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Stemming the tide of diabetes mellitus
COMMENTARY
COMMENTARY
Stemming the tide of diabetes mellitus The epidemic of type 2 diabetes mellitus is particularly evident among people who have undergone rapid acculturation from a traditional lifestyle to a way of life characterised by a high intake of energy-dense foods (rich in fats and sugar) and by a low level of physical activity. Even among people who are not appreciably overweight—ie, whose body-mass index (BMI) is less than 25 kg/m2—the prevalence is much higher among Australian aboriginals (10 per 1000 person-years) than among those of European descent (fewer than 3 per 1000 person-years among Europeans and North Americans).1,2 In view of the cost, in terms of disability, premature mortality, and consumption of health-care resources, attempts to reverse the increasing rates of type 2 diabetes are clearly major public-health priorities in developing as well as affluent societies. Excess adiposity, especially when it is centrally distributed, lack of physical activity, and a high intake of foods with a high glycaemic index or a high proportion of total and saturated fatty acids have been identified as potentially modifiable risk factors for the development of type 2 diabetes or the progression from impaired glucose tolerance (IGT) to diabetes. Carefully controlled, shortterm studies have shown that modification of these factors can improve glycaemic control and favourably influence cardiovascular risk factors in those with IGT or type 2 diabetes.3 Furthermore, a substantial improvement in carbohydrate and lipid metabolism was noted among Australian-Aboriginal people with diabetes after they had reverted to their traditional lifestyle for 7 weeks.4 However, clinical-trial data about the extent to which such lifestyle changes can influence the progression of IGT to diabetes are sparse. The Da Qing IGT and Diabetes Study5 reported statistically significant differences in progression rates between intervention (intensive diet and exercise) and control groups, but even in the intervention group nearly 50% with IGT progressed to diabetes over a 6-year follow-up. Other trials among individuals with IGT have reported encouraging interim results.6,7 Two observations suggest that an approach aimed at high-risk individuals who have already developed IGT is unlikely to be sufficient to stem the tide of the epidemic of diabetes. First, by the time IGT has developed, -cell function is already impaired.8 Thus, intervention at this stage may be too late to “prevent” most cases of type 2 diabetes. Second, even intensive intervention programmes using well-developed behaviour-modification approaches seem to produce high relapse rates, with weight gain and an increase in blood glucose after an initially encouraging response.9,10 What then are the chances of success for primary prevention with attempts to modify risk factors in a population? At first glance, the answer seems to be “not 1454
good”. Central adiposity is the strongest risk factor, yet, despite a growing awareness of the risks associated with obesity, the proportion of obese individuals is increasing in virtually all countries for which relevant statistics are available. In the light of these rather pessimistic observations, the study by Kevin Rowley and colleagues11 provides some encouragement. Community-based screening for diabetes of adult volunteers was carried out in 1988 among a group of Aboriginal people in central Australia before the introduction of a health-promotion intervention programme. The intervention consisted of informing community leaders, health workers, and community groups of the benefits of physical activity and appropriate eating practices, including advice to hunt for traditional foods rather than to rely on storebought foods. Informal education was also provided by clinicians as part of their routine practice. About 90% of the community participated in the initial screening and most had another assessment in 1995. Frequency of IGT was halved at the 7-year follow-up (in men from 12·2 to 6·5%; in women from 22·5 to 10·1%), although the prevalence of diabetes remained unchanged and the average BMI increased from 22·8 to 24·2 kg/m2. Weight gain was greater among those living close to a store than among those in more remote locations. The prevalence of hypercholesterolaemia also decreased. The value of IGT as a criterion for successful intervention is controversial, principally because of the poor reproducibility of the diagnosis on glucose-tolerance testing.12 However, the decrease in both the fasting glucose and 2 h postload glucose concentration suggests that these results may well be clinically meaningful. Failure to show a reduction in the prevalence of diabetes is consistent with the observation that progressive decrease in -cell function starts early in the disease. The decrease in the frequency of IGT was probably due to fewer people with insulin resistance progressing to IGT. Although supportive evidence is not available from this study, the assumption is that increased physical activity and qualitative changes in the diet have produced this result. That it has occurred despite increasing prevalence of obesity provides at least a glimmer of hope that increased physical activity and dietary modification may help to reduce the steady increase in rates of diabetes. It seems to be rather easier to persuade populations to reduce fat intakes than to reduce obesity rates.13 There is probably general agreement that the latter is likely to be essential to achieving more substantial reductions in prevalence of diabetes. The results of other community programmes involving different approaches are eagerly awaited. Macauley and co-workers14 have reported a high level of awareness and participation in a programme incorporating native culture and community expertise in a Mohawk community near
