes, as we found endothelin levels to be actually decreased in men with Type 1 diabetes and normal urinary albumin excretion when compared with age-matched healthy control subjects [ 3 ]. Such factors should be taken into account when analysingthe relationships between urinary albumin excretion and plasma endothelinlevels. Nevertheless, we agree that the role of endothelinin the microangiopathyof diabetes needs to be investigated. On behalf of the authors, Yours sincerely, C.D. A. Stehouwer Response from the Authors Dear Sir, We thank Dr. Vermes and colleagues for their interestingdata. However, we think that their contention-that endothelin may be a more Dr. C. D. A. Stehouwer Department of Internal Medicine Free UniversityHospital De Boelelaan 1117 NL-1081 HV Amsterdam The Netherlands 1. Stehouwer CDA , Nauta JJP , Zeldenrust GC , Hackeng WHL , Donker AJM , den Ottolander GJH ( 1992 ) Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependentdiabetes mellitus . Lancet 340 : 31 % 323 2. Polderman KH , Stehouwer CDA , van Kamp GJ , Dekker GA , Verheugt FWA , Gooren LJG ( 1993 ) Influence of sex hormones on plasma levels of endothelin . Arm Intern Med (in press) 3. Smulders RA , Stehouwer CDA , Olthof GC , van Kamp GJ , Donker AJM ( 1992 ) Plasma endothelin levels and vascular effects of L-arginine in type 1 (insulin-dependent) diabetes . Diabetologia 35 : [Suppl. 1] :A19 (Abstract)

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I. Vermes, C. D. A. Stehouwer. In addition to von Willebrand factor and urinary albumin excretion, plasma endothelin is an indicator of endothelial dysfunction in diabetes mellitus, Diabetologia, 1993, 472-473, DOI: 10.1007/BF00402288