ELSEVIER 0RlC;lNAL ARTICLES The Global Epidemiology of Non-Insulin-Dependent Diabetes Mellitus and the Metabolic Svndrome J Paul Z. Zimmet Daniel 1. McCarty Maximilian P. de Courten ABSTRACT Non-insulin-dependent diabetes mellitus (NIDDM) constitutes about 65% of all cases of diabetes in developed countries and it has now reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican- and African-Americans and Australian Aborigines and Torres Strait Islanders. The diagnosis of NIDDM is usually made after the age of 50 years in Europids, but it is seen at much younger age in these high prevalence populations, which also include Pacific Islanders, Native Americans, and migrant Asian Indians and Chinese. There is enormous variation in NIDDM prevalence between populations, and exceptionally high rates have been documented in populations who have changed from a traditional to a modem lifestyle, e.g., American Pima Indians, Micronesians, and other Pacific Islanders, Australian Aborigines, migrant Asian Indians, and INTRODUCTION N the world. on-insulin-dependent diabetes mellitus (MDDM) affects large numbers of people of a wide range of ethnic groups and at all social and economic levels throughout At least 100 million people today suffer International Diabetes Institute, a WHO Collaborating Center for the Epidemiology of Diabetes Mellitus and Health Promotion for Non-communicable Dii Control (P.Z.Z., D.J.M., M.D.C.), Gaulfield Australia. Reprint requests to be sent to: Prof. Paul Z. Zimmet, International Diabetes Institute, 260 Kooyong Road, Caulfield, Victoria 3162, Australia. lournal of Diabetes and Its Complications 11:60-M C Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010 Mexican-Americans. Over the next decade, following the initial phase of the NIDDM epidemic, macro- and microvascular complications will emerge as a major threat to future public health throughout the world with huge economic and social costs. The major cause of death in NIDDM is macrovascular disease (coronary artery, peripheral vascular, and cerebrovascularl, which accounts for at least two-thirds of NIDDM mortality. A key strategy in reducing macrovascular disease lies in the better understanding of the Deadly Quartet or Metabolic Syndrome. New data suggest that hyperleptinemia rather than hyperinsulinemia may play an important and central role in the genesis of the cardiovascular disease risk factor cluster that constitutes the Metabolic Syndrome. t journal of Diabetes and Its Complications 11;2:60-68, 1997.) 0 Elsevier Science Inc., 1997 from NIDDM, but, by A.D. 2010, 215 million people are projected to have the disease.’ Diabetes is among the five leading causes of death by disease in most countries.2 However, mortality statistics greatly underestimate the true diabetes-related mortality as diabetes is frequently underreported on death certificates,‘,” hence ensuring diabetes is often ignored in setting public health priorities. Apart from the health impact, the economic cost of diabetes and its complications is enormous, both for health care and loss of productivity to society.3 NIDDM is a health problem of modern times. From a historical perspective, the main causes of morbidity and mortality in all countries of the world resulted 1056-8727/97/$17.00 PII S1056-8727(96)000904 ] Diab Comp 1997; 11:60-68 THE from epidemics of communicable diseases including typhoid, cholera, smallpox, diphtheria, and influenza until the latter part of the 19 century.4 While many of these diseases are still epidemic in many developing countries, industrialization and progressive modernization with major improvements in housing, sanitation, water supply, and nutrition, along with the use of antibiotics and immunization, have brought about dramatic increases in life expectancy. Unfortunately, improved longevity has brought with it a marked increase in the prevalence of noncommunicable diseases (NCDs) such as NIDDM, cardiovascular disease (CVD), hypertension, strokes, and cancer4 and their risk factors. NCDs are now major contributors to morbidity and mortality in modern society. The emergence of NIDDM and the Metabolic Syndrome, also call the New World Syndrome5,6 Syndrome X,7 or the Deadly Quartet: appears to be a result of socioeconomic and demographic change. We have described this process in Pacific and Indian Ocean populations. 