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Epidemiology of diabetes
DIABETES: BASIC FACTS
Epidemiology of diabetes
Scotland) show an incidence of 15.3/100,000/year in children aged 0–4 years, increasing to 24.4/100,000/year at 5–9 years and 31.9/100,000/year at 10–14 years. Overall, the incidence is slightly higher in boys than in girls (1.08:1).2 The peak incidence in boys is generally at 12–13 years, whereas in girls the peak occurs at 9–12 years. Ethnic variation ranges from a higher incidence in Hispanic children compared with white children in Philadelphia, USA, to a 4.5-fold greater incidence in white children compared with Maori children in New Zealand. In Leicestershire, UK, the incidence in South Asian children is similar to that in white children, despite the lower rates reported in Asia.3 Temporal variation – an increase in the incidence of type 1 diabetes of about 2% per year was described in Scotland in 1984–1993.2 Pooled increases of 3.0% per year in 37 populations worldwide4 and of 3.2% per year in Europe5 have been reported. Generally, the magnitude of increase is greater in low-incidence countries, but occurs in both high-incidence and low-incidence areas. The greatest increase is in the youngest age group (0−4 years). The incidence of type 1 diabetes also varies with season, being highest in autumn and winter. Aetiological factors – genetic susceptibility is necessary but not sufficient as a cause of type 1 diabetes. The nature of the environmental factors that affect this genetic predisposition are unclear. One possible hypothesis links improved living standards with reduced exposure to micro-organisms and increased risk of autoimmune-mediated disease in childhood. Studies have concentrated on the ecological correlation between incidence and geographical variation in environmental factors such as population density, household overcrowding and population mixing. These studies are ecological, because the data on the risk of outcome (diabetes) are not collected from the same individuals as those on exposure (social factors). Inferences about causality from such data are weaker than evidence from studies based on the association between individual exposure and risk. However, prospective cohort studies are difficult to conduct in type 1 diabetes, because of the relatively low incidence; many individuals would have to be recruited and assessed and only a few would progress to disease. The case-control approach is efficient, but is subject to recall bias because exposure is assessed by proxy from parents after the diagnosis has been made. Case-control studies have shown associations with early social mixing, viral infections, toxins, and dietary factors such as exclusive breast-feeding and delayed introduction of cows’ milk.
Nita Gandhi Forouhi Nicholas J Wareham
Type 1 diabetes The acute onset of type 1 diabetes and the fact that almost all cases rapidly reach medical attention means that registers of new cases can be relatively easily established. Provided ascertainment can be verified, these data can be combined with population denominator data to give age-specific and sex-specific incidences. Geographical variation – the marked geographical variation in the incidence of type 1 diabetes is shown in Figure 1.1 In Finland, the age-standardized incidence in children aged 14 years and under is 36.8/100,000/year. A high rate is also observed in Sardinia (36.5/100,000/year) that is notably discordant with the incidence in Italy as a whole. These two countries have incidences 350-fold greater than those in China and Venezuela, where the incidence is 0.1/100,000/year. In general, countries in Europe and North America have either high or intermediate incidences. The incidence in Africa is generally intermediate and that in Asia is low. Variation with age, sex and ethnicity – in the UK, wellestablished registers with high ascertainment (98.6%, e.g. in
Nita Gandhi Forouhi is an MRC Clinical Investigator Scientist and Honorary Public Health Physician in Cambridge, UK. She qualified from the University of Newcastle upon Tyne, and trained in clinical epidemiology at the London School of Hygiene and Tropical Medicine. Her main research interests are ethnic differences in the risk of diabetes and the aetiology of diabetes. Conflicts of interest: none.
Type 2 diabetes The slow onset of type 2 diabetes, and its presentation without the acute metabolic disturbance seen in type 1 diabetes, means that the true time of onset is difficult to determine. Thus, the distinction between abnormality and normality is more blurred, there is a long pre-detection period, and as many as one-half of cases in the population are undiagnosed. Data on the prevalence of clinically detected type 2 diabetes provide information that is useful for health service planning, but cannot provide insights into the true prevalence unless the prevalence of undetected diabetes is also known. Because the ratio of detected to undetected cases may vary over time and between places, epidemiological research aimed at defining the true preva-
Nicholas J Wareham is Director of the MRC Epidemiology Unit and Honorary Public Health Physician in Cambridge, UK. He qualified from St Thomas’ Hospital Medical School, London, and trained in clinical epidemiology at the London School of Hygiene and Tropical Medicine, Harvard University, Boston, USA and the University of Cambridge. His principal research interests are the aetiology of diabetes, and primary and secondary prevention. Conflicts of interest: none.
