Objective: Pharmacological lowering of LDL cholesterol potently reduces cardiovascular risk while concurrently increasing type 2 diabetes risk. The aim of this study was to investigate the relationship between LDL cholesterol concentrations and insulin secretion and glucagon levels.

Methods: 3,039 subjects without cholesterol lowering therapy, but with increased risk for diabetes, underwent routine blood tests and a 5-point oral glucose tolerance test (OGTT). Glucagon concentrations, insulin secretion and insulin clearance indices were derived from the OGTT.     Results: There was no association between LDL cholesterol and fasting glucagon (p=0.7, ß=-0.01) or post glucose load glucagon levels (p=0.7, ß=-0.07), but we detected significant positive associations of LDL cholesterol and C-peptide-based indices of insulin secretion (AUC_{C-Peptide(0-30min)/}AUC_{Glucose(0-30min):} p=0.0001, ß=0.06; AUC_{C-Peptide(0-120min)}/AUC_{Glucose(0-120min)}: p<0.0001, ß=-0.08). In contrast we found a negative association of insulin-based insulin secretion indices with LDL concentrations (Insulinogenic index: p=0.014, ß=-0.04; disposition index: p=0.0005, ß=-0.06). Though, LDL cholesterol levels were positively associated with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state and post glucose load (p<0.0001, ß=0.09 and p<0.0001, ß=0.06, respectively).

Conclusion: As C-peptide based indices reflect insulin secretion independent of hepatic clearance, our results indicate lower insulin secretion in case of lesser LDL cholesterol. This could explain deteriorating glycemic control in response to cholesterol lowering drugs.