Differential associations of glutamic acid decarboxylase antibodies (GADA) and C-peptide with insulin initiation, glycemic responses and severe hypoglycemia in patients diagnosed with type 2 diabetes

Objective

We examined the associations of glutamic acid decarboxylase antibodies (GADA) and C-peptide (CP) with insulin initiation, glycemic responses and severe hypoglycemia in type 2 diabetes (T2D).

Research Design and Methods

In 5230 Chinese patients with T2D (mean±SD age: 56.5±13.9 years, diabetes duration (median, IQR): 6 (1-12) years, 47.6% men) enrolled consecutively in 1996-2012 and prospectively observed till 2019, we retrospectively measured fasting CP and GADA in stored serum and examined their associations with aforementioned outcomes.

Results

At baseline, 28.6% had low CP (<200 pmol/L) (n=1494) and 4.9% (n=257) had positive GADA (GADA+). In the low-CP group, 8.0% had GADA+ and in the GADA+ group, 46.3% had low CP. The GADA+ group had an adjusted hazard ratio (aHR) of 1.46 (95% CI: 1.15-1.84, p=0.002) for insulin initiation versus the GADA- group, while the low-CP group had an aHR of 0.88 (0.77-1.00, p=0.051) versus the high-CP group. Following insulin initiation, the GADA+ plus low-CP group had the largest decrements in HbA1c (-1.9% at month 6; -1.5% at month 12) versus -1% in the other 3 groups. The aHR of severe hypoglycemia was 1.29 [(95% CI 1.10-1.52), p=0.002] in the low-CP and 1.38 [(95% CI 1.04-1.83) p=0.024] in the GADA+ group. 

Conclusions

There is considerable heterogeneity in autoimmunity and beta-cell dysfunction in T2D with GADA+ and high CP associated with early insulin initiation while GADA+ and low CP, increased risk of severe hypoglycemia. Extended phenotyping is warranted to increase the precision of classification and treatment in T2D.