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DIABETES: BASIC FACTS
lence of type 2 diabetes has had to rely on special studies in which the presence and absence of disease are defined by the oral glucose tolerance test (OGTT). However, the distinction between normality and abnormality is unclear, and debate continues about how
it should be defined. The WHO currently recommends use of the 75 g OGTT, with diabetes defined by fasting glucose 7.0 mmol/litre or more and/or 2-hour post-challenge glucose 11.1 mmol/litre or more. Geographical and ethnic variation – Figure 2 shows the agestandardized and sex-standardized prevalence of type 2 diabetes and impaired glucose tolerance (IGT) as defined by the 75 g OGTT in various countries. As in type 1 diabetes, there is marked geographical variation, but the pattern is different. The prevalence is lowest in rural areas of developing countries, is generally intermediate in developed countries, and is highest in certain ethnic groups that have adopted Western lifestyle patterns. The populations with the highest prevalences (Pima Indians in Arizona and Nauruans in Micronesia) have a high prevalence of obesity. It is hypothesized that genetic
Incidence of type 1 diabetes Finland Sweden Canada Norway UK New Zealand Kuwait Puerto Rico Denmark USA Australia Italy Portugal Virgin Islands Netherlands Spain Belgium Luxembourg Germany Estonia Greece Austria Hungary Slovakia France Bulgaria Uruguay Brazil Slovenia Lithuania Tunisia Russia Israel Argentina Latvia Dominica Algeria Poland Romania Sudan Colombia Cuba Barbados Japan Chile Mexico Mauritius Paraguay China Pakistan Peru Venezuela
Age-standardized prevalence of type 2 diabetes and impaired glucose tolerance Mapuche Indian, Chile Urban Chinese, Da Qing Rural Melanesian, Papua New Guinea Polish Rural Polynesian, Western Samoa Rural Bantu, Tanzania Rural Indian, India Russian Brazilian Rural Melanesian, Fiji Italian, Sanza Maltese Urban Bantu, Tanzania Italian, Laurino White, USA Tunisian Upper-income urban Hispanic, USA Rural Micronesian, Kiribati Urban Polynesian, Western Samoa Urban Indian, India Urban Melanesian, Fiji Rural Hispanic, USA Black, USA Urban Indian, South Africa Puerto Rican, USA Middle-income urban Hispanic, USA Chinese, Mauritius Low-income urban Hispanic, USA Rural Indian, Fiji Urban Indian, Fiji Urban Micronesian, Kiribati Micronesian, Nauru Pima Indian, USA 0 0
5
10
15
20
25
30
35
Prevalence (%)
40
Incidence (/100,000/year)
Diabetes mellitus
Impaired glucose tolerance
2
1
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DIABETES: BASIC FACTS
Aetiological factors – prospective population-based cohort studies suggest that the main pathophysiological defects leading to type 2 diabetes are insulin resistance and a relative insulin secretory defect. The main aetiological risk factors for type 2 diabetes are age, obesity, family history, physical inactivity, and dietary factors such as a high proportion of energy consumed as saturated fat and low intake of fruit and vegetables. Although there is evidence of heritability of type 2 diabetes, progress in finding genes that explain this risk has been slow. The marked exception to this is maturityonset diabetes of the young (MODY), in which the genetic basis of the disease has been characterized. More common variants in the genes that give rise to MODY when mutations are present (e.g. HNF4α) have been associated with typical type 2 diabetes. Other genes now accepted to be associated with type 2 diabetes include the Pro12Ala polymorphism in PPAR-γ and variants in CALPAIN10 and KCNJ11.12 The observation of an association between low birth weight and risk of diabetes in later life has led to the development of an alternative to the thrifty genotype hypothesis. In this ‘thrifty phenotype’ hypothesis, the risk of diabetes and other adult disorders is programmed by fetal nutrition and the pattern of early growth.
