Dysglycemia and Progression to Type 1 Diabetes

Incident dysglycemia in those who are ICA positive is strongly predictive of Type 1 diabetes. Children with incident dysglycemia have an especially high risk.

There is increasing evidence that impaired glucose tolerance (IGT) is a predictor and common precursor of Type 1 diabetes. Still, little is known about the incidence of IGT and other forms of dysglycemia in individuals who have pancreatic autoantibodies and normal glucose tolerance. In addition, there is no information about the risk of Type 1 diabetes when dysglycemia occurs in those individuals. Moreover, it is not known whether dysglycemia is sustained once it occurs.

The study looked at the incidence of dysglycemia and its prediction of the development of Type 1 diabetes in islet cell autoantibody (ICA)-positive individuals. In addition, they assessed whether dysglycemia was sustained.

Participants (n = 515) in the Diabetes Prevention Trial-Type 1 (DPT-1) with normal glucose tolerance who underwent periodic oral glucose tolerance tests (OGTTs) were followed for incident dysglycemia (impaired fasting glucose, impaired glucose tolerance, and/or high glucose levels at intermediate time points of OGTTs). Incident dysglycemia at the 6-month visit was assessed for Type 1 diabetes prediction.

The results showed that of 515 participants with a normal baseline OGTT, 310 (60%) had at least one episode of dysglycemia over a maximum follow-up of 7 years. Dysglycemia at the 6-month visit was highly predictive of the development of Type 1 diabetes, both in those aged <13 years (P < 0.001) and those aged ≥13 years (P < 0.01). Those aged <13 years with dysglycemia at the 6-month visit had a high cumulative incidence (94% estimate by 5 years). Among those who developed Type 1 diabetes after a dysglycemic OGTT and who had at least two OGTTs after the dysglycemic OGTT, 33 of 64 (52%) reverted back to a normal OGTT. However, 26 (79%) of the 33 then had another dysglycemic OGTT before diagnosis.

The findings in this report have significant implications with regard to increasing the efficiency of prevention trials for Type 1 diabetes. Because the data show that dysglycemia will occur in an appreciable percentage of autoantibody-positive individuals whose initial screening is negative for dysglycemia, repeating OGTTs in those individuals should increase the yield of potential high-risk participants. Moreover, because children aged <13 years with incident dysglycemia have a very high risk for Type 1 diabetes (94% 5-year estimate despite the variability of dysglycemia), dysglycemia could possibly be used as an early indicator of efficacy in prevention trials for those with normal glucose tolerance at baseline.

The pathogenetic development of Type 1 diabetes appears to be an ongoing process with an initial immunologic insult to β-cells followed by progressive metabolic deterioration before and after diagnosis. Therefore, from both clinical and research perspectives, it may be advantageous to identify individuals as early as possible in this process. The very high likelihood that autoantibody-positive children will develop Type 1 diabetes within 5 years after the occurrence of dysglycemia suggests that the earlier identification of the disease is a distinct possibility.

From the results it was concluded that, ICA-positive individuals with normal glucose tolerance had a high incidence of dysglycemia. Incident dysglycemia in those who are ICA positive is strongly predictive of Type 1 diabetes. Children with incident dysglycemia have an especially high risk. Fluctuations in and out of the dysglycemic state are not uncommon before the onset of Type 1 diabetes.

Diabetes Care September 2009 vol. 32 no. 9 1603-1607