Stabilization of Underlying Factors May Prevent Glycemic Deterioration

insulin testing
Blood sugar self-testing equipment, for diabetes, blue filter
Researchers investigated the processes underlying glycemic deterioration in patients with type 2 diabetes.

Declining insulin sensitivity, deteriorating β-cell function, and increased insulin clearance are crucial in mediating glycemic deterioration in patients with type 2 diabetes (T2D) immediately after diagnosis, according to research results published in Diabetes Care. Stabilization of a single trait can potentially prevent further progression.

Using data from a cohort of people recently diagnosed with T2D who took part in the Diabetes Research on Patient Stratification (DIRECT) study, investigators sought to understand the underlying processes of glycemic deterioration. In a multicenter, prospective study ( identifier: NCT03814915), investigators reviewed 3 years of data on hemoglobin A1c (HbA1c), β-cell function, insulin sensitivity, and other parameters.

At baseline, participants (n=732) were a mean age of 62 years, were moderately obese (BMI, 30.4±4.9 kg/m2), had a HbA1c of 6.41%, and a fasting glucose of 7.1 mmol/L. In total, 34% of participants were treated with metformin, and the remaining participants were treatment naive.

After adjustment for changes in BMI and diabetes medication, individual HbA1c progression rates distributed close to their mean, though the distribution showed a heavy right-sided tail with values up to 0.897% per year (9.8 mmol-1 year-1). The standardized coefficient for BMI effect was 0.37.

Faster HbA1c progression was independently associated with lower baseline values (P <.001), subsequent faster deterioration of insulin sensitivity and β-cell function (P <.001), and higher baseline values of mixed-meal tolerance test and insulin clearance (P <.001). Another multivariable analysis showed that baseline visceral fat, female sex, and younger age were positively and independently correlated with HbA1c progression rate.

When reviewing the trajectories of the variables that independently affected HbA1c progression, investigators found that in fast progressors, insulin sensitivity and β-cell glucose sensitivity “strongly declined,” while fasting triacylglycerol and insulin clearance markedly increased. At baseline, these patients had lower insulin sensitivity (P <.001), lower insulin clearance (P <.01), lower high-density lipoprotein cholesterol (P <.05), and higher BMI (P <.01).

To avoid fast progression, researchers emphasized the importance of maintaining stability in just 1 of 3 factors: insulin sensitivity, β-cell glucose sensitivity, or insulin clearance. When all 3 factors were deteriorating, 56% of patients became fast progressors. When a single trait is stable, this decreased to 8% to 10%.

A significant study limitation is the short follow-up period of only 3 years, which results in limited accuracy of estimated HbA1c progression. Additionally, causal relationships could not be inferred from the regression analyses.

“This study contributes to the understanding of the factors underlying diabetes progression, elucidating the processes that might be targeted for personalized treatments,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Bizzotto R, Jennison C, Jones AG, et al; for the IMI DIRECT consortium. Processes underlying glycemic deterioration in type 2 diabetes: an IMI DIRECT study. Diabetes Care. Published online December 15, 2020. doi:10.2337/dc20-1567