When Does Type 2 Diabetes Start? Changes Evident 20 Years Before

BERLIN — Type 2 diabetes may start up to 20 years before diagnosis with a slow build-up of metabolic changes including alterations in fasting plasma glucose and insulin sensitivity, shows a study that explored the timeline of progression to diabetes by comparing data from people who did and did not go on to develop the disease.

Hiroyuki Sagesaka, MD, from Aizawa Hospital in Matsumoto, Japan, led the research, along with Mitsuhisa Komatsu, MD, PhD, from Shinshu University Graduate School of Medicine, Matsumoto, Japan, and colleagues. Komatsu presented the results here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting.

"As the vast majority of people with type 2 diabetes go through the stage of prediabetes, our findings suggest that elevated metabolic markers for diabetes are detectable more than 20 years before its diagnosis," Komatsu told Medscape Medical News.

The time point at which individuals who go on to develop diabetes and those who don't first become substantially different from each other was not known until now, he explained.

"What is new about our study is that we reveal the trajectory of prediabetes. This allows us to evaluate the very early stages of the disease."

Asked how he believed these data might serve a practical purpose, Komatsu suggested that the results "show that very early intervention or lifestyle modifications are needed not just upon diagnosis but in young adults, or even children. The sooner, the better in the fight against diabetes."

The research was published earlier this year (J Endocr Soc. 2018;2:476-484).

Asked to comment, Dan Howarth, Head of Care at Diabetes UK, said: "This research seems to hint at the possibility of spotting the signs of type 2 diabetes long before an official diagnosis."

"While this research was carried out in a specific Japanese population, we know that there are around a million people in the UK alone who already have type 2 diabetes and don't yet know it."

"Knowing your risk at any point in time is of course helpful in avoiding or preventing a diagnosis of type 2 diabetes. Whether you're at increased risk of type 2 diabetes or not, everyone should be encouraged to live a healthier lifestyle by eating better and moving more."

Dataset of More Than 27,000 People Followed

The Japanese researchers aimed to clarify when plasma glucose starts to rise in those who eventually develop diabetes to shed more light on the developmental timeline of the disease.

In total, 27,392 people without diabetes were initially tracked between 2005 and 2016 until a diagnosis of type 2 diabetes or prediabetes, or the end of 2016, whichever came first. Mean age was 49 years, mean body mass index (BMI) was 22.6 kg/m², and 11,495 were female.

At the start of the study, 15,778 participants had had normal glucose regulation and 11,614 had prediabetes.

Over the study period, 1067 new cases of type 2 diabetes were identified. Findings showed that, on average, several risk factors were more common among individuals who went on to develop type 2 diabetes compared with those who didn't. In particular, BMI, fasting glucose, and insulin resistance were increased up to 10 years before diagnosis, and these differences widened over time.

"Plasma glucose is already elevated at -10 years, and this is followed by a gradual rise up to 1 year prior to diagnosis, and then finally, there is a sharp rise within the year leading up to diagnosis," reported Komatsu.

For example, mean fasting glucose at 10 years prior to diagnosis was 101.5 mg/dL in those who went on to develop diabetes versus 94.5 mg/dL in those who did not. By 5 years prior to diagnosis, fasting plasma glucose was increased to 105 mg/dL versus 94 mg/dL, and then at 1 year before diabetes diagnosis, these respective numbers were 110 mg/dL versus 94 mg/dL.

In people diagnosed with diabetes, BMI rose from around 24 kg/m²to 25.5 kg/m², but remained relatively stable in those who did not develop diabetes. And insulin sensitivity (estimated by the surrogate measure Single Point Insulin Sensitivity Estimator [SPISE]) also dropped in people who progressed to type 2 diabetes (7.4 to 6.6 over 10 years) but remained relatively stable in those who didn't develop diabetes.

Of the 15,778 individuals with normal blood glucose at the initial health exam, 4781 went on to develop prediabetes over the study period, and the same abnormalities, although to a milder degree, were present at least 10 years before diagnosis of prediabetes.

Komatsu said that, in those who are destined to develop diabetes, "we think that sedentary lifestyle and overeating cause mild liver insulin resistance and elevate fasting glucose because of insufficient insulin secretion from the pancreas."

In contrast, "Obese people whose pancreas secretes insulin as required simply have obesity without diabetes," he added.

Senior author Sagesaka stressed that their new findings emphasize the importance of very early intervention.

"Because trials of prevention in people with prediabetes seem to be less successful over long-term follow-up, we may need to intervene much earlier than the prediabetes stage to prevent progression to full-blown diabetes," he said.

"A much earlier intervention trial, either drug- or lifestyle-related, is warranted."

Komatsu, Sagesaka, and Howarth have reported no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 1-5, 2018; Berlin, Germany. Abstract 312.

J Endocr Soc. 2018;2:476-484. Full text

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