susceptibility to obesity in these populations would be disadvantageous in times of food abundance, but would be advantageous when food is scarce, giving rise to maintenance of the gene by natural selection. This ‘thrifty genotype’ hypothesis is supported by evidence of gene–environment interaction; individuals who migrate from low-prevalence areas (e.g. Japan) to the West are at increased risk of type 2 diabetes. The prevalence of diabetes is up to 4−6-fold higher in immigrant South Asians in the UK compared with European Caucasians,6 and a high prevalence is also noted in urban-dwelling South Asians in India. Variation with age and sex – in the UK, the Health Survey for England estimated the prevalence of self-reported diabetes to be about 4.3% in men and 3.4% in women. The prevalence increases sharply with age in both sexes in all populations.7 The true incidence of diabetes is difficult to determine, because this requires repeated glucose tolerance testing. However, such studies have been undertaken and the incidence found to be about 6/1000 person-years of follow-up.8 The incidence in individuals known to have IGT is about eight times greater than in those with normal glucose tolerance; the absolute cumulative incidence is 10% over 5 years in Caucasians, but may be higher in high-risk populations. The risk of future progression to diabetes is also greater in those with other hyperglycaemic states, including gestational diabetes mellitus. Temporal variation – data from studies such as the National Health and Nutrition Examination Survey show that the prevalence of type 2 diabetes in the USA increased by 33%, from 4.9% in 1990 to 6.5% in 1998. This increase mirrors the increasing prevalence of obesity. Worldwide, there is a projected increase in the prevalence of diabetes from 171 million (2.8%) in 2000 to 366 million (4.8%) in 2030.9 Estimates of the prevalence in developing countries show even more marked increases, particularly in areas where populations are rapidly adopting Western lifestyles (Figure 3). The increase in the prevalence of obesity in childhood has led to the appearance of type 2 diabetes in children and young adults, particularly those in highly susceptible ethnic groups.10,11
Prevention and screening Primary prevention Recent clinical trials in Finland, the USA, China and India, and a multicentre trial in several countries, have provided evidence that, in high-risk individuals with IGT, progression to type 2 diabetes can be reduced by intensive lifestyle intervention or drug therapy with metformin or acarbose.13−16 Lifestyle interventions include maintenance of a healthy body weight through reducing sedentary behaviour and increasing physical activity, and eating a healthy diet rich in fibre and low in fat. In addition to the clinical effectiveness, there is now also evidence from the US Diabetes Prevention Program for the cost-effectiveness of these interventions; lifestyle intervention was cost-effective at all ages (cohort of those aged > 25 years) compared with usual care, whereas metformin was less cost-effective, particularly in older individuals. The challenges that remain are how high-risk individuals should be identified, and how lifestyle changes of healthier diet and regular physical activity can be sustained. It is unknown whether those with non-diabetic hyperglycaemia defined by fasting glucose status (impaired fasting glucose), or by simpler risk-scoring systems based on existence of known risk factors for diabetes, would also benefit from primary prevention. For pragmatic reasons, clinical trials have focused on individuals who already have a degree of hyperglycaemia (IGT); there has been no trial of primary prevention in those who are at high risk of diabetes but who do not biochemically have non-diabetic hyperglycaemia. The potential preventability of type 2 diabetes also raises the possibility of primary prevention of cardiovascular disease in those with non-diabetic hyperglycaemia. The multicentre STOP-NIDDM study reported a risk reduction in the incidence of cardiovascular disease risk markers with acarbose. A recent report from the US Diabetes Prevention Program did not replicate that finding with metformin, but reported a risk reduction in hypertension with intensive lifestyle intervention.
