SHALOM

Diabetes Mellitus is a disease caused by an insufficiency of insulin secretion or activity There are several types of diabetes mellitus (DM) . Type I DM – caused by an autoimmune process which progressively destroys the insulin producing beta cells in the pancreas. Type II DM, which is a form of insulin resistance, mostly accompanied by obesity, Gestational DM-appearing during pregnancies as Type II DM and a variety of less frequent genetic diseases, affecting either insulin secretion or action. Also Type I and Type II are linked to certain genes which make individuals predisposed or protected to develop these diseases some time during life time. Following is a review on childhood diabetes which is almost in all countries (US exepted) of the autoimmune type (i.e. Type I) with emphasis on the Israeli contributions. Until the first half of the last century, when children and adolescents were treated by general diabetologists, no registers were available. Starting in the 1960 ies when due to the founding of the International Beilinson Symposium in Israel by Zvi Laron, pediatricians caring for children with diabetes from all over the world gathered and discussed the needs to learn more about this disease, in order to improve the care of children with DM. National or regional registers were established and the International Society for Pediatric and Adolescent Diabetes founded , headed by the Committee of H.Lestradet (Paris) A. Loeb (Brussels) and Zvi Laron (Petah Tikva/Tel Aviv) Thus the Institue of Pediatric and adolescent Endocrinology at the Beilinson Hospital (since 1991 part of the Schneider Children’s Medical Center) became one of the leading Centers for Research and Care for children with diabetes. Other important centers developed in Pittsburgh and Helsinki. The whole country registry in Israel conducted by Laron’s group, revealed a great increase in incidence between the years 1965-1993 (Fig 1) A surprising finding was, that when comparing the incidence between the various ethnic groups , the highest incidence was found among the Yemenite Jews, the lowest in the Israeli Arabs. Similar findings of an increasing incidence were also found in other countries; high incidence being registered in Finland and Scandinavia in general and Sardinia. As genetical factors did not change much, it was concluded that the increase in incidence must be due to environmental factors. Clinical and laboratory observations have shown that with the exception of infants, type I DM is a progressive disease (Fig.2). The autoimmune disease once triggered, starts a destructive process which can at time be monitored by measuring anti islet antibodies (ICA) Once 70-80% of the pancreatic islet cells have been destroyed, the clinical symptoms (weight loss, polymia, polydipsia ) appear during metabolic decompensation, resulting in high blood glucose. If untreated, keto-acidosis (acidity of the blood due to burning of the body fat) and even coma, (loss of conciousness and even death ) will occur. Accepting the hypothesis that environmental factors evolving from urbanization and lifestyle change during the latter half of last century, are the cause of the fast increase in incidence of DM . The question is, which are those factors. Are these chemical toxins in pollutions, certain foods (cow’s milk) food additives or infectious agents? There are evidences pointing towards a viral origin of Type I DM. Since 1972 it is known that the clinical onset of disease occurs more often in autumn and winter during virus epidemics, that is the last hit (trigger) caused by a viral infection. The question is, is the first hit, starting the autoimmune process virus induced? Evidence for this was the appearance of diabetes in children after a rubella epidemic in the USA, as well as rare findings of viruses (CMV (cytomegalic viruses or coxackie B4) in pancreatic beta cells in children who died of acute diabetes. The question what initiates Type I DM is crucial to developing prevention trials . Analyzing the cohort of 1865 children with Type I DM in Israel, we made the observation that in contradistinction to the seasonality of clinical onset, which occurs more in autumn and winter, the birth of children who subsequently develop DM occurs more in spring and summer (Fig3) providing a mirror image to the onset of disease. These data are interpreted, that pregnant mothers transmit pathogenic viruses to the fetus during autumn or winter, initiating the autoimmune process and children, who will be born mainly in spring or summer who are genetically susceptible will subsequently sooner or later develop the disease, depending on the number of subsequent damages. To ascertain that our observation is valid, we performed epidemiological surveys in other countries, first Europe (Sardinia with a high incidence of Type I DM, South Germany, Berlin,Slovenia, Belgium, Ireland with similar findings. Next we checked the Southern Hemisphere - New Zealand, and found the same. In population with low incidence of Type I DM, there was no different seasonality of month of birth from that of the general population. (Cuba,China Japan) In regions with a mixed population of high and low incidence (USA, Sydney) the results were statistically non significant. Studies performed in Sweden and Finland prove that viruses can cross the placenta to the fetus, and saving blood samples from mothers after delivery and the newborn, it was shown that mothers of children who subsequently developed Type I DM had more antivirus antibodies than mothers whose children did not develop the disease. In a recent multicenter study including also our group, which analyzed the blood of pregnant women in their 20th week of gestation in the winter months, the Finnish virologists were able to show an inverse relationship between the incidence of Type I DM and enterovirus infections in the background population. This data is interpreted that infected mothers can also transmit antiviral antibodies to the fetus, who may become protected against the infection agent. 3/…. Israel is a small country with various ethnic groups with both high incidence of Type I DM (Yemenite Jews) medium incidence (Ashkenazi Jews) and low incidence (Israeli Arabs) is an ideal country to further the study on the primary cause of Type I DM, to find out which conditions predispose towards protection against Type I DM (number of pre-pregnancy infections) and which environmental factors (repeated infections , nutritional factors, toxins such as fertilizer, water nitrites etc) are later triggers after the autoimmune process has been started. Getting answers may lead to ways of primary prevention of this life long disease in which even the improved therapeutic means developed in recent years are unable to stop the chronic debilitating complications and earlier deaths. The trials of secondary prevention in Europe (Nicotinamide, heat shock peptide analog) and in the USA (insulin) have failed. In the meantime the incidence increases and affects more younger children. Research towards a primary prevention (vaccination?) early immune intervention? and identification of the major environmental factors have become a public health necessity. Among those trying to find the answer is the Endocrinology & Diabetes Research Unit headed by Professor ZVI LARON at the Schneider Children’s Medical Centre. Only lack of research funds impedes the progress.