Prediabetes Does Not Predict Diabetes

It is estimated that 7.3% of the global adult population has some alterations in their metabolism resulting in hyperglycemia, an increase in blood sugar, not to the range we determine is diabetes, but heading in that direction, the individual with “prediabetes.”

Increasingly, we are learning that the road to that particular perdition is not one-way, nor is there any specific speed. A new paper in the Journal of Internal Medicine seeks to elucidate our natural history as we slide from what we consider healthy glucose metabolism to a state we consider markedly abnormal. 

The population being studied are Swedish volunteers, age 60 or more, living in central Stockholm. The report on 2575 of these volunteers represents roughly 75% that were eligible and completed the twelve-year study. Average age 74.4, 65% women and 36% had a diagnosis of prediabetes, based on an HbA1c, at the initiation of the study.

• Of those individuals already considered to be prediabetic, 42% remained unchanged, 22% returned to normoglycemia, and 13% went on to develop diabetes. [1] 
• Increasing age was associated with more individuals developing diabetes or reverting to normoglycemia. But this trend was “biased” by decreasing population size as mortality also increased with age. It may be “truer” to say that the conversion rates to both diabetes or normoglycemia decreased with age, for many pre-diabetes was the destination, not a way station. 
• Those who were overweight were almost three times as likely to go on to diabetes and in the same group those who lost weight (in the range of 5 to 33 pounds) were three times as likely to become normoglycemic.
• Physical activity was noted to decrease mortality having no “direct” effect on glucose metabolism. The statistical significance of physical activity was lost when weight losses were adjusted suggesting that weight loss and physical activity are entangled

You can quibble about several aspects of the study, relatively small sample, very limited criteria for the diagnosis of prediabetes, and no information presented on the other 64% of patients. But that is not my purpose. 

Consider type 2 diabetes to be some summit. As with any mountain, there are many paths to the top, some paths are more difficult, others easier, but in both instances, you will arrive at the summit. When I go for a hike in my local park, the trails are constructed so that if you want a longer walk, you can combine trail 1 and trail 2 seamlessly; you needn’t finish one to begin another. 

Currently, there are at least 20 genes implicated in type 2 diabetes, and each resulting protein may have a positive, negative, or no effect on any of the others. The combinatorial space, the map of the trails on the mountain that is the type 2 diabetes phenotype for these interactions I’m sure exceeds 5000 or more possible configurations. Some of those paths are more used than others. In this study, the trail involved HbA1c and described the subsequent destination of its climbers. But there are already, as the authors acknowledge, other known trails, fasting blood glucose, oral glucose tolerance testing, any of the measurements we can make are merely markers upon the paths and each path is entangled with one another. When we speak of phenotypic disease, the summit in my metaphor, these paths are not clearly identified or understood.

42% of patients stayed on one trail and never reached the summit, 22% found an alternative path, a side branch, weight loss/physical activity, that lead them down the mountain while the remaining 13% continued upwards. Is there an advantage to conceptualizing diseases in this way? Of course, the answer is it depends. For those interested in the details of the trail, its changing elevations, walking surfaces, then comprehension precedes competence. For those more interested in the destination, then perhaps it is sufficient to be competent without full understanding. While my analytic side seeks the former, my clinical side sees the practicality of the second view; and yes, those two sides are as entangled as the pathways.

In terms of prediabetes, whatever that may actually mean, it seems that losing weight is an easy path down the mountain; whether weight loss reduces insulin insensitivity or increases the conversion of the delta to beta cells makes little difference. Perhaps that is why the tenets of a long “health span,” the latest term for a healthy life, include exercise and maintaining your healthy weight.

[1] The remaining 23% had died during the interval

Source: Natural history of prediabetes in older adults from a population-based longitudinal study Journal of Internal Medicine DOI: 10.1111/joim.12920