Reduced Matsuda Index and increased HOMA-IR levels predict progression to type 1 diabetes in AAb+ relatives

These findings, published in Diabetologia, suggest that targeting insulin resistance may be an important therapeutic strategy to prevent progression towards the advanced stages of T1D.

"By analysing data from a cohort of 6256 autoantibody+ relatives of individuals with type 1 diabetes, we found that transitioning from Stage 1 to Stage 2 and progression to Stage 3 of T1D was associated with reduced levels of Matsuda Index and increased levels of HOMA-IR, only when adjusted for insulin secretion," Alessandra Petrelli, IRCCS Ospedale San Raffaele, Milan, Italy, and colleagues reported.

Surrogate markers of insulin resistance (IR) have been evaluated in autoantibody-positive relatives of patients with T1D, with varied results. Dr. Petrelli and the team aimed to assess whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes.

For this purpose, the researchers studied autoantibody (AAb)--positive relatives of patients with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention. They assessed associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp), with adjustments for measures of insulinogenic index (IGI), Index60, and insulin secretion.

Cox regression was used to investigate if tertiles of Matsuda Index and HOMA-IR predicted transitions from Not Staged (<2 AAbs) to Stage 1 (≥2 AAbs and normoglycaemia), from Stage 1 to Stage 2 (≥2 AAbs with dysglycaemia), and progression to Stage 3 (diabetes as defined by WHO/ADA criteria).

The key findings of the study were as follows:

· There were strong associations of HOMA-IR (positive) and Matsuda Index (inverse) with baseline age and BMIp.

· After adjustments for Index60, transitioning from Stage 1 to Stage 2 was associated with higher HOMA-IR and lower Matsuda Index (HOMA-IR: HR=1.71; Matsuda Index, HR=0.40), as with progressing from Stages 1 or 2 to Stage 3 (HOMA-IR: HR=1.98; Matsuda Index: HR=0.46).

· Without adjustments, associations of progression to Stage 3 were inverse for HOMA-IR and positive for the Matsuda Index, opposite in directionality with adjustments.

· The findings were similar when the insulinogenic index was used in place of Index60.

"These results highlight the possible importance of targeting IR to delay the progression towards advanced stages of type 1 diabetes," the researchers wrote.

"They thus provide a rationale and a means for investigating therapeutic strategies, such as metformin, diet and/or glucagon-like peptide-1 (GLP-1) agonists, in combination with the targeting of autoimmunity, for preventing the progression to type 1 diabetes," they concluded.

Reference:

Petrelli, A., Cugnata, F., Carnovale, D. et al. HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives. Diabetologia 67, 290–300 (2024). https://doi.org/10.1007/s00125-023-06034-y