9 Rapid socioeconomic development over the last 40-50 years has resulted in a dramatic change of lifestyle from traditional to modern described as “Coca-colonization.” These changes and their relevance to the etiology and prevention of NIDDM and its devastating complications will be discussed in this review. EPIDEMIOLOGY OF NIDDM Regional Differences in NIDDM Prevalence. The number of studies relating to the epidemiology of NIDDM over the last 15 years has been extraordinary, particularly in Asia and the Pacific, and in the Latin American countries.’ However, there are still only very crude estimates of the total number of people with diabetes at a national, regional, or global level. Despite the number of epidemiological studies on the incidence and prevalence of diabetes, governments and most public health planners still remain largely unaware of the current magnitude, or-more importantly-the future potential for increases in diabetes and its devastating complications in their own country. To address this gap in knowledge, we produced the publication “Diabetes 1994 to 2010: Global Estimates and Projections,“’ applying the best epidemiological information that was currently available to estimate the world-wide prevalence of NIDDM by regions in 1994 and project the global burden for the years 2000 and 2010. Estimates and projections for the various regions of the world are shown in Table 1. Because NIDDM is epidemic in many regions, projections were included in an attempt to forecast the potential impact of NIDDM for the next lo-15 years. These projections may help public health agencies take the first step in evaluating the potential social and economic cost associated with NIDDM, and may METABOLIC SYNDROME IN NIDDM 61 provide a rationale and the basis for the development of prevention programs. Ethnic and Country Differences in NIDDM Prevalence. Currently, the prevalence of NIDDM varies dramatically 5~10 from less than 2% in rural Bantu in Tanzania, and Chinese in mainland China, to 40%-50% in Pima Indians and Micronesians in Nauru (Figure 1). This variation in prevalence results from a combination of differences in genetic susceptibility and social risk factors such as change in diet, obesity, physical inactivity, and, in certain situations, possibly factors relating to intrauterine development.“,‘* A steady stream of reports have continued to highlight the explosion of NIDDM in many societies associated with lifestyle change. Populations previously free of NIDDM are showing prevalences that are extraordinarily high when compared to developed countries. For example, the urbanized Wanigela people of the Koki settlement in Papua New Guinea13 have recently been shown to have one of the world’s highest community prevalences of glucose intolerance, comparable to that of the Micronesian Nauruans and American Pima Indians.‘O Studies in Mauritius, a multiethnic nation in the Indian Ocean, show dramatically the potential public health catastrophe resulting from NIDDM. This may similarly occur in many other countries given that the ethnic composition of the Mauritius population mirrors the ethnic composition of over two-thirds of the global community. i4,15Mauritius has among the highest diabetes prevalence and diabetes-related mortality in the world with the age- and gender-standardized prevalence of NIDDM in adults very similar across ethnic groups-12.4% in Hindu Indian, 13.3% in Muslim Indians, 10.4% in Creoles, and 11.9% in Chinese, respectively. l5 The high prevalence found in Asian Indians has also been reported from the United Kingdom, Singapore, South Africa, Fiji, and Tanzania, and NIDDM is already common in some Indian subcontinent communities5J1J5 The implications for public health in modernizing India from the expected NIDDM epidemic are enormous. The Mauritius findings and evidence that the prevalence of NIDDM doubled between 1984 and 1992 in Singaporean Chinese provide alarming indicators of the size of the potential NIDDM epidemic which might occur in The Peoples’ Republic of China where the prevalence of NIDDM is currently less than l%.l” If China were to experience one-half the current rate of diabetes in Taiwan, the number of individuals with diabetes will increase dramatically from 7.7 million in 1994 to almost 32 million by 2010.’ The global projections for NIDDM for the years A.D. 2000 and 2010 are the best rationale for developing primary prevention programs for diabetes. Before em- 62 ZIMMET TABLE ] LX& Comp 1997; 1l:hU-68 ET AL. 1. GLOBAL ESTIMATES AND PROJECTIONS OF DIABETES: 1994 TO 2010 (IN THOUSANDS) 2000 1994 World/Region NIDDM Population* World Africa Asia North America Latin America Europe Former USSR+ Oceania 5,638,219 698,388 3‘346,376 286,041 483,862 510,873 284,654 28,025 2010. . ~~_.. NIDDM NIDDM 157,338 10,881 86,563 15,094 14,790 20,225 98,868 4,766 46,864 13,402 11,315 16,044 5,735 742 215,616 16,956 126,224 16,787 18,179 24,391 11,946 1,133 8,844 941 * In thousands. + Estonia, Latvia and Lithuania are included in Europe. barking on intervention activities, however, it is essen- Family and twin studies, along with the evidence for tial to have a better understanding of both the genetic heightened genetic susceptibility in certain populations, and genetic admixture studies provide firm eviand environmental determinants of NIDDM. dence that the role of the genetic component is very GENETIC AND ENVIRONMENTAL FACTORS strong.‘l IN THE ETIOLOGY OF NIDDM Numerous candidate genes have been studied in Genetic Factors. Progess in understanding the ge- relation to possible association with NIDDM, but linknetic component of NIDDM, particularly in defining age of NIDDM with these genes has been mostly negative.16 However, there have been some promising repotential candidate genes, has been slow until recently. sults from studies of families with maturity-onset diabetes of the young (MODY), where associations have beep found with the glucokinase gene and with mitochort&ial DNA mutations in families with NIDDM az$l nerve deafness.16,17 However, these forms would account for less than 2% of all casesof NIDDM. Nevertheless, the rapid advances in molecular genetics and the intense study of the human genome provide hope that the location of gene(s) that may be essential in defining susceptibility for the majority of cases of NIDDM may soon be discovered. Environmental Factors. While genetic susceptibility to NIDDM is clearly important, there is strong evidence that the disease is unmasked by environmental factors.5,9,1*,1s Several environmental risk determinants are associated with NIDDM, and these are shown in Table 2. More extensive reviews of these factors can be found TABLE (Standardized lceofN1 to Segi’s World Population) FIGURE 1 Prevalence of non-insulin-dependent diabetes mellitus (NIDDM) (type II diabetes) in selected countries. 2. ENVIRONMENTAL OF NIDDM 9 Age 9 Nutritional Factors l Obesity (central) l Physical inactivity l Intra-uterine l Modernization l Stress? l Others? DETERMINANTS 1 Diab Comp 1997; 1150-68 elsewhere.5,‘1,16,‘8 However, obesity, particularly centralized distribution of body fat (abdominal obesity), has been implicated as a primary risk factor for NIDDM in Europids, Mexican-Americans, Native Americans, Asian Indians, Chinese, and Creoles, and in both cross-sectional and longitudinal studies.5,“*‘6,‘9 (Figure 2). Physical inactivity emerges in epidemiological studies as another independent risk factor for the development of NIDDM. Cross-sectional studies have shown two- to fourfold increases in NIDDM prevalence in the least-active versus the most-active individuals and this finding seems to hold among a range of ethnic groups including Europids, Native Americans, Asian Indians, Chinese, Creoles, Polynesians, Micronesians, and Melanesians5,“,lhJ9 Exercise is also associated with a reduced risk of NIDDM in prospective studies.“,‘6,20 The association between physical inactivity and the risk of NIDDM remains even when adjusted for obesity, hypertension, and family on NIDDM.5,“,21 Exercise appears to have a protective effect against NIDDM possibly through improved insulin sensitivity,2’ which can be accentuated by weight loss obtained through increased physical activity. These findings assume great importance as physical activity has beneficial effects on blood lipids, blood pressure, and body weight/fat distribution, i.e., on several key components of the Metabolic Syndrome,21 so that exercise may also be important in preventing CVD in people with diabetes. Thus, exercise as a single intervention may reduce the incidence of more than one chronic disease. Low Birth Weight and Thrifty Phenotype. Low birth weight has been proposed as a new risk factor for NIDDM.22 Studies in the United Kingdom have demonstrated an inverse relationship between birthweight and glucose tolerance in adult life as well as other features of the Metabolic Syndrome.