Journal of Human Nutrition (1976) 30, 113-116
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Recent advances in the genetics of diabetes* A.G. CUDWORTH, MD, MRCP Lecturer in Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3BX.
PRIOR TO the discovery of insulin, the diagnosis of diabetes in a young person was a virtual death sentence, with the remaining weeks or months of survival a miserable existence on a near starvation diet. Today, not only can the young diabetic expect t o live a normal life, but also to marry and have children. An important question which is constantly being posed by these new generations of insulin-dependent diabetics is ‘What is the risk of my own children developing diabetes?’ Despite the fact that insulin became available more than half a century ago, we still know little concerning the basic mechanisms which underlie the aetiology of diabetes. In 1969 Morton described a family with four affected children and since then the familial tendency of the disease has been repeatedly emphasised indicating the existence of genetic determination. In the past 40 years studies of the familial aggregation of the disorder have led to just about every possible mode of inheritance being postulated at some time or another to explain the mode of genetic transmission. An important question is whether ‘diabetes’ should be regarded as a homogenous disorder, that is, basically a single disease with a complete spectrum of severity. It is unlikely that a disease as common as ‘diabetes’ can be due t o the effects of a single gene and the tendency in recent years has been to consider the condition as being under multifactorial control, that is the combined effect of perhaps several or many genes plus a host of different environmental factors. Thus, any new approach t o the study of the causation of diabetes should attempt to dissect the relative importance of these genetic and environmental factors. It is likely that there will be considerable variability in both genetic and environmental determination in different countries and in different ethnic groups. For example the high incidence of diabetes in the American Pima Indians (30-40 per cent) may suggest a strong genetic component, but their way of life and diet also probably play a significant part. *Based on a lecture given at a general meeting of The British Dietetic Association, a t Doncaster Royal Infirmary, 17 January 1976.
113
Table 1. Diabetes
- clinical heterogeneity
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
Juvenile-onset‘ or classical (JOD) Maturity-onset (MOD) Mild diabetes i n the young (MODY) or Insulin dependent (ID) Non-insulin dependent (NID)
‘Juvenile’ and ‘maturity’ onset diabetes Looking at the problem of susceptibility it is not unreasonable to use a working hypothesis that there are two polar forms of diabetes which appear on clinical grounds t o be quite distinct in terms of age of onset, abruptness of onset, dependence on insulin, and tendency t o ketosis. Thus, diabetes can be classified into ‘juvenile’ onset diabetes which predominantly occurs in children and adolescents and which, clinically is a quite different disease from ‘maturity’ onset diabetes that occurs later in life and is rarely insulin-dependent (Table 1). Perhaps from a biochemical stand point the differences are less apparent because the biochemical changes reflect the metabolic disturbances due to vaqing degrees of insulin insufficiency. The important question is: ‘Are the pathogenic factors involved in the production of this insulin-lack fundamentally different in these two different clinical types of dabetes?’ It is also well recognised that the classical ‘juvenile’ type can sometimes occur in later life, even in the elderly, and conversely mild maturity onset diabetes is occasionally seen in children, although the latter seems t o be rare. Possibly a simpler classification might be t o divide diabetes into insulin-dependent and insulin-independent types. Evidence for a probable different basis for these two major forms of diabetes has come from studies on identical twins (Tattersall 8c Pyke, 1972) and in certain families with ‘maturity’ onset diabetes in the young (Tattersall & Fajans, 1975). It is well established that concordance for diabetes (both twins diabetic) is greater in identical twins than among non-identical twins. Since identical twins are genetically identical and non-identical twins are like any pair of siblings, this provides evidence for an important genetic component in the susceptibility t o diabetes. However, even in identical twins with ‘juvenile’ onset diabetes (age of onset 40 years or less) concordance is only 50 per cent (i.e. in 50 per cent of pairs only one twin is diabetic) which led t o the concept that possibly environmental factors alone can often produce ‘juvenile’ diabetes. From more recent studies it seems likely that genetic susceptibility is involved in the development of ‘juvenile’ diabetes in both concordant and discordant identical twins, and whether the second twin develops diabetes or not is a chance environmental event. (Nelson et al, 1975). Pathogenesis of ‘juvenile’ onset diabetes In the past two years important new light on the possible pathogenesis of ‘juvenile’ diabetes has. come from two different lines of research indicating the possible co-dependent roles of specific genetic and environmental factors: (1) the evidence for a gene operating on the major histo-compatibility chromosome conferring genetic susceptibility t o this type of diabetes; (2) epidemiological evidence from the British Diabetic Association Register for newly diagnosed 114
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
diabetic children, providing further circumstantial evidence for virus infection as a possible important aetiological factor.