THE LANCET • Vol 356 • October 28, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Montreal, Canada. Similar studies are underway in other high-risk Native-American populations. There can be few greater research needs than the development of effective validated interventions aimed at reducing the devastating effects of diabetes and its complications on many populations worldwide. Approaches aimed at high-risk individuals should almost certainly be started in those with insulin resistance before IGT has developed. However, community-based primaryprevention programmes aiming to reduce obesity rates by modifying clearly identified risk factors will be essential in order to stem the tide of the epidemic of diabetes. Jim Mann Departments of Human Nutrition and Medicine, University of Otago, Dunedin, New Zealand 1
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Daniel M, Rowley KG, McDermott R, Mylvaganam A, O’Dea K. Diabetes incidence in an Australian aboriginal population: an 8-year follow-up study. Diabetes Care 1999; 22: 1993–98. Colditz GA, Willett WC, Stampfer MJ, et al. Weight as a risk factor for clinical diabetes in women. Am J Epidemiol 1990; 132: 501–13. Recommendations for the nutritional management of patients with diabetes mellitus. Eur J Clin Nutr 2000; 54: 353–55. O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–44. Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia 1999; 42: 793–801. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999; 22: 623–34. Ferrannini E. Insulin resistance is central to the burden of diabetes. Diabetes Metab Rev 1997; 13: 81–86. Wing RR, Venditti E, Jakicic JM, Polley BA, Lang W. Lifestyle intervention in overweight individuals with a family history of diabetes. Diabetes Care 1998; 21: 350–59. Bourn DM. The potential for lifestyle change to influence the progression of impaired glucose tolerance to non-insulin-dependent diabetes mellitus. Diabet Med 1996; 13: 938–45. Rowley KG, Gault A, McDermott R, Knight S, McLeay T, O’Dea K. Reduced prevalence of impaired glucose tolerance and no change in prevalence of diabetes despite increasing BMI among Aboriginal people from a group of remote homeland communities. Diabetes Care 2000; 23: 898–904. Yudkin JS, Alberti KG, McLarty DG, Swai AB. Impaired glucose tolerance. BMJ 1990; 301: 397–402. Russell D, Parnell W, Wilson N and the principal investigators of the 1997 National Nutrition Survey. NZ Food: NZ People: Key results of the 1997 National Nutrition Survey. LINZ Activity and Health Research Unit, University of Otago for the Ministry of Health, 1999. Macaulay AC, Paradis G, Potvin L, et al. The Kahnawake Schools Diabetes Prevention Project: intervention, evaluation, and baseline results of a diabetes primary prevention program with a native community in Canada. Prev Med 1997; 26: 779–90.
Conundrum of the hereditary component of testicular cancer No reason has been found for the tenfold increase in incidence of testicular cancer in industrialised countries during the twentieth century1 beyond the bland notion that there is very likely to be an environmental cause. It is ironic therefore that the largest case-control study, done at the end of that century, should show that the greatest risk factor for testicular cancer was hereditary.2,3 Several statistically significant environmental factors were also found—testicular maldescent (as usual), early onset of puberty, increased sexual activity, sedentary lifestyle, reduced exercise, and being a first-born child—but these
THE LANCET • Vol 356 • October 28, 2000
effects were small. However, patients with testicular cancer were four times more likely than controls to have a father, and eight times more likely to have a brother, with the same cancer.2 Elsewhere these risks were found to be 4 and 10, respectively.4 These levels of risk are much higher than in almost all other cancer types, most notably breast cancer, for which a familial pattern of disease has gained so much attention. The concept of testicular cancer arising, albeit as a result of environmental influences, in a genetically predisposed population finds resonance with observations on the distribution of this cancer between racial communities of the same nationality. In the USA whites have a very much higher incidence than non-white races. The offspring of western immigrants in Israel retain their high incidence.5 The low incidence in Italy is seen also in Italian migrants in other countries.6 This retention of racial susceptibility contrasts sharply with the situation with breast, stomach, colon, and ovarian cancers, for which the incidence in immigrant populations tends rapidly towards that of the host population. Familial testicular cancer is not common (present in 1·0–2·8% of cases of the cancer)7 and rarely does a family have more than two members with the disease. This rarity has caused much frustration in the search for a gene for testicular cancer. The International Testicular Cancer Linkage Consortium, working with up to 137 testicular-cancer families, has conducted a genome-wide search without