‘2,16,” Hales and Barker suggest that low birth weight, a reflection of nutritional deficiency in utero, is related to the later development of glucose intolerance, either IGT or NIDDM and the Metabolic Syndrome independent of current body-mass index and social class.22 Their interpretation of these findings is that impaired development of the endocrine pancreas and other tissues results from the long-term effects of the nutritional deprivation affecting fetal and infant growth. They proposed a “thrifty phenotype” hypothesis suggesting that NIDDM mainly results from environmental determinants, and genetic factors play minimal or no role.Z The “thrifty phenotype” hypothesis has created considerable interest, but does it hold up against available evidence? This interpretation of the low birth weight and diabetes data has been questionedI because, paradoxically, THE METABOLIC SYNDROME 63 IN NIDDM 8 15.0 I g 10.0 P 5.0 0.0 1 2 3 B 1 19.4 14.8 25.0 20.0 z 0 15.0 f? 2 f 10.0 E LL 5.0 0.0 Tertile of WHR FIGURE 2 Age-standardized prevalence of non-insulin-dependent diabetes mellitus (NIDDM) within crossed textiles of bodymass index (BMI) and waist/hip ratio WHR) in Mauritian men (A) and women (B). Prevalence of NIDDM f%) is shown above each bay and rates are age adjusted by the direct method to the total 1996 Mauritian population. Reprinted with permission from reference 33. it is also consistent with the thrifty genotype hypothesis.‘6,23*24 That is, those fetuses carrying a thrifty gene in an environment of intrauterine malnutrition were more likely to survive. The United Kingdom study is of necessity limited to survivors (small infants genetically predisposed to insulin resistance and NIDDM), and the thrifty phenotype hypotheses takes no account of the high mortality associated with a low birth weight.23,24 COMPLICATIONS OF DIABETES Persons with NIDDM have a substantially reduced life expectancy. 25,26 Their age-specific mortality rate is twice that of the population without NIDDM. This rate varies between populations and tends to diminish with in- 64 ZIMMET ] Dlab Cmp ET AL. creasing age at onset of NIDDM. Mortality data are readily available for most countries and have been used as indicators of the impact and scope of diabetes for international comparisons. There are, however, major limitations to their use including: inconsistent criteria used for classifying NIDDM variation in sampling, e.g., population compared to clinic-based studies underascertainment of NIDDM mortality on death certificates; and different death coding countries. practices within and among Space limitations prevent a detailed description of the microvascular and macrovascular complications of diabetes, which are reviewed in detail elsewhere.‘,27-30 Their main relevance in a public health perspective is the relationship to human suffering and disability, and socioeconomic costs through premature morbidity and mortality.3,31 For example, the major microvascular complications are diabetic retinopathy, nephropathy and neuropathy. The extent to which they occur is influenced predominantly by duration of diabetes and degree of metabolic control.2 Diabetic retinopathy may be apparent at the time of diabetes diagnosis, especially in NIDDM.32 Diabetes is the commonest cause of adult blindness in developed countries, either due to retinopathy, cataracts, or glaucoma.28 Diabetic patients are 17 times more prone to kidney disease, and diabetes is now the leading known cause of endstage renal disease in the United States2 As for diabetic neuropathy, it is probably the commonest complication being present in about 30%40% of insulin-dependent diabetes mellitus (IDDM) and NIDDM subjects.’ Atherosclerosis is the most common macrovascular complication of diabetes mellitus among Europids.2,6,27 It accounts for at least two-thirds of their deathsF6 a figure that is two to three times that in people without diabetes, and CAD and cerebrovascular diseases are also two to three times more common in diabetics as in nondiabetics. The WHO Multinational Study of Vascular Disease in Diabetics found marked differences in prevalence of macrovascular disease between 14 countries.27 The increase in atherosclerosis in diabetics as compared with nondiabetics was seen in all populations, even in those where the incidence of atherosclerosis was low, but the prevalence and pattern of microvascular disease was similar between countries. NIDDM AND THE METABOLIC SYNDROME There is still considerable debate as to whether the increased mortality from CAD in NIDDM is due to higher levels of known CVD risk factors along with 1997; ll:fX-68 NIDDM, or the greater clustering of these risk factors given the known association of IGT (a precursor of NIDDM) and NIDDM with other features of the Metabolic Syndrome or the Deadly Quartet.’ Epidemiological studies confirm that the Metabolic Syndrome does occur commonly in a number of ethnic groups including Europids, African-Americans, Mexican-Americans, Asian Indians, Chinese, Australian Aborigines, Polynesians, and Micronesiansn It has been suggested that insulin resistance and hyperinsulinemia are involved in the etiology and natural history of three chronic diseases-NIDDM, hypertension, and CAD.5,21 The cluster of related variables known as “Syndrome X” was described in certain individuals by Reaven.7 These variables include resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, very-low-density lipoprotein (VLDL) triglyceride, high-density lipoprotein (HDL) cholesterol, and hypertension. Sufficient evidence exists to include central obesity as part of the more aptly named Metabolic Syndrome.6,21 However, as our Pacific and Mauritius studies have demonstrated,5*33 the relationship of circulating insulin concentration with hypertension and CAD is inconsistent between ethnic groups and studies. As discussed below, hyperleptinemia/leptin resistance may play an important role and may be the missing link in the epidemiological association between insulin and the end points of CAD and hypertension.34 Haffner et a1.35have raised another most important issue: “When does the clock start ticking for CVD in persons with NIDDM?” From their data35 and our own in Nauru and Mauritius5s21 it is clear that the antecedent putative risk factors for CVD, particularly hyperinsulinemia, are present many years before NIDDM actually develops. This has important implications with respect to our attempts to prevent CVD in NIDDM. It would appear that unless NIDDM can be prevented, or the high-risk individuals pinpointed years before clinical onset of NIDDM, then it will be too late to prevent CVD in many persons. THRIFTY GENES, NIDDM, AND THE METABOLIC SYNDROME-A ROLE FOR LEPTIN? An attempt to explain the high prevalence of obesity and NIDDM in the American Pima Indians, Australian Aborigines, and Pacific Islanders comes through the thrifty gene hypothesises. 36 The basis for the genetic susceptibility to obesity and NIDDM has been unclear but could be the result of an evolutionary advantageous “thrifty” gene, which promoted fat deposition and storage of calories in times of plenty and provided a positive selective advantage during periods of food shortage and starvation. 36-38This would have conferred a survival advantage during the regular famines and natural disasters that were interspersed with feast peri- ] Diab Comp 1997; 11:60-68 TABLE THE METABOLIC 3. CORRELATIONS OF LEPTIN WITH ANTHROPOMETRIC AND IN WESTERN SAMOAN MEN AND WOMEN. Men Age Body mass index Waist/hip ratio Waist circumference Fasting insulin 2-hour insulin Fasting glucose 2-hour glucose Note: metabolic variables used in correlations *II = 55. 1 M = 65. r -0.10 0.81 0.54 0.81 0.69 0.65” 0.27 0.18+ were SYNDROME METABOLIC (n = 64) IN NIDDM VARIABLES Women (II = 71) P r P 0.441 <O.OOl <O.OOl <O.OOl <O.OOl <O.OOl 0.033 0.190 -0.23 0.82 0.28 0.84 0.73 0.55% 0.11 0.10 0.052 <O.OOl <O.OOl <O.OOl <O.OOl <O.OOl 0.363 0.415% log,, transformed. ods,37,38 but would result in NIDDM once they adopted a sedentary lifestyle and a diet with an excessof energy, simple carbohydrates, and saturated fats. It has previously been suggested that hyperinsulinemia/insulin resistance could be the phenotypic expression of the thrifty gene.21,37 However, we have preliminary data to suggest that the effects may be mediated by the newly described hormone, leptin. Leptin, the ob gene product secreted by fat cells, may have a role in appetite regulation, energy expenditure, and possibly modulation of insulin sensitivity in animal models of obesity,39,40and the location of its action is assumed to be situated in the hypothalamus. A major question is whether these observations apply to humans, or whether the leptin concentration measured in human blood is solely a reflection of the size of adipose tissue stores, the site of leptin production. We have studied the epidemiological associations of serum leptin with anthropometric, demographic, behavioural and metabolic factors in Polynesians (Western Samoa):* a population with a high prevalence of NIDDM and obesity!