Histocompatibility The major histocompatibility (HLA) system in man is determined by multiple genes or alleles operating at two closely linked loci on chromosome 6. Each individual inherits a pair of alleles from each parent which are expressed as antigens on cell surface membranes. Thus, each person has four antigens which are in two pairs. The potential importance of this system has stemmed from extensive. research in the mouse in which it has been established that there are important genes in the major histocompatibility (H2) chromosomal region which control the specific immune responsiveness of the animal t o viruses and other exogenous agents. As a working hypothesis it would seem reasonable therefore t o extrapolate from mouse t o man and seek evidence forthe existence of genes with a similar role in the HLA chromosomal region (McDevitt SC Bodmer, 1974). In the Department of Medicine at the University of Liverpool, HLA typing has been performed on 200 cases of ‘juvenile’ diabetes with an age of onset of 30 years or less, all of whom were insulin dependent. A significant departure from the expected normal frequency of certain HLA antigens (HLA B8, BW15 and BW18) was observed and this population data provided suggestive evidence for the presence of a gene on the HLA chromosome producing susceptibility to this type of diabetes. No association was found between these or other antigens and 80 cases of maturity onset diabetes, but in a series of insulin-dependent diabetics with a later age of onset (30-80 yr), a significant positive association with HLA B8 was found. The significant association between ‘juvenile’ onset diabetes and the HLA system provides strong evidence for the existence of genetic heterogeneity in diabetes, and gives credence t o the concept that from a pathogenic point of view they are two different diseases. Most important of all, however, was the information derived from the family studies. In 15 families on hlerseyside, each containing a pair of diabetic siblings, 10 pairs possessed two identical HLA chromosomes, and in a further 4 pairs one HLA chromosome was identical. In one family, two diabetic brothers did not possess a common HLA chromosome. The probability of any two siblings in a family possessing one identical HLA chromosome is 0.5, but the probability of a pair of siblings having 2 identical HLA chromosomes is only 0.25. Thus in this series of families with pairs of diabetic brothers or sisters there is a marked disturbance of the expected probability for possessing one or both identical HLA chromosomes. These findings indicate that in order t o develop diabetes the affected brothers and/or sisters had t o inherit at least one identical HLA chromosome in common from one of their parents, and that susceptibility was particularly increased when two identical HLA chromosomes weie inherited suggesting that there may be a gene dosage effect (Cudworth & Woodrow, 1975). Thus the families provided conclusive evidence for the existence of an HLA-linked gene conferring the major genetic susceptibility t o ‘juvenile’ diabetes. A fundamental question is how does this HLA-linked diabetogenic gene exert its effect resulting in the destruction of the islet cells and the development of clinical diabetes? Does the interaction of H2-linked immune response genes 115
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
with viruses in the mouse provide any clues t o the possible causation of ‘juvenile’ diabetes in man? Virus infection Circumstantial evidence for virus infection being a possible cause of ‘juvenilei diabetes has been accumulating for some time. There have been a number of reports of cases following mumps and other virus infections (Steinke & Taylor, 1974). Injecting certain strains of a particular virus into mice has been shown to produce destruction of the beta cells and the development of diabetes (Craighead & McLane, 1968) but direct evidence of this nature for viral mediated islet cell damage in man is lacking. In 1972 the British Diabetic Associaiion, under the Chairmanship of Dr. Arnold Bloom, started a register for newly diagnosed diabetic children under the age of 16 years. All physicians and paediatricians in Great Britain were regularly circularised. Over 2500 newly diagnosed cases were notified in the first two complete years which indicates an incidence of approximately 8 per 100000 children per year. Some interesting variations have