hitherto discovering any significant genetic linkages.8,9 Now comes a positive report. Markers on the X chromosome produced faintly positive lod scores. (Father-son pairs and other families in which Xlinkage was impossible were excluded from this analysis.) When only the 15 families that contained one individual with bilateral testicular cancer were considered, every one of the families was linked at Xq27. A positive association was also found in families with a history of testicular maldescent.10 It was estimated that about 20% of all the testicular-cancer families could be carrying a gene at this site, so there will be other testis-cancer genes to find. The finding is intriguing for several reasons. The presence of a cancer-susceptibility gene on a non-paired chromosome will puzzle people familiar with the tumoursuppressor-gene model of inherited cancer—a mutated gene is inherited and carried on every cell, cancer being initiated when the allele in a single cell undergoes a “somatic” mutation. Yet the X chromosome has also recently been found to be the site of a predisposing gene in familial prostate cancer.11 Clearly the model is incomplete. In the case of testicular cancer, a predisposing gene on the X chromosome provides an explanation for the higher risk to brothers of cases than to fathers and sons. Could it also account for some non-malignant features? There is an association between cryptorchidism, hypospadias, infertility, and testicular cancer, which form an “epidemiological syndrome”, since only rarely are more than two of these disorders present in the same individual.12,13 And what effects would an X-linked gene have on female carriers who occasionally could be homozygous for it? But it is the fact that bilateral testicular cancer comprises as many as 5% of cases of testicular cancer14 that gives the result its importance. Could the great majority of these bilateral cases carry this gene? It seems plausible. Bilateral cancers in paired organs—the breast, the kidney, the retina—have proved to be markers of hereditary cancer. However, where are the affected 1455
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Stemming the tide of diabetes mellitus The epidemic of type 2 diabetes mellitus is particularly evident among people who have undergone rapid acculturation from a traditional lifestyle to a way of life characterised by a high intake of energy-dense foods (rich in fats and sugar) and by a low level of physical activity. Even among people who are not appreciably overweight—ie, whose body-mass index (BMI) is less than 25 kg/m2—the prevalence is much higher among Australian aboriginals (10 per 1000 person-years) than among those of European descent (fewer than 3 per 1000 person-years among Europeans and North Americans).1,2 In view of the cost, in terms of disability, premature mortality, and consumption of health-care resources, attempts to reverse the increasing rates of type 2 diabetes are clearly major public-health priorities in developing as well as affluent societies. Excess adiposity, especially when it is centrally distributed, lack of physical activity, and a high intake of foods with a high glycaemic index or a high proportion of total and saturated fatty acids have been identified as potentially modifiable risk factors for the development of type 2 diabetes or the progression from impaired glucose tolerance (IGT) to diabetes. Carefully controlled, shortterm studies have shown that modification of these factors can improve glycaemic control and favourably influence cardiovascular risk factors in those with IGT or type 2 diabetes.3 Furthermore, a substantial improvement in carbohydrate and lipid metabolism was noted among Australian-Aboriginal people with diabetes after they had reverted to their traditional lifestyle for 7 weeks.4 However, clinical-trial data about the extent to which such lifestyle changes can influence the progression of IGT to diabetes are sparse. The Da Qing IGT and Diabetes Study5 reported statistically significant differences in progression rates between intervention (intensive diet and exercise) and control groups, but even in the intervention group nearly 50% with IGT progressed to diabetes over a 6-year follow-up. Other trials among individuals with IGT have reported encouraging interim results.6,7 Two observations suggest that an approach aimed at high-risk individuals who have already developed IGT is unlikely to be sufficient to stem the tide of the epidemic of diabetes. First, by the time IGT has developed, -cell function is already impaired.8 Thus, intervention at this stage may be too late to “prevent” most cases of type 2 diabetes. Second, even intensive intervention programmes using well-developed behaviour-modification approaches seem to produce high relapse rates, with weight gain and an increase in blood glucose after an initially encouraging response.9,10 What then are the chances of success for primary prevention with attempts to modify risk factors in a population? At first glance, the answer seems to be “not 1454