* Correlations between serum leptin and indices of obesity, and fasting and 2-hour insulin and glucose were computed (Table 3) and showed that leptin is closely correlated with bodymass index (BMI) and waist circumference in both genders, but less so with waist/hip ratio. Fasting and 2-h insulin also correlated strongly with leptin, whereas glucose and age did not. Mean leptin levels were compared in men and women across a range of 50 q Men (n=64) lWomen (n=71) 40 30 Leptin (ng/mI) I ~25 30-34 25-29 BMI FIGURE 3 65 Geometric mean lepfin concenfrafions 35-39 40+ (kg/m2) by class of body-mass index (BMI) in Polynesians (Western Samoa). 66 ZIMMET 1 Dlah Conrp IYY7; 1 I:611-68 ET AL. TABLE 4. LINEAR REGRESSION FOR VARIABLES ASSOCIATED 135 WESTERN SAMOANS Variable Sex BMI Fasting insulin BMI sex Intercept Note: metabolic P SE P p-value 1.66 0.091 0.19 0.011 0.067 0.006 0.32 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.41 -0.034 -3.30 variables COEFFICIENTS WITH LEPTIN IN (R = 0.82) used in correlations were log,, transformed. “vicious” cycle of hyperinsulinemia, more fat, and more leptin and resistance to its action is perpetuated. Another possible scenario is that insulin resistance may cause increased body fat, particularly centrally. More leptin is secreted from the expanding adipose tissue, the leptin receptor downregulates and appetite control is lost, and a similar vicious cycle is perpetuated. Underlying these pathogenic models and calculation is the assumption that all leptin detected in the serum is at least potentially biologically active. In conclusion, there is the possibility that leptin rather than insulin is a central factor of the Metabolic Syndrome. We have preliminary data to show significant and independent correlations between plasma leptin and BMI, fasting and 2-h plasma insulin, triglycerides, HDL cholesterol, and blood pressure,34 suggesting a possible underlying role for leptin. Further longitudinal studies examining the effect of leptin on insulin resistance using eugylycemic clamp techniques or other estimates of insulin resistance will clarify the direction of association between the two. Certainly, there is every reason to add hyperleptinemia to the risk factor cluster that constitutes the Metabolic Syndrome (Table 5). Resistance to leptin may well be the phenotypic expression of Neel’s “thrifty gene.“36 This is consistent with the natural history of obesity and NIDDM in Polynesians in Western Samoa and other Pacific Islanders whereby a metabolism suited to rapid weight gain through hyperleptinemia, then hyperinsulinemia and selective tissue insulin resistance would have been an advantage under alternating conditions of feast or famine.“7 BMI categories (Figure 3), which demonstrated that at any level of BMI, leptin was higher in women than men. Multiple linear regression was used to develop a model explaining variation in leptin levels in this population. A model including fasting insulin, gender, BMI, and a BMI by gender interaction term explained 82% of variance in leptin (Table 4). The strong relation of leptin with obesity, assessedby BMI or waist circumference, is consistent with leptin production being proportional to adipose tissue mass. However, the relation with insulin independent of BMI suggests a possible role for leptin in insulin resistance/hyperinsulinemic states. Studies in both animals43,44 and humans34,41,45,46 suggest potential roles for leptin in both the pathogenesis of NIDDM and insulin resistance. Several possible scenarios exist. First, that a hypothalamic-mediated resistance to leptin causes a rise in leptin and initiates hyperinsulinemia/insulin resistance.47Hyperinsulinemia leads to increased body fat, dyslipidemia due to lipoREDUCING MORTALITY FROM NIDDM genesis, and selective insulin resistance in muscle.21,38 The increased adipose mass produces more leptin, but, It is now well documented that features of the Metaas a result of downregulation of the hypothalamic