ADA 2009: Glucose Metabolism Changes Evident 13 Years Before Diabetes Diagnosis

Martha Kerr

June 12, 2009

June 12, 2009 (New Orleans, Louisiana) — The prospective Whitehall II study of British civil servants shows “...changes in glucose concentrations, insulin sensitivity, and insulin secretion as much as 3 to 6 years before diagnosis of diabetes.”

Insulin resistance and beta-cell dysfunction are evident up to 13 years before diagnosis, but the trajectory of the change really begins to accelerate in the 3 to 4 years before diagnosis.

These results from the prospective Whitehall II study were presented here this week during the American Diabetes Association (ADA) 69th Scientific Sessions by principal investigator Adam G. Tabak, MD, of the Department of Epidemiology and Public Health at University College London, United Kingdom. Study findings were simultaneously published online June 8 in The Lancet.

Whitehall II involved 6538 subjects without diabetes at baseline. Nearly all (91%) were white and 71% were men. Age range at baseline was 35 to 55 years.

The investigators measured fasting and 2-hour postload glucose levels, insulin sensitivity, and beta-cell function for an average of 9.7 years, but for as long as 13 years before a diagnosis of diabetes was made.

During follow-up, 505 diabetes cases were diagnosed, with 49.1% of diagnoses made based on oral glucose tolerance testing.

“All metabolic measures followed linear trends in the group of nondiabetics...except for insulin secretion that did not change during follow-up,” Dr. Tabak and colleagues report in their abstract.

Among diabetics, fasting glucose was accompanied by “...a steep quadratic increase.” Fasting glucose levels averaged 5.79 mmol/L at baseline and increased to 7.40 mmol/L “...starting three years before a diagnosis of diabetes,” Dr. Tabak and colleagues report.

Two-hour postload glucose “...showed a rapid increase starting three years before diagnosis,” from 7.60 mmol/L at baseline to 11.90 mmol/L after 3 years.

Steep Increase Before Diagnosis

Insulin resistance was evident 13 years before diagnosis. “There was a faster increase beginning at about four years. By the year before diagnosis, there was a very fast, very steep increase,” Dr. Tabak told meeting attendees.

Insulin sensitivity “decreased steeply during the 5 years before diagnosis, to 86.7%," he said. "Beta-cell function showed a compensatory increase beginning 13 years before diagnosis. At 3 to 4 years before diagnosis, beta-cell function increased from 85.0% to 92.6% at the time of diagnosis. Beta-cell function decreased to 62.4% after the diagnosis of diabetes had been made."

“The description of biomarker trajectories leading to diabetes diagnosis could contribute to more accurate risk prediction models that use repeated measures available for patients through regular check-ups,” the authors write.

“We think that our study confirms on a population level that both insulin resistance and beta-cell dysfunction are already present years before diagnosis,” Dr. Tabak told meeting participants.

“We hope that this might help build new risk prediction models that make use of the wealth of repeated measures of glucose already present in patient records over the years in clinical practice during regular checkups and point to window of opportunity of screening and prevention.”

Prevention More Effective in Preclinical Period

“It also supports hypothesis that prevention is more effective in the preclinical period, before the classic symptoms are evident,” Dr. Tabak said. His conclusion was echoed by R. Paul Robertson, the American Diabetes Association’s president of medicine and science, and an endocrinologist at Swedish Medical Center in Seattle, Washington.

“I recommend treating patients when they have prediabetes, when impaired glucose metabolism is present, but A1C levels might still be normal,” Dr. Robertson told Medscape Diabetes & Endocrinology. “Early, aggressive treatment might prevent some of the complications of diabetes that might already be present by the time the diagnosis is made.

“And early intervention might head off some cases of prediabetes from developing into overt diabetes,” he added. “Prediabetes does not mean that diabetes is inevitable.”

Dr. Tabak has disclosed no relevant financial relationships. Dr. Robertson receives support from Merck & Co.

American Diabetes Association (ADA) 69th Scientific Sessions: Abstract 1050-P. Presented June 8, 2009.

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