Mapuche Indian, Chile urban Chinese, Da Qing rural Melanesian, PNG Polish rural Polynesian, W. Samoa rural Bantu, Tanzania rural Indian, India Russian Brazilian rural Melanesian, Fiji Italian, Sanza Maltese urban Bantu, Tanzania Italian, Laurino White, USA Tunisian urban Hispanic, USA* rural Micronesian, Kiribati urban Polynesian, W. Samoa urban Indian, India urban Melanesian, Fiji rural Hispanic, USA Black, USA urban Indian, S. Africa Puerto Rican, USA urban Hispanic, USA # Chinese, Mauritius urban Hispanic, USA • rural Indian, Fiji urban Indian, Fiji urban Micronesian, Kirabati Micronesian, Nauru Pima Indian, USA

30 40

Prevalence (%)

I Diabetes mellitus

* upper income

# middle income

30 40

Prevalence (%)

I Diabetes mellitus

I I Impaired glucose tolerance

Figure 5 Prevalence (%) of diabetes and IGT in selected populations in the age range of 30-64years; genders combined. Copyright © 1993 American Diabetes Association. From Diabetes Care volume 16, page 170. Reprinted with permission from the American Diabetes Association.

prevalence of IGT and type 2 diabetes is steadily increasing. Hence, the prevalence reported in 1993 is an underestimation of the prevalence today. It has to be emphasized, however, that the difference in reported prevalence rates between different populations may be partially explained by methodological differences. For example, the prevalence of IGT and type 2 diabetes is increased by age, and in many populations there is also a higher prevalence in women than in men, at least in younger age groups. Different studies have not controlled for these confounders. Furthermore, due to migration patterns in some populations, generalization of study results is questionable, and there may also be differences in the likelihood of subjects attending a study between different populations. Nevertheless, a true ethnic difference seems to exist, with extremely high values in some Pacific island and North American Indian populations and a low prevalence in South American Indian and Bantu populations. An interesting observation is that the increase in prevalence of IGT and type 2 diabetes seems to be higher in populations with low prevalence rates and vice versa, which probably will result in diminished differences in prevalence rates between different populations in the future.

Clinical Consequences of IGT

IGT is an important risk factor for development of type 2 diabetes. However, prospective and long-term studies report different predictive values for the development of type 2 diabetes in different populations. In general, the risk of transition of IGT into type 2 diabetes ranges from 1-2% to 5% and as high as 15-20% per year. The risk is higher for those older than 50 years of age. There is also evidence that hyperglycemia, even at levels not reaching the threshold for type 2 diabetes, is associated with a substantial risk for the development of cardiovascular diseases. One explanation for this is that glucose initiates metabolic perturbations of importance for developing angiopathy, such as tissue peroxidation, production of plasminogen activation inhibition-1, and impairment of endothelial function, such as nitric oxide production. Another explanation is that hyperglycemia is associated with a number of risk factors for cardiovascular diseases, such as high blood pressure, hyperinsulinemia, dyslipidemia, and microalbuminuria, which all are included in the metabolic syndrome. In fact, if hyperglycemia is present, the risk for developing cardiovascular diseases for each of the other risk factors is augmented. Attempts to define cutoff values of glucose for cardiovascular risks have been problematic, however, probably due to the fact that the risk is continuously increased across the glucose ranges. Hence, the use of defined cutoff values is more a convenient practical issue, which is important in a clinical setting, but offers limitations from a theoretical standpoint.

Since IGT is a risk factor for type 2 diabetes and cardiovascular diseases, it is also a risk factor for overall mortality. Alberti and coworkers attempted to quantify this by performing a meta-analysis on 13 prospective studies, and they identified a hazard ratio of 1.34 (95% confidence interval, 1.14-1.57) by comparing subjects with IGT to those with normal glucose tolerance. The hazard ratio is higher for subjects with IGT than for subjects with IFG, suggesting that the 2-h glucose value is more predictive of mortality than the fasting glucose value. This shows that an individual with IGT has an increased risk not only for type 2 diabetes but also for cardiovascular diseases and hence mortality. This indicates that attempts should be made to prevent IGT from progressing to cardiovascular diseases and type 2 diabetes.

Treatment of IGT

During recent years, the issue of whether IGT may be treated to prevent progression to type 2 diabetes or cardiovascular diseases has gained considerable interest. On the one hand, it has been argued that it is important to prevent progression of IGT. On the other hand, it has been argued that treating such a large population group as those with IGT would be risky. Table 2 lists criteria that need to be fulfilled to justify prevention of a condition. In fact, most of these criteria are met for IGT; therefore, it may be argued that treating IGT is now justified. The optimal preventive intervention for IGT is not known, however. The intervention may include lifestyle changes, notably increased physical activity and dietary regulations. Such interventions have been shown to be efficient in highly motivated populations and study centers. However, whether generalization of these results to the general population is possible is not known. A clinical experience is that the outcome of advice on lifestyle changes is often disappointing in the long term. Another mode of

Table 2 Criteria for recommending population-based intervention for preventing a disease3

Criterion 1: The disease (IGT and type 2 diabetes) should pose a major health problem.

Criterion 2: Early development and natural history of the disease (IGT and type 2 diabetes) should be understood to identify parameters that measure its progression.

Criterion 3: Tests should exist for diagnosing the presumptive population (OGTT).

Criterion 4: Preventive methods should be safe, efficient, and reliable.

Criterion 5: Effort to find subjects and cost of intervention should not be burdensome and should be cost-effective.

aBased on recommendations from the American Diabetes Association (2004).

IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test.

intervention is pharmacological treatment using compounds to stimulate insulin secretion, suppress hepatic glucose production, and/or enhance insulin sensitivity. These may be efficient, perhaps more efficient than advice on lifestyle changes, but may in turn pose other questions concerning long-term efficiency and potential adverse events. These two strategies are not mutually exclusive, however, and introducing pharmacological intervention without giving lifestyle advice is not appropriate in a clinical setting.

Recently, interesting data from large population studies on the prevention of progression of IGT have been obtained. Two studies, the Finnish diabetes prevention study and the Diabetes Prevention Program, have shown that lifestyle changes (i.e., individualized diet and exercise counseling) in subjects with IGT reduced the incidence of diabetes by more than 50%. In addition, in the Diabetes Prevention Program, it was shown that metformin (which reduces glucose output from the liver) reduces the risk by approximately 30%. This suggests that pharmacological treatment of IGT prevents development of type 2 diabetes. Several large studies are ongoing and results are expected within a few years.

Whether interventional programs on IGT are valid also for the prevention of cardiovascular diseases is not clearly established, mainly because long-term studies have not been performed. The STOP-NIDDM study, however, showed that acarbose, which reduces glucose absorption from the gut, reduced cardiovascular events by more than 30% during a 3-year study period. This suggests that cardiovascular diseases may be prevented by treating IGT. It should be noted, however, that for prevention of cardiovascular diseases and mortality, more studies and longer follow-up periods are required.

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