As the epidemic of diabetes continues to worsen, developing and implementing preventive strategies has become critical. A number of clinical trials (2
) have demonstrated the effectiveness of lifestyle and/or drug therapy at preventing diabetes in people with pre-diabetes, but none have examined the effectiveness of an intervention on returning those with pre-diabetes to NGR. To expand the paradigm of diabetes prevention, the aim of the current study was to examine the effect of basal biologic factors, weight change, and prevention strategies (ILS or metformin) on the incidence of regression from pre-diabetes to NGR. The major findings from this analysis were that 1
) insulin secretion, and other biologic processes that are retained with younger age, are key in the restoration of NGR in people with pre-diabetes; however, 2
) NGR may also be attained through weight loss and additional aspects of ILS, such as healthy eating and exercise.
ILS and metformin both have been shown to be effective strategies for diabetes prevention, but in the DPP only ILS restored NGR significantly more frequently than did placebo (2
). Different impact of ILS versus metformin on parameters of insulin sensitivity or secretion did not explain these results. This observation lends support for the notion that aspects of ILS beyond insulin sensitization per se are key in truly reducing diabetes risk.
Weight loss appears to be the most important component of ILS predicting regression, with every 1 kg lost associated with a 16% reduction in diabetes risk (14
). Weight loss strategies inclusive of exercise preferentially mobilize fat from the visceral depot, inducing more favorable metabolic results than would fat mobilized from the subcutaneous depot (15
). Interestingly, however, ILS, independent of weight loss, also predicted regression to NGR in our study. This finding implies a role for the other aspects of ILS, such as healthy eating or exercise, in restoring NGR. Indeed, healthy eating (16
) and exercise (17
) without weight loss have been previously and independently demonstrated as positive effectors on the metabolic milieu; however, we found no predictive effect toward regression for either in the current analysis. The combination of healthy eating with exercise or other pleiotropic effects of exercise may explain these findings but were not assessed in DPP participants.
In contrast to lifestyle change, some predictors of regression to NGR are not modifiable. For example, younger age was associated with regression to NGR in the current study. This was seen despite the previous finding that older DPP participants had greater success meeting ILS goals and with it the beneficial effect of lower diabetes incidence (18
). What age-related processes may be responsible is speculative. Considerable controversy exists as to whether age by itself (19
) (versus age-related body composition change [20
]) leads to the deterioration of insulin action and/or secretion.
Greater insulin secretion also predicted regression to NGR and may reflect the critical link between ILS, weight loss, and age in restoring and maintaining NGR. Weight loss and younger age either resulted in, or were associated with, lower baseline 2-h glucose levels in the DPP, likely reflecting the more robust β-cell responsiveness in these groups. Insulin sensitivity and secretion are integrally related, and the deterioration of each is felt to be requisite in the development of type 2 diabetes (21
). Nevertheless, longitudinal data (22
) clearly demonstrate the failure of the β-cell as the seminal event in this process. Therefore, one could surmise that the maintenance of insulin secretion is vital, as insulin sensitivity may be modified more readily than insulin secretion by ILS, weight loss, and/or age-related body composition changes.
All participants in the DPP had elevated 2-h and high-normal fasting glucose concentrations. As the combination of increasing fasting and 2-h glucose levels confers greater risk for diabetes than either in isolation (3
), there is reason to believe that regression from IFG/IGT to isolated IFG or IGT may also decrease diabetes risk. Other than the expected predictive effects of glucose concentration itself (high fasting and low 2-h glucose for IFG and the converse for IGT) and intervention effects on glucose concentration (ILS on fasting and 2-h glucose, metformin on fasting), we observed distinct predictors for reversion to isolated IFG and isolated IGT, likely reflecting their different pathophysiology (23
). Consistent with some, but not all, cross-sectional studies, those with isolated IFG were more likely to be insulin sensitive and male, whereas those with isolated IGT were more likely to have retained insulin secretion and be female (24
Several limitations of the current study are worth noting. First, the primary analyses were conducted using the ADA definition of IFG, which reduced the sample size and power to find differences. Additionally, the considerable amount of missing data exacerbated this issue. Nevertheless, when the entire cohort was analyzed, the results were largely unchanged. Second, by virtue of our analysis plan, the fate of those who may have changed glucose tolerance status more than once, spontaneously regressed, or were incorrectly classified due to the inaccuracy of the oral glucose tolerance test, was not captured. Finally, analyses were post hoc and exploratory with the intention of generating hypotheses and discussion on this topic. Prospective studies are needed to confirm the current findings.
In conclusion, true diabetes prevention likely resides in the restoration of NGR rather than in the maintenance of a high-risk state, such as pre-diabetes. Some factors governing the return to NGR are modifiable, and others are not. For example, age-related changes, particularly when leading to diminished insulin secretion, may permanently impede restoration of NGR. In other circumstances, however, NGR may be attained through weight loss and the combined aspects of ILS. Establishing healthy habits early in life, before age-related changes occur, is most likely the best strategy for diabetes prevention.