Countries with the highest estimated numbers of cases of diabetes in 2000 and 2030 2000 Individuals with diabetes (millions) India 31.7 China 20.8 USA 17.7 Indonesia 8.4 Japan 6.8 Pakistan 5.2 Russian 4.6 Federation Brazil 4.6 Italy 4.3 Bangladesh 3.2
Rank Country
1 2 3 4 5 6 7 8 9 10
2030 Individuals with diabetes (millions) India 79.4 China 42.3 USA 30.3 Indonesia 21.3 Pakistan 13.9 Brazil 11.3 Bangladesh 11.1 Country
Japan Philippines Egypt
8.9 7.8 6.7
3
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Secondary prevention: screening It is estimated that the onset of diabetes occurs an average of about 4−7 years before clinical diagnosis based on symptoms, and that one-third to one-half of individuals with type 2 diabetes are undiagnosed at any given time. The proportion undiagnosed varies with age, ethnicity, gender and other factors. Given that a high proportion of individuals exhibit evidence of end-organ damage at the time of clinical diagnosis, and that undiagnosed diabetes is common, screening has been proposed in the hope that early detection and early treatment would reduce the longterm burden to individuals and the health services. There is no definitive evidence that screening results in net benefit, however, and most authorities have proposed further research and limited screening in high-risk subgroups. Although diabetes meets several of the classic Wilson and Junger criteria for a systematic screening programme, many uncertainties remain, including: • lack of direct evidence that early detection and treatment would yield significant benefit over delayed treatment • an agreed protocol on who to screen • which test is best for screening (contenders are fasting glucose, 2-hour glucose on an OGTT, random blood glucose, glycated haemoglobin (HbA1c), finger-prick blood sample, a risk score, and urinalysis for glycosuria) • frequency of testing • the cost-effectiveness of screening. There is a need for randomized trials to determine the degree of the benefit of early detection and treatment, and to assess the potential harm of ‘labelling’ individuals with the diagnosis of diabetes.17 Such trials are now in progress.
6 McKeigue P M, Shah B, Marmot M G. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991; 337: 382−6. 7 DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care 2003; 26: 61−9. 8 Wareham N J, Byrne C D, Williams R et al. Fasting proinsulin concentrations predict the development of type 2 diabetes. Diabetes Care 1999; 22: 262−70. 9 Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047−53. 10 Ehtisham S, Hattersley A T, Dunger D B et al. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child 2004; 89: 526–9. 11 Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005; 146: 693−700. 12 O’Rahilly S, Barroso I, Wareham N J. Genetic factors in type 2 diabetes: the end of the beginning? Science 2005; 307: 370−3. 13 Tuomilehto J, Lindstrom J, Eriksson J G et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343−50. 14 Knowler W C, Barrett-Connor E, Fowler S E et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393−403. 15 Pan X R, Li G W, Hu Y H 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. 16 Chiasson J L, Josse R G, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072−7. 17 Wareham N J, Griffin S J. Should we screen for type 2 diabetes? Evaluation against National Screening Committee criteria. BMJ 2001; 322: 986−8. FURTHER READING Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26: (Suppl. 1): S5−20. (Describes the American Diabetes Association definition of diabetes and includes recommendations for screening for diabetes.) Hales C N , Barker D J. The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5−20. (A comprehensive description of the thrifty phenotype hypothesis.) Hamman R F. Genetic and environmental determinants of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Metab Rev 1992; 8: 287–338. Swinburn B A. The thrifty genotype hypothesis: how does it look after 30 years? Diabet Med 1996; 13: 695–9. Todd J A. From genome to aetiology in a multifactorial disease, type 1 diabetes. Bioessays 1999; 21: 164–74. WHO. Definition, diagnosis and classification of diabetes mellitus. Part I: diagnosis and classification of diabetes mellitus. Geneva: WHO, 1999. (A clear description of WHO criteria for diagnosing and classifying diabetes.)
REFERENCES 1 Karvonen M, Viik-Kajander M, Moltchanova E et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23: 1516−26. 2 Rangasami J J, Greenwood D C, McSporran B et al. Rising incidence of type 1 diabetes in Scottish children, 1984−93. The Scottish Study Group for the Care of Young Diabetics. Arch Dis Child 1997; 77: 210−13. 3 Raymond N T, Jones J R, Swift P G et al. Comparative incidence of type I diabetes in children aged under 15 years from South Asian and white or other ethnic backgrounds in Leicestershire, UK, 1989 to 1998. Diabetologia 2001; 44: (Suppl. 3): B32−6. 4 Onkamo P, Vaananen S, Karvonen M et al. Worldwide increase in incidence of type I diabetes − the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395−403. 5 Green A, Patterson C C. Trends in the incidence of childhood-onset diabetes in Europe 1989−1998. Diabetologia 2001; 44: (Suppl. 3): B3−8.