good”. Central adiposity is the strongest risk factor, yet, despite a growing awareness of the risks associated with obesity, the proportion of obese individuals is increasing in virtually all countries for which relevant statistics are available. In the light of these rather pessimistic observations, the study by Kevin Rowley and colleagues11 provides some encouragement. Community-based screening for diabetes of adult volunteers was carried out in 1988 among a group of Aboriginal people in central Australia before the introduction of a health-promotion intervention programme. The intervention consisted of informing community leaders, health workers, and community groups of the benefits of physical activity and appropriate eating practices, including advice to hunt for traditional foods rather than to rely on storebought foods. Informal education was also provided by clinicians as part of their routine practice. About 90% of the community participated in the initial screening and most had another assessment in 1995. Frequency of IGT was halved at the 7-year follow-up (in men from 12·2 to 6·5%; in women from 22·5 to 10·1%), although the prevalence of diabetes remained unchanged and the average BMI increased from 22·8 to 24·2 kg/m2. Weight gain was greater among those living close to a store than among those in more remote locations. The prevalence of hypercholesterolaemia also decreased. The value of IGT as a criterion for successful intervention is controversial, principally because of the poor reproducibility of the diagnosis on glucose-tolerance testing.12 However, the decrease in both the fasting glucose and 2 h postload glucose concentration suggests that these results may well be clinically meaningful. Failure to show a reduction in the prevalence of diabetes is consistent with the observation that progressive decrease in -cell function starts early in the disease. The decrease in the frequency of IGT was probably due to fewer people with insulin resistance progressing to IGT. Although supportive evidence is not available from this study, the assumption is that increased physical activity and qualitative changes in the diet have produced this result. That it has occurred despite increasing prevalence of obesity provides at least a glimmer of hope that increased physical activity and dietary modification may help to reduce the steady increase in rates of diabetes. It seems to be rather easier to persuade populations to reduce fat intakes than to reduce obesity rates.13 There is probably general agreement that the latter is likely to be essential to achieving more substantial reductions in prevalence of diabetes. The results of other community programmes involving different approaches are eagerly awaited. Macauley and co-workers14 have reported a high level of awareness and participation in a programme incorporating native culture and community expertise in a Mohawk community near
THE LANCET • Vol 356 • October 28, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Montreal, Canada. Similar studies are underway in other high-risk Native-American populations. There can be few greater research needs than the development of effective validated interventions aimed at reducing the devastating effects of diabetes and its complications on many populations worldwide. Approaches aimed at high-risk individuals should almost certainly be started in those with insulin resistance before IGT has developed. However, community-based primaryprevention programmes aiming to reduce obesity rates by modifying clearly identified risk factors will be essential in order to stem the tide of the epidemic of diabetes. Jim Mann Departments of Human Nutrition and Medicine, University of Otago, Dunedin, New Zealand 1
2 3 4
5
6
7
8 9
10
11
12 13
14
Daniel M, Rowley KG, McDermott R, Mylvaganam A, O’Dea K. Diabetes incidence in an Australian aboriginal population: an 8-year follow-up study. Diabetes Care 1999; 22: 1993–98. Colditz GA, Willett WC, Stampfer MJ, et al. Weight as a risk factor for clinical diabetes in women. Am J Epidemiol 1990; 132: 501–13. Recommendations for the nutritional management of patients with diabetes mellitus. Eur J Clin Nutr 2000; 54: 353–55. O’Dea K. Marked improvement in carbohydrate and lipid metabolism in diabetic Australian aborigines after temporary reversion to traditional lifestyle. Diabetes 1984; 33: 596–603. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–44. Eriksson J, Lindstrom J, Valle T, et al. Prevention of type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia 1999; 42: 793–801. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999; 22: 623–34. Ferrannini E. Insulin resistance is central to the burden of diabetes. Diabetes Metab Rev 1997; 13: 81–86. Wing RR, Venditti E, Jakicic JM, Polley BA, Lang W. Lifestyle intervention in overweight individuals with a family history of diabetes. Diabetes Care 1998; 21: 350–59. Bourn DM. The potential for lifestyle change to influence the progression of impaired glucose tolerance to non-insulin-dependent diabetes mellitus. Diabet Med 1996; 13: 938–45. Rowley KG, Gault A, McDermott R, Knight S, McLeay T, O’Dea K. Reduced prevalence of impaired glucose tolerance and no change in prevalence of diabetes despite increasing BMI among Aboriginal people from a group of remote homeland communities. Diabetes Care 2000; 23: 898–904. Yudkin JS, Alberti KG, McLarty DG, Swai AB. Impaired glucose tolerance. BMJ 1990; 301: 397–402. Russell D, Parnell W, Wilson N and the principal investigators of the 1997 National Nutrition Survey. NZ Food: NZ People: Key results of the 1997 National Nutrition Survey. LINZ Activity and Health Research Unit, University of Otago for the Ministry of Health, 1999. Macaulay AC, Paradis G, Potvin L, et al. The Kahnawake Schools Diabetes Prevention Project: intervention, evaluation, and baseline results of a diabetes primary prevention program with a native community in Canada. Prev Med 1997; 26: 779–90.
