Several studies have investigated the factors predicting the development of type 2 diabetes in women with a history of gestational diabetes. However, in many studies only glycemic levels were analyzed, possibly with the addition of few basic clinical variables and anthropometric data 
. Other studies performed more detailed analyses, also including indices of insulin sensitivity or beta-cell function, but the follow-up period was short, being limited to 1–2 years 
Some recent studies partially overcame the main limitations of the previous analyses 
. In the study by Seghieri et al.
, both indices of insulin sensitivity and beta-cell function were studied. However, surprisingly insulin sensitivity was not found a significant predictor of diabetes development. Similarly, in the study by Ekelund et al.
, the findings about insulin sensitivity were inconclusive. The study by Xiang, Kjos et al.
reported a detailed analysis of several possible predictors of diabetes development, including indices of insulin sensitivity and beta-cell function from three different glucose tolerance tests, and extending the follow-up period to twelve years. Indices of both insulin sensitivity and beta-cell function were found to be predictors, together with the glycemic levels, of diabetes development 
. Thus, our findings are in agreement with those of the study 
. However, in the study 
no OGTT-based indices of insulin sensitivity or beta-cell function were found to be predictors of diabetes development. In the clinical routine, cumbersome tests such as the IVGTT or the glucose clamp may not be feasible, and this would prevent the application of the findings of study 
in terms of identification of the subjects at higher risk for later diabetes.
Among the substantial number of previous studies in women with a history of gestational diabetes, to our knowledge none reported detailed analysis of time trajectories of metabolic parameters in fGDM women that actually progressed to type 2 diabetes. This is the main novelty of our study. The only previous study that reported some information on time trajectories in fGDM women was the study by Xiang, Kawakubo et al.
, but the temporal analysis was limited to few metabolic parameters. Besides, in the study 
the subjects were not stratified between progressors and non-progressors, thus a direct comparison with our results is not possible. Finally and most importantly, our population included selected Central European women, while both studies by Xiang et al.
described Hispanic women, which may have metabolic differences compared to our women 
; furthermore, disparities in the diabetes risk for different populations of fGDM women have been outlined by another recent study by Xiang et al.
In our study, we have shown for the first time that the onset of hyperglycemia in fGDM is rapid, as it has been observed in other populations progressing to type 1 or type 2 diabetes 
. However, the mechanisms behind the development of hyperglycemia in fGDM appear to be specific, and related to exacerbation of insulin resistance on a background of a considerable impairment in beta-cell function since baseline (i.e., immediately after partum). It should be noted that both defects in insulin sensitivity and beta-cell function were clearly present at baseline in PROG. In fact, beta-cell glucose sensitivity and rate sensitivity (see ) were markedly lower in PROG than in NONPROG, and the difference remained significant after adjusting for age, BMI or both (Fisher's PLSD post hoc
Analysis of Covariance on logarithmically transformed values: P<0.003 for glucose sensitivity; P<0.01 for rate sensitivity). This is consistent with the findings of a previous study where beta-cell function defect was observed already 4–6 months after delivery in fGDM women that had both normal glucose tolerance and body weight 
. In addition, analysis of the time trajectories showed that, in PROG, some of the beta-cell function parameters exhibited a tendency to further decline during the observation period. Thus, we conclude that in PROG, beta-cell function showed both baseline impairment and some degree of further deterioration thereafter, and this is in agreement with the findings of study by Xiang, Kjos et al.
. It should be noted that beta-cell glucose sensitivity is not related to insulin sensitivity 
, thus the pattern represented in , c, correctly estimates the degree of beta-cell function deterioration. Insulin secretion at 5.5 mmol/l glucose (, d) may require some adjustment for insulin sensitivity 
, but this cannot be easily taken into account, since precise relationship between this parameter and the OGTT insulin sensitivity indices has not been determined. Adjustment for insulin sensitivity may yield a more marked decrease of insulin secretion at 5.5 mmol/l glucose.
Thus, the defects in beta-cell function appear evident in the PROG group. The defects in insulin sensitivity were also evident, since both OGIS and HOMA-R were markedly lower in PROG at baseline, and similarly to beta-cell function parameters they also exhibited a tendency to further decline during years. However, based on our analysis, these defects seem insufficient to explain the onset of diabetes, which occurs only when a rapid, marked deterioration in insulin sensitivity occurs, in correspondence with the rise of glucose levels. To our knowledge, this was not reported in any of the previous studies on fGDM.
As regards the progression towards type 2 diabetes of populations different than fGDM, a major study is that of Tabák et al.
. In that study, diabetes onset is due to a marked decline in beta-cell function, occurring in a relatively short time, accompanied by hyperglycemia, on a background of progressive decline in insulin sensitivity. It should be noted, however, that in the study 
an empirical surrogate of beta-cell function was employed, which may not yield the same evaluation of beta-cell function as does our OGTT-based approach. Therefore, although beta-cell dysfunction is a key factor for diabetes development also in our fGDM population, insulin resistance is likely to be the triggering phenomenon.
This observation on the crucial role of insulin sensitivity has potentially important therapeutic implications. In fact, our findings suggest that prevention strategies aimed at opposing to the insulin sensitivity derangement may be particularly beneficial. This may be feasible through lifestyle intervention only 
, whereas preserving beta-cell can be difficult without pharmacological intervention.
Some limitations of our study should be considered. The size of the analyzed population and consequently the number of progressors is limited, due mainly to the strict selection criteria of the analyzed subjects. However, a relatively small population size was also common to other relevant longitudinal studies on fGDM, including studies by Xiang et al.
. Another limitation of our study was that it was not possible to confirm our main findings, especially on insulin sensitivity, through tests different than the OGTT. Nonetheless, all the insulin sensitivity indices that we have evaluated are concordant in indicating the pattern observed in . It should also be acknowledged that, although our study shows a clear association between insulin sensitivity deterioration and diabetes onset, whether this is a causal relationship cannot be concluded with certainty. In fact, the causes of the deterioration in insulin sensitivity remain unclear. BMI may be one factor; however, a significant BMI change was observed only between year −2 and year −1, and not when the marked deterioration of insulin sensitivity was observed (year −1 to 0). An aspect recently emerging as possible factor affecting insulin sensitivity is breast feeding. Unfortunately, this information was not recorded precisely in our study. We know that all women breast fed at least partially, except for two of them (one in PROG, one in NONPROG), but further information was not collected. On the other hand, at the time of recruitment in the study, the women were not breastfeeding any more. In any case, the effect of breast feeding is still controversial, as recent studies reported either favorable effects on glucose metabolism 
or no significant effects 
In our study, subjects received the diagnosis of gestational diabetes according to criteria that were recommended when the study started 
. Recently, different criteria have been proposed by the American Diabetes Association 
and the International Association of Diabetes and Pregnancy Study Groups 
. However, these new criteria 
do not affect the present analysis, since all the subjects analyzed, diagnosed as having gestational diabetes with the old criteria 
, would receive the same diagnosis with the new criteria 
In conclusion, we have studied a selected group of Central European women with former gestational diabetes for a period up to seven years. During the follow-up period, 25% of the women developed type 2 diabetes. The main finding based on the analysis of the time trajectories of the metabolic parameters was that, on a background of impaired and slowly declining beta-cell function and insulin sensitivity, a further marked deterioration of insulin sensitivity is likely to be the crucial factor for the onset of diabetes.