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Scotland) show an incidence of 15.3/100,000/year in children aged 0–4 years, increasing to 24.4/100,000/year at 5–9 years and 31.9/100,000/year at 10–14 years. Overall, the incidence is slightly higher in boys than in girls (1.08:1).2 The peak incidence in boys is generally at 12–13 years, whereas in girls the peak occurs at 9–12 years. Ethnic variation ranges from a higher incidence in Hispanic children compared with white children in Philadelphia, USA, to a 4.5-fold greater incidence in white children compared with Maori children in New Zealand. In Leicestershire, UK, the incidence in South Asian children is similar to that in white children, despite the lower rates reported in Asia.3 Temporal variation – an increase in the incidence of type 1 diabetes of about 2% per year was described in Scotland in 1984–1993.2 Pooled increases of 3.0% per year in 37 populations worldwide4 and of 3.2% per year in Europe5 have been reported. Generally, the magnitude of increase is greater in low-incidence countries, but occurs in both high-incidence and low-incidence areas. The greatest increase is in the youngest age group (0−4 years). The incidence of type 1 diabetes also varies with season, being highest in autumn and winter. Aetiological factors – genetic susceptibility is necessary but not sufficient as a cause of type 1 diabetes. The nature of the environmental factors that affect this genetic predisposition are unclear. One possible hypothesis links improved living standards with reduced exposure to micro-organisms and increased risk of autoimmune-mediated disease in childhood. Studies have concentrated on the ecological correlation between incidence and geographical variation in environmental factors such as population density, household overcrowding and population mixing. These studies are ecological, because the data on the risk of outcome (diabetes) are not collected from the same individuals as those on exposure (social factors). Inferences about causality from such data are weaker than evidence from studies based on the association between individual exposure and risk. However, prospective cohort studies are difficult to conduct in type 1 diabetes, because of the relatively low incidence; many individuals would have to be recruited and assessed and only a few would progress to disease. The case-control approach is efficient, but is subject to recall bias because exposure is assessed by proxy from parents after the diagnosis has been made. Case-control studies have shown associations with early social mixing, viral infections, toxins, and dietary factors such as exclusive breast-feeding and delayed introduction of cows’ milk.
Nita Gandhi Forouhi Nicholas J Wareham
Type 1 diabetes The acute onset of type 1 diabetes and the fact that almost all cases rapidly reach medical attention means that registers of new cases can be relatively easily established. Provided ascertainment can be verified, these data can be combined with population denominator data to give age-specific and sex-specific incidences. Geographical variation – the marked geographical variation in the incidence of type 1 diabetes is shown in Figure 1.1 In Finland, the age-standardized incidence in children aged 14 years and under is 36.8/100,000/year. A high rate is also observed in Sardinia (36.5/100,000/year) that is notably discordant with the incidence in Italy as a whole. These two countries have incidences 350-fold greater than those in China and Venezuela, where the incidence is 0.1/100,000/year. In general, countries in Europe and North America have either high or intermediate incidences. The incidence in Africa is generally intermediate and that in Asia is low. Variation with age, sex and ethnicity – in the UK, wellestablished registers with high ascertainment (98.6%, e.g. in
Nita Gandhi Forouhi is an MRC Clinical Investigator Scientist and Honorary Public Health Physician in Cambridge, UK. She qualified from the University of Newcastle upon Tyne, and trained in clinical epidemiology at the London School of Hygiene and Tropical Medicine. Her main research interests are ethnic differences in the risk of diabetes and the aetiology of diabetes. Conflicts of interest: none.
Type 2 diabetes The slow onset of type 2 diabetes, and its presentation without the acute metabolic disturbance seen in type 1 diabetes, means that the true time of onset is difficult to determine. Thus, the distinction between abnormality and normality is more blurred, there is a long pre-detection period, and as many as one-half of cases in the population are undiagnosed. Data on the prevalence of clinically detected type 2 diabetes provide information that is useful for health service planning, but cannot provide insights into the true prevalence unless the prevalence of undetected diabetes is also known. Because the ratio of detected to undetected cases may vary over time and between places, epidemiological research aimed at defining the true preva-
Nicholas J Wareham is Director of the MRC Epidemiology Unit and Honorary Public Health Physician in Cambridge, UK. He qualified from St Thomas’ Hospital Medical School, London, and trained in clinical epidemiology at the London School of Hygiene and Tropical Medicine, Harvard University, Boston, USA and the University of Cambridge. His principal research interests are the aetiology of diabetes, and primary and secondary prevention. Conflicts of interest: none.
