Low-Density Lipoprotein Cholesterol Is Associated With Insulin Secretion

Abstract

Context: Pharmacological lowering of low-density lipoprotein (LDL) cholesterol potently reduces cardiovascular risk while concurrently increasing type 2 diabetes risk.

Objective: The aim of this study was to investigate the relationship between LDL cholesterol concentrations and insulin secretion and glucagon levels.

Methods: A total of 3039 individuals 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 = .7, β = -.01) or post-glucose load glucagon levels (P = .7, β = -.07), but we detected significant positive associations of LDL cholesterol and C-peptide-based indices of insulin secretion (area under the curve [AUC]C-Peptide(0-30min)/AUCGlucose(0-30min): P < .001, β = .06; AUCC-Peptide(0-120min) /AUCGlucose(0-120min): P < .001, β = -.08). In contrast, we found a negative association of insulin-based insulin secretion indices with LDL concentrations (insulinogenic index: P = .01, β = -.04; disposition index: P < .001, β = -.06). LDL cholesterol levels, however, were positively associated with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state and post-glucose load (P < .001, β = .09 and P < .001, β = .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.

Keywords: LDL cholesterol; glucagon; insulin clearance; insulin secretion; type 2 diabetes.

Figure 1.

Low-density lipoprotein (LDL) cholesterol levels and insulin secretion. Displayed are C-peptide–based insulin secretion parameter A, area under the curve (AUC)_{C-Peptide(0-30min)}/AUC_{Glucose(0-30min)}; B, AUC_{C-Peptide(0-120min)}/AUC_{Glucose(0-120min)} and insulin-based secretion parameter; C, insulinogenic index; and D, disposition index after stratification of participants in LDL cholesterol quartiles. Bars represent means + SEM. P values are for comparison of LDL quartiles by analysis of variance for illustrative purpose, while P values from continuous models are reported in the text. Note: Figure Replacement Requested.

Figure 2.

Low-density lipoprotein receptor (LDLR) expression across pancreatic cells. Recently published single-cell expression profiles (21) were analyzed for expression of LDLR. A t-distributed stochastic neighbor embedding (tSNE) plot from 2544 pancreatic single-cell data sets was generated. A, We assigned each cell to a probable cell type based on the highest expression of the cell type–specific marker genes indicated in the figure legend in parentheses. B, Next, we plotted the log-transformed LDLR expression on these cells with high expression indicated in dark red.