Can measures of pancreatic alpha-cell function predict long-term glycemic outcomes in adults with type 2 diabetes (T2DM) receiving additional glucose-lowering therapy? In Diabetes Care, a multicenter randomized study evaluated longitudinal measures of alpha-cell and beta-cell function in adults with T2DM treated with metformin.

A total of 5,047 participants aged 30 years or older, with hemoglobin A1c (HbA1c) levels between 6.8% and 8.5% while taking 1,000 to 2,000 mg of metformin daily, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin. In a subset of 724 participants, alpha-cell function was assessed using fasting glucagon concentration and the glucagon index (GGI), defined as the change in glucagon from fasting to 30 minutes following oral glucose. Beta-cell function was evaluated using fasting C-peptide and the C-peptide index (CPI).

Baseline fasting glucagon concentration and glucagon index were not associated with the primary metabolic outcome of HbA1c of at least 7.0% (2 degrees of freedom; P = 0.55), whereas beta-cell function measures were associated with the outcome (2 degrees of freedom; P = 0.04). Treatment-associated changes in fasting glucagon, glucagon index, and fasting C-peptide were not associated with the primary outcome. In contrast, changes in the C-peptide index were associated with glycemic outcomes in both unadjusted models (P < 0.05) and models adjusted for alpha-cell function (P < 0.001). A one–standard deviation increase in the C-peptide index was associated with a 17% reduction in the risk of reaching the primary endpoint. No clear differential effects of the medications on glucagon responses were observed.

These findings show that beta-cell function measures, rather than alpha-cell function, were associated with worsening glycemia in this randomized study population.