Beta cell stress in a 4-year follow-up of patients with type 2 diabetes: A longitudinal analysis of the BetaDecline Study

Background: Type 2 diabetes mellitus (T2DM) is associated with a progressive deterioration in beta cell function and loss of glycaemic control. Clinical predictors of beta cell failure are needed to guide appropriate therapy. Methods: A prospective evaluation of a large set of potential predictors of beta cell stress, measured as change in the proinsulin/insulin (PI/I) ratio, was conducted in a cohort of 235 outpatients with T2DM on stable treatment with oral hypoglycaemic agents or diet followed up for ~4 years (median value 3.9 years; interquartile range 3.8-4.1 years). Results: Overall, metabolic control deteriorated over time, with a significant increase in glycated haemoglobin (HbA1c; P <.0001), proinsulin (P <.0001), and PI/I ratio (P =.001), without significant changes in the homeostatic model assessment of insulin resistance. Multivariate regression analysis showed that for each 1% (10.9 mmol/mol) increase from baseline in HbA1c, the risk of beta cell stress increased by 3.8 times; for each 1% (10.9 mmol/mol) incremental increase in HbA1c during the study, risk of beta cell stress increased by 2.25 times that at baseline. By contrast, baseline anthropometric and clinical variables, lipid profile, inflammatory markers (PCR, IL-6), non-esterified fatty acids, and current therapies did not independently influence PI/I ratio variation during follow-up. Conclusions: In this cohort of patients with T2DM, beta cell function progressively deteriorated despite current therapies. Among a large set of clinical and biochemical predictors, only baseline HbA1c levels and their deterioration overtime were associated with higher beta cell stress over time.