Glucose Metabolism can Forecast Diabetes Five Years Ahead

But beta-cell function abnormalities emerged three to four years before onset and insulin sensitivity fell sharply over the five years before diagnosis, they reported here at the American Diabetes Association meeting and online in The Lancet.

These biomarker trajectories, determined at regular check-ups over time, could improve the accuracy of risk prediction models to allow for earlier prevention efforts, the researchers said.

The models typically use only the most recent blood glucose measurements, with prevention then focusing on patients who meet glucose-based prediabetes criteria, they noted. However, waiting to intervene until prediabetes may be too late, since they are “already on the steep part of the glucose trajectory,” the researchers said. “We hypothesize that prevention would be more effective before this unstable period.”

“If a person could be kept on the linear part of the fasting glucose (or postload glucose) trajectory, the onset of diabetes might be substantially delayed,” they said.

The results provide “unique longitudinal data illuminating what had long been suspected from cross-sectional data,” said David R. Matthews, M.D., and Jonathan C. Levy, M.D., both of the Oxford Centre for Diabetes at the University of Oxford in Oxford, England, in an accompanying editorial.

Although they expressed skepticism that the results could be used for earlier screening because the predictions would have poor sensitivity and specificity, they said beta-cell function and insulin resistance could be valuable additions to risk prediction.

“We know that we have proven advice and therapies that we can give,” they said. “Now the hunt has to be intensified for the pathology that causes the decompensation that precipitates diabetes.”

Dr. Tabák’s group examined the Whitehall II study for a “high-resolution” look at changing glucose metabolism over time in 6,538 British civil servants (71% male, 91% white) without baseline diabetes who were followed with repeated serum glucose measurements and oral glucose tolerance tests. Over up to 13 years of follow-up (median 9.7 years), 505 participants were diagnosed with diabetes.

Among those who did not develop the disease, metabolic changes were fairly gradual. Insulin secretion changed little. Modest, linear rises occurred in fasting glucose and slight falls for insulin sensitivity — a decline of about 15% over 13 years, which Drs. Matthews and Levy called “doubtless the effect of progressive inactivity and middle-age spread.”

For incident diabetes cases, fasting plasma glucose also declined linearly until three years before diagnosis, although with a 0.028-mmol/L-per-year steeper slope than seen in nondiabetics.

But the last three years leading up to diagnosis showed a rapid drop in fasting glucose levels following a quadratic trajectory.
For postload glucose levels, the rate of increase up until six years prior to the end of follow-up was not significantly different between study participants who would go on to develop incident diabetes and those who would not.

Again, though, diabetes cases showed 1.5-fold higher postload glucose concentrations that rose in a cubic trajectory during the six years before diagnosis to the end of follow-up. In the two years before diagnosis, cases had a rapid increase in glucose concentrations from 7.60 to 11.90 mmol/L.

Insulin sensitivity declined identically between groups (1.11% per year) until five years before diagnosis. After that point, the slope was an absolute 2.76% steeper among diabetes cases to reach 86.7% by the end of the 13-year follow-up.

Beta-cell function measured by calculated insulin secretion averaged 10.4% higher in individuals who would develop diabetes up until the four years prior to diagnosis, which the editorialists explained as a compensatory effort to “maintain normoglycemia in a prevailing climate of insulin resistance.”

Then roughly three years before diabetes onset, beta-cell function revealed “a further last-ditch increase” with a quadratic increase before crashing to 62.4% of normal.

Sensitivity analyses, including body mass index adjustment, had little impact on difference in trajectory of metabolic changes between groups.

The researchers said their findings supported a multistage model of diabetes development with a long compensatory period, then a stable adaptation, and finally “a transient unstable period with a rapid rise of glucose to overt diabetes.”
Practice Pearls:

Explain to interested patients that the body’s insulin-producing cells and its use of blood sugar can change years before meeting standard criteria for a diabetes diagnosis.

Note that the longitudinal study was done in a largely white, male population but likely would generalize to other populations.

Tabák AG, et al “Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study” Lancet 2009.