come to light between urban and country areas, but most striking is the bimodal age of onset with peaks at 5 and 11 years of age, and the marked seasonal variation with twice as many cases occurring in the winter as in the summer which was replicated in each year (Bloom, Hayes & Gamble, 1975). These findings could be compatible with a virus aetiology. For example the peaks in age of onset fit in well with the times that children start school and change school and thus may be exposed to a new background of viruses or different stresses. Conclusion There is now good evidence for t he existence of an important gene on the HLA chromosome which confers genetic susceptibility t o ‘juvenile’ onset diabetes. The circumstantial evidence for virus infection as an important environmental aetiological factor continues t o grow but as yet no specific single virus capable of inducing islet cell destruction has been identified in man. A unifying hypothesis is that the environmental agent (probably a virus or different viruses) acts as the ‘trigger’ to produce this type of diabetes only in those children who are genetically susceptible, by interacting with the HLA linked diabetogenic gene resulting in a defective or abnormal immune response to the virus. It is perhaps premature t o speculate, but if it is possible t o identify the child who is genetically susceptible, not only in families but also in the general population, and also to identify the environmental agent(s), then possibly methods will be found which will lead t o prevention. REFERENCES Bloom, A., Hayes, T.M. & Gamble, D.R. (1975): Brit. Med. J. 3, 580. Craighead, J.E. & McLane, M.F. (1968): Science 1 6 2 , 9 1 3 . Cudworth, A.G. & Woodrow, J.C. (1975): Brit. Med. J. 3, 133. McDevitt, H.O. & Bodmer, W.F. (1974): Lancet, 1 , 1269. Nelson, P.G., Pyke, D.A., Cudworth, A.G., Woodrow, J.C. & Batchelor, J.A. (1975): Lancet 2, 193. Steinke, J . &Taylor, K.W. (1974): Diabetes 23, 631. Tattersal1,”R.B. & Fajans, S.S. (1975): Diabetes 24, 44. Tattersal1,~R.B.& Pyke, D.A. (1972): Lancet 2, 1120. 116
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
Recent advances in the genetics of diabetes* A.G. CUDWORTH, MD, MRCP Lecturer in Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3BX.
PRIOR TO the discovery of insulin, the diagnosis of diabetes in a young person was a virtual death sentence, with the remaining weeks or months of survival a miserable existence on a near starvation diet. Today, not only can the young diabetic expect t o live a normal life, but also to marry and have children. An important question which is constantly being posed by these new generations of insulin-dependent diabetics is ‘What is the risk of my own children developing diabetes?’ Despite the fact that insulin became available more than half a century ago, we still know little concerning the basic mechanisms which underlie the aetiology of diabetes. In 1969 Morton described a family with four affected children and since then the familial tendency of the disease has been repeatedly emphasised indicating the existence of genetic determination. In the past 40 years studies of the familial aggregation of the disorder have led to just about every possible mode of inheritance being postulated at some time or another to explain the mode of genetic transmission. An important question is whether ‘diabetes’ should be regarded as a homogenous disorder, that is, basically a single disease with a complete spectrum of severity. It is unlikely that a disease as common as ‘diabetes’ can be due t o the effects of a single gene and the tendency in recent years has been to consider the condition as being under multifactorial control, that is the combined effect of perhaps several or many genes plus a host of different environmental factors. Thus, any new approach t o the study of the causation of diabetes should attempt to dissect the relative importance of these genetic and environmental factors. It is likely that there will be considerable variability in both genetic and environmental determination in different countries and in different ethnic groups. For example the high incidence of diabetes in the American Pima Indians (30-40 per cent) may suggest a strong genetic component, but their way of life and diet also probably play a significant part. *Based on a lecture given at a general meeting of The British Dietetic Association, a t Doncaster Royal Infirmary, 17 January 1976.