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DIABETES: BASIC FACTS
lence of type 2 diabetes has had to rely on special studies in which the presence and absence of disease are defined by the oral glucose tolerance test (OGTT). However, the distinction between normality and abnormality is unclear, and debate continues about how
it should be defined. The WHO currently recommends use of the 75 g OGTT, with diabetes defined by fasting glucose 7.0 mmol/litre or more and/or 2-hour post-challenge glucose 11.1 mmol/litre or more. Geographical and ethnic variation – Figure 2 shows the agestandardized and sex-standardized prevalence of type 2 diabetes and impaired glucose tolerance (IGT) as defined by the 75 g OGTT in various countries. As in type 1 diabetes, there is marked geographical variation, but the pattern is different. The prevalence is lowest in rural areas of developing countries, is generally intermediate in developed countries, and is highest in certain ethnic groups that have adopted Western lifestyle patterns. The populations with the highest prevalences (Pima Indians in Arizona and Nauruans in Micronesia) have a high prevalence of obesity. It is hypothesized that genetic
Incidence of type 1 diabetes Finland Sweden Canada Norway UK New Zealand Kuwait Puerto Rico Denmark USA Australia Italy Portugal Virgin Islands Netherlands Spain Belgium Luxembourg Germany Estonia Greece Austria Hungary Slovakia France Bulgaria Uruguay Brazil Slovenia Lithuania Tunisia Russia Israel Argentina Latvia Dominica Algeria Poland Romania Sudan Colombia Cuba Barbados Japan Chile Mexico Mauritius Paraguay China Pakistan Peru Venezuela
Age-standardized prevalence of type 2 diabetes and impaired glucose tolerance Mapuche Indian, Chile Urban Chinese, Da Qing Rural Melanesian, Papua New Guinea Polish Rural Polynesian, Western Samoa Rural Bantu, Tanzania Rural Indian, India Russian Brazilian Rural Melanesian, Fiji Italian, Sanza Maltese Urban Bantu, Tanzania Italian, Laurino White, USA Tunisian Upper-income urban Hispanic, USA Rural Micronesian, Kiribati Urban Polynesian, Western Samoa Urban Indian, India Urban Melanesian, Fiji Rural Hispanic, USA Black, USA Urban Indian, South Africa Puerto Rican, USA Middle-income urban Hispanic, USA Chinese, Mauritius Low-income urban Hispanic, USA Rural Indian, Fiji Urban Indian, Fiji Urban Micronesian, Kiribati Micronesian, Nauru Pima Indian, USA 0 0
5
10
15
20
25
30
35
Prevalence (%)
40
Incidence (/100,000/year)
Diabetes mellitus
Impaired glucose tolerance
2
1
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DIABETES: BASIC FACTS
Aetiological factors – prospective population-based cohort studies suggest that the main pathophysiological defects leading to type 2 diabetes are insulin resistance and a relative insulin secretory defect. The main aetiological risk factors for type 2 diabetes are age, obesity, family history, physical inactivity, and dietary factors such as a high proportion of energy consumed as saturated fat and low intake of fruit and vegetables. Although there is evidence of heritability of type 2 diabetes, progress in finding genes that explain this risk has been slow. The marked exception to this is maturityonset diabetes of the young (MODY), in which the genetic basis of the disease has been characterized. More common variants in the genes that give rise to MODY when mutations are present (e.g. HNF4α) have been associated with typical type 2 diabetes. Other genes now accepted to be associated with type 2 diabetes include the Pro12Ala polymorphism in PPAR-γ and variants in CALPAIN10 and KCNJ11.12 The observation of an association between low birth weight and risk of diabetes in later life has led to the development of an alternative to the thrifty genotype hypothesis. In this ‘thrifty phenotype’ hypothesis, the risk of diabetes and other adult disorders is programmed by fetal nutrition and the pattern of early growth.