lep- bolic Syndrome can be present many years before diagtin receptor, feedback regulation of appetite and en- nosis of NIDDM.21,35This assumes great importance in ergy balance break down. Hyperinsulinemia is sus- relation to our understanding of the etiology of tained by unregulated and continued feeding and the NIDDM and the associated CVD risk, and the potential to prevent CVD and its morbidity and mortality in persons with glucose intolerance. If the risk and the actual development of CVD starts TABLE 5. COMPONENTS OF THE REVISED many years before glucose intolerance manifests, then METABOLIC SYNDROME INCLUDING paradoxically the prevention of CVD in patients with HYPERLEPTINEMIA __NIDDM should commence before they are diagnosed . Glucose intolerance with diabetes. The diagnosis of the Metabolic Syn. Hyperinsulinemia drome without NIDDM provides a group at very high . Insulin resistance risk of future NIDDM. Thus, aggressive early manage. Microalbuminuria ment of the Syndrome may have a significant impact . Leptin resistance on both the prevention of NIDDM and CVD globally. . IncreasedVLDL triglycerides . Decreased HDL cholesterol ACKNOWLEDGEMENT . Hypertension This work was supported by grant no. DK-25446 from the . Upper body obesity National Institute of Diabetes and Digestive and Kidney Dis. Hyperleptinemia eases. We are erateful to Ameen Inc., Thousand Oaks, Cali- ] Din6 Camp THE 1997; 11:60-68 fornia, for performance of the leptin assays, and in particular Drs. M. Staten and M. Nicholson. REFERENCES World Health Organization (WHO): Prevention ofDiubetes Mel&us, Geneva, Technical Report Series no. 844, 1994. 3. Songer T: The economic costs of NIDDM. Rev 8:389404, 1992. 4. Hennekens GH, Buring JE: Epidemiology in Medicine. Boston, Little, Brown and Company, 1987. 5. Zimmet P: Challenges in diabetes epidemiology-From West to the rest. Diabetes Care 15:232-252, 1992. 6. Zimmet P: Non-insulin-dependent (type 2) diabetes mellitus-Does it really exist? Diabetic Med 6:728-738, 1989. 67 IN NIDDM (NIDDM). 19. Dowse GK, Zimmet PZ, Gareeboo H, Alberti KGMM, Tuomilehto J, Finch CF, Chitson P, Tulsidas H: Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole and Chinese Mauritians. Diubetes Cure 14:271-282, 1991. 20. Tuomilehto J, Knowler WC, Zimmet P: Primary prevention of non-insulin-dependent diabetes mellitus. Diubetes Metub Rev 8:339-353, 1992. 21. Zimmet stander. 22. Hales CN, Barker DJP: Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. abetologiu 35:595-601, 1992. Diabetes Metab 7. Reaven GM: Role of insulin resistance in human Diabetes 371595-1607, 1988. SYNDROME of non-insulin dependent diabetes mellitus Diabetes Metub Rev 8~287-338, 1993. 1. McCarty D, Zimmet P: Diabetes 2994 to 2020: Global Estimates and Projections. Melbourne, International Diabetes Institute, 1994. 2. METABOLIC P: Hyperinsulinaemia-How Diabetes Care 16:56-70, 1993. innocent a by- Di- 23. McCance DR, Pettit DJ, Hanson RL, Jacobsson LTH, Knowler WC, Bennett PH: Birth weight and non-insulin dependent diabetes: Thrifty genotype, thrifty phenotype, or surviving small baby genotype? B M J 308:942945, 1994. disease. 8. Kaplan NM: The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridaemia, and hypertension. Arch Intern Med 149:1514-1520, 1989. 24. WaldhBusl W, Fasching I’: Fetal growth and impaired glucose tolerance in men and women. Diubetologia 36:973-974, 1993. 9. Zimmet P, Dowse G, Serjeantson S, Finch C, King H: The epidemiology and natural history of NIDDM-Lessons from the South Pacific. Diabetes Metab Rev 6:91-124, 1990. 25. Finch CF, Zimmet PZ: Mortality from diabetes, in Alberti KGMM, Krall LP (eds), The Diabetes Annunl/4. Amsterdam, Elsevier, 1988, pp. 1-16. 26. 10. King H, Rewers M: WHO Ad Hoc Diabetes Reporting Group: Global estimates for prevalence of diabetes mellitus and impaired glucose tolerance in adults. Diabetes Care 16:157-177, 1993. Panzram G: Mortality and survival in type 2 (non-insulin-dependent) diabetes mellitus. Diubetologia 30:123131, 1987. 27. Bennett PH, Bogardus C, Tuomilehto J, Zimmet P: Epidemiology and natural history of NIDDM: Non-obese and obese, in Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds), International Textbook of Diabetes Mellitus. London, John Wiley, 1992, pp. 147-176. Jarrett RJ: Epidemiology of macrovascular disease and hypertension in diabetes mellitus, in Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds), International Textbook of Diabetes Mellitus. John Wiley and Sons, 1992, pp. 1459-1470. 