113
Table 1. Diabetes
- clinical heterogeneity
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
Juvenile-onset‘ or classical (JOD) Maturity-onset (MOD) Mild diabetes i n the young (MODY) or Insulin dependent (ID) Non-insulin dependent (NID)
‘Juvenile’ and ‘maturity’ onset diabetes Looking at the problem of susceptibility it is not unreasonable to use a working hypothesis that there are two polar forms of diabetes which appear on clinical grounds t o be quite distinct in terms of age of onset, abruptness of onset, dependence on insulin, and tendency t o ketosis. Thus, diabetes can be classified into ‘juvenile’ onset diabetes which predominantly occurs in children and adolescents and which, clinically is a quite different disease from ‘maturity’ onset diabetes that occurs later in life and is rarely insulin-dependent (Table 1). Perhaps from a biochemical stand point the differences are less apparent because the biochemical changes reflect the metabolic disturbances due to vaqing degrees of insulin insufficiency. The important question is: ‘Are the pathogenic factors involved in the production of this insulin-lack fundamentally different in these two different clinical types of dabetes?’ It is also well recognised that the classical ‘juvenile’ type can sometimes occur in later life, even in the elderly, and conversely mild maturity onset diabetes is occasionally seen in children, although the latter seems t o be rare. Possibly a simpler classification might be t o divide diabetes into insulin-dependent and insulin-independent types. Evidence for a probable different basis for these two major forms of diabetes has come from studies on identical twins (Tattersall 8c Pyke, 1972) and in certain families with ‘maturity’ onset diabetes in the young (Tattersall & Fajans, 1975). It is well established that concordance for diabetes (both twins diabetic) is greater in identical twins than among non-identical twins. Since identical twins are genetically identical and non-identical twins are like any pair of siblings, this provides evidence for an important genetic component in the susceptibility t o diabetes. However, even in identical twins with ‘juvenile’ onset diabetes (age of onset 40 years or less) concordance is only 50 per cent (i.e. in 50 per cent of pairs only one twin is diabetic) which led t o the concept that possibly environmental factors alone can often produce ‘juvenile’ diabetes. From more recent studies it seems likely that genetic susceptibility is involved in the development of ‘juvenile’ diabetes in both concordant and discordant identical twins, and whether the second twin develops diabetes or not is a chance environmental event. (Nelson et al, 1975). Pathogenesis of ‘juvenile’ onset diabetes In the past two years important new light on the possible pathogenesis of ‘juvenile’ diabetes has. come from two different lines of research indicating the possible co-dependent roles of specific genetic and environmental factors: (1) the evidence for a gene operating on the major histo-compatibility chromosome conferring genetic susceptibility t o this type of diabetes; (2) epidemiological evidence from the British Diabetic Association Register for newly diagnosed 114
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
diabetic children, providing further circumstantial evidence for virus infection as a possible important aetiological factor.
Histocompatibility The major histocompatibility (HLA) system in man is determined by multiple genes or alleles operating at two closely linked loci on chromosome 6. Each individual inherits a pair of alleles from each parent which are expressed as antigens on cell surface membranes. Thus, each person has four antigens which are in two pairs. The potential importance of this system has stemmed from extensive. research in the mouse in which it has been established that there are important genes in the major histocompatibility (H2) chromosomal region which control the specific immune responsiveness of the animal t o viruses and other exogenous agents. As a working hypothesis it would seem reasonable therefore t o extrapolate from mouse t o man and seek evidence forthe existence of genes with a similar role in the HLA chromosomal region (McDevitt SC Bodmer, 1974). In the Department of Medicine at the University of Liverpool, HLA typing has been performed on 200 cases of ‘juvenile’ diabetes with an age of onset of 30 years or less, all of whom were insulin dependent. A significant departure from the expected normal frequency of certain HLA antigens (HLA B8, BW15 and BW18) was observed and this population data provided suggestive evidence for the presence of a gene on the HLA chromosome producing susceptibility to this type of diabetes. No association was found between these or other antigens and 80 cases of maturity onset diabetes, but in a series of insulin-dependent diabetics with a later age of onset (30-80 yr), a significant positive association with HLA B8 was found. The significant association between ‘juvenile’ onset diabetes and the HLA system provides strong evidence for the existence of genetic heterogeneity in diabetes, and gives credence t o the concept that from a pathogenic point of view they are two different diseases. Most important of all, however, was the information derived from the family studies. In 15 families on hlerseyside, each containing a pair of diabetic siblings, 10 pairs possessed two identical HLA chromosomes, and in a further 4 pairs one HLA chromosome was identical. In one family, two diabetic brothers did not possess a common HLA chromosome. The probability of any two siblings in a family possessing one identical HLA chromosome is 0.5, but the probability of a pair of siblings having 2 identical HLA chromosomes is only 0.25. Thus in this series of families with pairs of diabetic brothers or sisters there is a marked disturbance of the expected probability for possessing one or both identical HLA chromosomes. These findings indicate that in order t o develop diabetes the affected brothers and/or sisters had t o inherit at least one identical HLA chromosome in common from one of their parents, and that susceptibility was particularly increased when two identical HLA chromosomes weie inherited suggesting that there may be a gene dosage effect (Cudworth & Woodrow, 1975). Thus the families provided conclusive evidence for the existence of an HLA-linked gene conferring the major genetic susceptibility t o ‘juvenile’ diabetes. A fundamental question is how does this HLA-linked diabetogenic gene exert its effect resulting in the destruction of the islet cells and the development of clinical diabetes? Does the interaction of H2-linked immune response genes 115
Int J Food Sci Nutr Downloaded from informahealthcare.com by Nyu Medical Center on 12/14/14 For personal use only.