susceptibility to obesity in these populations would be disadvantageous in times of food abundance, but would be advantageous when food is scarce, giving rise to maintenance of the gene by natural selection. This ‘thrifty genotype’ hypothesis is supported by evidence of gene–environment interaction; individuals who migrate from low-prevalence areas (e.g. Japan) to the West are at increased risk of type 2 diabetes. The prevalence of diabetes is up to 4−6-fold higher in immigrant South Asians in the UK compared with European Caucasians,6 and a high prevalence is also noted in urban-dwelling South Asians in India. Variation with age and sex – in the UK, the Health Survey for England estimated the prevalence of self-reported diabetes to be about 4.3% in men and 3.4% in women. The prevalence increases sharply with age in both sexes in all populations.7 The true incidence of diabetes is difficult to determine, because this requires repeated glucose tolerance testing. However, such studies have been undertaken and the incidence found to be about 6/1000 person-years of follow-up.8 The incidence in individuals known to have IGT is about eight times greater than in those with normal glucose tolerance; the absolute cumulative incidence is 10% over 5 years in Caucasians, but may be higher in high-risk populations. The risk of future progression to diabetes is also greater in those with other hyperglycaemic states, including gestational diabetes mellitus. Temporal variation – data from studies such as the National Health and Nutrition Examination Survey show that the prevalence of type 2 diabetes in the USA increased by 33%, from 4.9% in 1990 to 6.5% in 1998. This increase mirrors the increasing prevalence of obesity. Worldwide, there is a projected increase in the prevalence of diabetes from 171 million (2.8%) in 2000 to 366 million (4.8%) in 2030.9 Estimates of the prevalence in developing countries show even more marked increases, particularly in areas where populations are rapidly adopting Western lifestyles (Figure 3). The increase in the prevalence of obesity in childhood has led to the appearance of type 2 diabetes in children and young adults, particularly those in highly susceptible ethnic groups.10,11
Prevention and screening Primary prevention Recent clinical trials in Finland, the USA, China and India, and a multicentre trial in several countries, have provided evidence that, in high-risk individuals with IGT, progression to type 2 diabetes can be reduced by intensive lifestyle intervention or drug therapy with metformin or acarbose.13−16 Lifestyle interventions include maintenance of a healthy body weight through reducing sedentary behaviour and increasing physical activity, and eating a healthy diet rich in fibre and low in fat. In addition to the clinical effectiveness, there is now also evidence from the US Diabetes Prevention Program for the cost-effectiveness of these interventions; lifestyle intervention was cost-effective at all ages (cohort of those aged > 25 years) compared with usual care, whereas metformin was less cost-effective, particularly in older individuals. The challenges that remain are how high-risk individuals should be identified, and how lifestyle changes of healthier diet and regular physical activity can be sustained. It is unknown whether those with non-diabetic hyperglycaemia defined by fasting glucose status (impaired fasting glucose), or by simpler risk-scoring systems based on existence of known risk factors for diabetes, would also benefit from primary prevention. For pragmatic reasons, clinical trials have focused on individuals who already have a degree of hyperglycaemia (IGT); there has been no trial of primary prevention in those who are at high risk of diabetes but who do not biochemically have non-diabetic hyperglycaemia. The potential preventability of type 2 diabetes also raises the possibility of primary prevention of cardiovascular disease in those with non-diabetic hyperglycaemia. The multicentre STOP-NIDDM study reported a risk reduction in the incidence of cardiovascular disease risk markers with acarbose. A recent report from the US Diabetes Prevention Program did not replicate that finding with metformin, but reported a risk reduction in hypertension with intensive lifestyle intervention.