Conundrum of the hereditary component of testicular cancer No reason has been found for the tenfold increase in incidence of testicular cancer in industrialised countries during the twentieth century1 beyond the bland notion that there is very likely to be an environmental cause. It is ironic therefore that the largest case-control study, done at the end of that century, should show that the greatest risk factor for testicular cancer was hereditary.2,3 Several statistically significant environmental factors were also found—testicular maldescent (as usual), early onset of puberty, increased sexual activity, sedentary lifestyle, reduced exercise, and being a first-born child—but these
THE LANCET • Vol 356 • October 28, 2000
effects were small. However, patients with testicular cancer were four times more likely than controls to have a father, and eight times more likely to have a brother, with the same cancer.2 Elsewhere these risks were found to be 4 and 10, respectively.4 These levels of risk are much higher than in almost all other cancer types, most notably breast cancer, for which a familial pattern of disease has gained so much attention. The concept of testicular cancer arising, albeit as a result of environmental influences, in a genetically predisposed population finds resonance with observations on the distribution of this cancer between racial communities of the same nationality. In the USA whites have a very much higher incidence than non-white races. The offspring of western immigrants in Israel retain their high incidence.5 The low incidence in Italy is seen also in Italian migrants in other countries.6 This retention of racial susceptibility contrasts sharply with the situation with breast, stomach, colon, and ovarian cancers, for which the incidence in immigrant populations tends rapidly towards that of the host population. Familial testicular cancer is not common (present in 1·0–2·8% of cases of the cancer)7 and rarely does a family have more than two members with the disease. This rarity has caused much frustration in the search for a gene for testicular cancer. The International Testicular Cancer Linkage Consortium, working with up to 137 testicular-cancer families, has conducted a genome-wide search without hitherto discovering any significant genetic linkages.8,9 Now comes a positive report. Markers on the X chromosome produced faintly positive lod scores. (Father-son pairs and other families in which Xlinkage was impossible were excluded from this analysis.) When only the 15 families that contained one individual with bilateral testicular cancer were considered, every one of the families was linked at Xq27. A positive association was also found in families with a history of testicular maldescent.10 It was estimated that about 20% of all the testicular-cancer families could be carrying a gene at this site, so there will be other testis-cancer genes to find. The finding is intriguing for several reasons. The presence of a cancer-susceptibility gene on a non-paired chromosome will puzzle people familiar with the tumoursuppressor-gene model of inherited cancer—a mutated gene is inherited and carried on every cell, cancer being initiated when the allele in a single cell undergoes a “somatic” mutation. Yet the X chromosome has also recently been found to be the site of a predisposing gene in familial prostate cancer.11 Clearly the model is incomplete. In the case of testicular cancer, a predisposing gene on the X chromosome provides an explanation for the higher risk to brothers of cases than to fathers and sons. Could it also account for some non-malignant features? There is an association between cryptorchidism, hypospadias, infertility, and testicular cancer, which form an “epidemiological syndrome”, since only rarely are more than two of these disorders present in the same individual.12,13 And what effects would an X-linked gene have on female carriers who occasionally could be homozygous for it? But it is the fact that bilateral testicular cancer comprises as many as 5% of cases of testicular cancer14 that gives the result its importance. Could the great majority of these bilateral cases carry this gene? It seems plausible. Bilateral cancers in paired organs—the breast, the kidney, the retina—have proved to be markers of hereditary cancer. However, where are the affected 1455
For personal use only. Not to be reproduced without permission of The Lancet.