with viruses in the mouse provide any clues t o the possible causation of ‘juvenile’ diabetes in man? Virus infection Circumstantial evidence for virus infection being a possible cause of ‘juvenilei diabetes has been accumulating for some time. There have been a number of reports of cases following mumps and other virus infections (Steinke & Taylor, 1974). Injecting certain strains of a particular virus into mice has been shown to produce destruction of the beta cells and the development of diabetes (Craighead & McLane, 1968) but direct evidence of this nature for viral mediated islet cell damage in man is lacking. In 1972 the British Diabetic Associaiion, under the Chairmanship of Dr. Arnold Bloom, started a register for newly diagnosed diabetic children under the age of 16 years. All physicians and paediatricians in Great Britain were regularly circularised. Over 2500 newly diagnosed cases were notified in the first two complete years which indicates an incidence of approximately 8 per 100000 children per year. Some interesting variations have come to light between urban and country areas, but most striking is the bimodal age of onset with peaks at 5 and 11 years of age, and the marked seasonal variation with twice as many cases occurring in the winter as in the summer which was replicated in each year (Bloom, Hayes & Gamble, 1975). These findings could be compatible with a virus aetiology. For example the peaks in age of onset fit in well with the times that children start school and change school and thus may be exposed to a new background of viruses or different stresses. Conclusion There is now good evidence for t he existence of an important gene on the HLA chromosome which confers genetic susceptibility t o ‘juvenile’ onset diabetes. The circumstantial evidence for virus infection as an important environmental aetiological factor continues t o grow but as yet no specific single virus capable of inducing islet cell destruction has been identified in man. A unifying hypothesis is that the environmental agent (probably a virus or different viruses) acts as the ‘trigger’ to produce this type of diabetes only in those children who are genetically susceptible, by interacting with the HLA linked diabetogenic gene resulting in a defective or abnormal immune response to the virus. It is perhaps premature t o speculate, but if it is possible t o identify the child who is genetically susceptible, not only in families but also in the general population, and also to identify the environmental agent(s), then possibly methods will be found which will lead t o prevention. REFERENCES Bloom, A., Hayes, T.M. & Gamble, D.R. (1975): Brit. Med. J. 3, 580. Craighead, J.E. & McLane, M.F. (1968): Science 1 6 2 , 9 1 3 . Cudworth, A.G. & Woodrow, J.C. (1975): Brit. Med. J. 3, 133. McDevitt, H.O. & Bodmer, W.F. (1974): Lancet, 1 , 1269. Nelson, P.G., Pyke, D.A., Cudworth, A.G., Woodrow, J.C. & Batchelor, J.A. (1975): Lancet 2, 193. Steinke, J . &Taylor, K.W. (1974): Diabetes 23, 631. Tattersal1,”R.B. & Fajans, S.S. (1975): Diabetes 24, 44. Tattersal1,~R.B.& Pyke, D.A. (1972): Lancet 2, 1120. 116