Countries with the highest estimated numbers of cases of diabetes in 2000 and 2030 2000 Individuals with diabetes (millions) India 31.7 China 20.8 USA 17.7 Indonesia 8.4 Japan 6.8 Pakistan 5.2 Russian 4.6 Federation Brazil 4.6 Italy 4.3 Bangladesh 3.2
Rank Country
1 2 3 4 5 6 7 8 9 10
2030 Individuals with diabetes (millions) India 79.4 China 42.3 USA 30.3 Indonesia 21.3 Pakistan 13.9 Brazil 11.3 Bangladesh 11.1 Country
Japan Philippines Egypt
8.9 7.8 6.7
3
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DIABETES: BASIC FACTS
Secondary prevention: screening It is estimated that the onset of diabetes occurs an average of about 4−7 years before clinical diagnosis based on symptoms, and that one-third to one-half of individuals with type 2 diabetes are undiagnosed at any given time. The proportion undiagnosed varies with age, ethnicity, gender and other factors. Given that a high proportion of individuals exhibit evidence of end-organ damage at the time of clinical diagnosis, and that undiagnosed diabetes is common, screening has been proposed in the hope that early detection and early treatment would reduce the longterm burden to individuals and the health services. There is no definitive evidence that screening results in net benefit, however, and most authorities have proposed further research and limited screening in high-risk subgroups. Although diabetes meets several of the classic Wilson and Junger criteria for a systematic screening programme, many uncertainties remain, including: • lack of direct evidence that early detection and treatment would yield significant benefit over delayed treatment • an agreed protocol on who to screen • which test is best for screening (contenders are fasting glucose, 2-hour glucose on an OGTT, random blood glucose, glycated haemoglobin (HbA1c), finger-prick blood sample, a risk score, and urinalysis for glycosuria) • frequency of testing • the cost-effectiveness of screening. There is a need for randomized trials to determine the degree of the benefit of early detection and treatment, and to assess the potential harm of ‘labelling’ individuals with the diagnosis of diabetes.17 Such trials are now in progress.
6 McKeigue P M, Shah B, Marmot M G. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991; 337: 382−6. 7 DECODE Study Group. Age- and sex-specific prevalences of diabetes and impaired glucose regulation in 13 European cohorts. Diabetes Care 2003; 26: 61−9. 8 Wareham N J, Byrne C D, Williams R et al. Fasting proinsulin concentrations predict the development of type 2 diabetes. Diabetes Care 1999; 22: 262−70. 9 Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047−53. 10 Ehtisham S, Hattersley A T, Dunger D B et al. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child 2004; 89: 526–9. 11 Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 2005; 146: 693−700. 12 O’Rahilly S, Barroso I, Wareham N J. Genetic factors in type 2 diabetes: the end of the beginning? Science 2005; 307: 370−3. 13 Tuomilehto J, Lindstrom J, Eriksson J G et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343−50. 14 Knowler W C, Barrett-Connor E, Fowler S E et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393−403. 15 Pan X R, Li G W, Hu Y H 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. 16 Chiasson J L, Josse R G, Gomis R et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072−7. 17 Wareham N J, Griffin S J. Should we screen for type 2 diabetes? Evaluation against National Screening Committee criteria. BMJ 2001; 322: 986−8. FURTHER READING Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26: (Suppl. 1): S5−20. (Describes the American Diabetes Association definition of diabetes and includes recommendations for screening for diabetes.) Hales C N , Barker D J. The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5−20. (A comprehensive description of the thrifty phenotype hypothesis.) Hamman R F. Genetic and environmental determinants of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Metab Rev 1992; 8: 287–338. Swinburn B A. The thrifty genotype hypothesis: how does it look after 30 years? Diabet Med 1996; 13: 695–9. Todd J A. From genome to aetiology in a multifactorial disease, type 1 diabetes. Bioessays 1999; 21: 164–74. WHO. Definition, diagnosis and classification of diabetes mellitus. Part I: diagnosis and classification of diabetes mellitus. Geneva: WHO, 1999. (A clear description of WHO criteria for diagnosing and classifying diabetes.)
REFERENCES 1 Karvonen M, Viik-Kajander M, Moltchanova E et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23: 1516−26. 2 Rangasami J J, Greenwood D C, McSporran B et al. Rising incidence of type 1 diabetes in Scottish children, 1984−93. The Scottish Study Group for the Care of Young Diabetics. Arch Dis Child 1997; 77: 210−13. 3 Raymond N T, Jones J R, Swift P G et al. Comparative incidence of type I diabetes in children aged under 15 years from South Asian and white or other ethnic backgrounds in Leicestershire, UK, 1989 to 1998. Diabetologia 2001; 44: (Suppl. 3): B32−6. 4 Onkamo P, Vaananen S, Karvonen M et al. Worldwide increase in incidence of type I diabetes − the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395−403. 5 Green A, Patterson C C. Trends in the incidence of childhood-onset diabetes in Europe 1989−1998. Diabetologia 2001; 44: (Suppl. 3): B3−8.
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