Beta cell functionality and hepatic insulin resistance are major contributors to type 2 diabetes remission and starting pharmacological therapy: from CORDIOPREV randomized controlled trial

Abstract

In order to assess whether previous hepatic IR (Hepatic-IR_fasting) and beta-cell functionality could modulate type 2 diabetes remission and the need for starting glucose-lowering treatment, newly-diagnosed type 2 diabetes participants who had never received glucose-lowering treatment (190 out of 1002) from the CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (a prospective, randomized and controlled clinical trial), were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was defined according to the American Diabetes Association recommendation for levels of HbA1c, fasting plasma glucose and 2h plasma glucose after oral glucose tolerance test, and having maintained them for at least 2 consecutive years. Patients were classified according to the median of Hepatic-IR_fasting and beta-cell functionality, measured as the disposition index (DI) at baseline. Cox proportional hazards regression determined the potential for Hepatic-IR_fasting and DI indexes as predictors of diabetes remission and the probability of starting pharmacological treatment after a 5-year follow-up. Low-Hepatic-IR_fasting or high-DI patients had a higher probability of diabetes remission than high-Hepatic-IR_fasting or low-DI subjects (HR:1.79; 95% CI 1.06-3.05; and HR:2.66; 95% CI 1.60-4.43, respectively) after a dietary intervention with no pharmacological treatment and no weight loss. The combination of low-Hepatic-IR_fasting and high-DI presented the highest probability of remission (HR:4.63; 95% CI 2.00-10.70). Among patients maintaining diabetes, those with high- Hepatic-IR_fasting and low-DI showed the highest risk of starting glucose-lowering therapy (HR:3.24;95% CI 1.50-7.02). Newly-diagnosed type 2 diabetes patients with better beta-cell functionality and lower Hepatic-IR_fasting had a higher probability of type 2 diabetes remission in a dietary intervention without pharmacological treatment or weight loss, whereas among patients not achieving remission, those with worse beta-cell functionality and higher Hepatic-IR_fasting index had the highest risk of starting glucose-lowering treatment after 5 years of follow-up.

Keywords: ALT = alanine aminotransferase; AUC = area under curve; Adipo-IR = Adipose tissue insulin resistance index; BMI = body mass index; CHD = coronary heart disease; CORDIOPREV = CORonary Diet Intervention with Olive oil and cardiovascular PREVention; DBP = diastolic blood pressure; DI = disposition index; FFA = free fatty acids; HDL-c = high-density lipoprotein; Hepatic-IR(fasting) = hepatic insulin resistance index derived from fasting values; IGI = insulinogenic index; IR = insulin resistance; ISI = insulin sensitivity index; LDL-c = low-density lipoprotein; LF diet = low-fat diet; MISI = muscular insulin sensitivity index; MUFA = monounsaturated fatty acids; Med diet = Mediterranean diet; OGTT = oral glucose tolerance test; PUFA = polyunsaturated fatty acids; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; TG = triglycerides.