28. Klein R, Moss SE: Visual impairment and diabetes, in Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds), International Textbook of Diabetes Mellitus. John Wiley and Sons, 1992, pp. 1373-1384. 29. Viberti GC, Walker JD, Pinto JD: Diabetic nephropathy, in Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds), International Textbook of Diabetes Mellitus, John Wiley and Sons, 1992, pp. 1267-1328. 30. Ward JD: Diabetic neuropathy, in Alberti KGMM, DeFronzo RA, Keen H, Zimmet P (eds), Intermtionul Textbook of Diabetes Mellitus. John Wiley and Sons, 1992, pp. 1385-1414. 31. Vaughan P, Gilson L, Mills A: Diabetes in developing countries: Its importance for public health. Health Policy Planning 4:97-109, 1989. 32. Harris MI, Klein R, Welborn TA, Knuiman MW: Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 15:815-819, 1992. 33. Collins VR, Dowse GK, Finch CF, Zimmet PZ: An inconsistent relationship between insulin and blood pressure in three Pacific island populations. J Clin Epidemiol 43:1369-1378, 1990. 34. De Courten M, Zimmet I’, Hodge A, Collins V, Nicolson M, Staten M, Dowse G, Alberti G: Hyperleptinaemia: 11. 12. 13. Humphrey ARG, Zimmet PZ, Hamman RF: The epidemiology of diabetes mellitus. Diabetes Annu 9:1-31,1995. Dowse GK, Spark RA, Mavo B, Hodge AM, Erasmus RT, Gwalimu M, Knight LT, Koki G, Zimmet PZ: Extraordinary prevalence of non-insulin-dependent diabetes mellitus and biomodal plasma glucose distribution in the Wanigela people of Papua New Guinea. Med J Australia 160:767-774, 1994. 14. Zimmet I? Diabetes care and prevention-Around the world in 80 days, in Rifkin H, Colwell JA, Taylor SI (eds), Diabetes 2991. New York, Elsevier, 1991, pp. 721-729. 15. Dowse GK, Gareeboo H, Zimmet PZ, Alberti KGGM, Tuomilehto J, Fareed D, Brissonnette LG, Finch CF: High prevalence of NIDDM and impaired glucose intolerance in Indian, Creole and Chinese Mauritians. Diubetes 39:390-396, 1990. 16. 17. 18. Zimmet P: The pathogenesis and prevention of diabetes in adults: Genes, autoimmunity and demography. Diubetes Cure 18:1050-1064, 1995. McCarthy MI, Froguel I’, Hitman GA: The genetics of non-insulin-dependent diabetes mellitus: Tools and aims. Diubetologia 37~959-968, 1994. Hamman RF: Genetic and environmental determinants 68 ZIMMET \ Dinb Camp 1997; 17:60-68 ET AL. the missing link in the Metabolic Medicine 1997 (in press). Syndrome? Diabetic 35. Haffner SM, Stern Ml?, Hazuda HP, Mitchell BD, Patterson JK: Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset on clinical diabetes? IA&IA 263:2893-2898, 1990. 36. Neel JV: Diabetes mellitus: detrimental by ‘progress’? 362, 1962. 37. Dowse G, Zimmet P: Editorial. The thrifty genotype in non-insulin-dependent diabetes. The hypothesis survives. B M J 306:532-533, 1993. 38. Zimmet I?, O’Dea K: Thrifty genotype, in Leslie RD (ed), Causes of Diabetes, London, John Wiley and Sons, 1993, pp. 269-290. 39. Zimmet P, Collier G: Of mice and (wo)men: (ob) gene, its product, leptin and obesity, 164:393-394, 1996. 40. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM: Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269:543-546, 1995. 41. Zimmet P. Hodge A, Nicolson M, Staten M, de Courten M, Moore J, Morawieczki A, Lubina J, Collier G, Alberti G, Dowse G: Serum leptin concentration, obesity, and a thrifty genotype rendered Am J Hum Genetics 14:353- 42. 43. 44. 45. the obesity Med I Aust 46. 47. insulin resistance in Western Samoans: cross sectional study. B M J 313:965-969. Collins VR, Dowse GK, Toelupe I’, Imo T, Aloaina F, Spark RA, Zimmet PZ: Increasing prevalence of NIDDM in the Pacific island population of Western Samoa over a 13-year period. Diabetes Care 17:288-296, 1994. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540-543, 1995. Campfield LA, Smith FJ, Guisez Y, Devos R, Bum I? Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546-549, 1995. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM: Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155-1161, 1995. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF: Serum immunoreactiveleptin concentrations in normal-weight and obese humans. N Engl 1 Med 334:292-295,1996. Collier G, Walder K, Lewandowski I’, Sanigorski A, Zimmet P: Does the ‘thrifty gene’ cause leptin resistance? Diabetes 1997, (in press).