Lower LDL-C levels linked to decreased insulin secretion

Insulin secretion is reduced in case of lesser low-density lipoprotein cholesterol (LDL-C), which possibly explains the deteriorated glycaemic control in response to cholesterol-lowering drugs, suggests a study.

“The observed inverse correlation of LDL-C concentrations and insulin-based estimates for insulin secretion is a result of enhanced insulin clearance in case of higher LDL levels,” the researchers said.

Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein, as a key component of hepatic insulin clearance may potentially associate hepatic insulin clearance and LDL metabolism in the liver, for which molecular mechanisms have not been identified yet, they added.

This study examined the relationship between LDL-C concentrations and insulin secretion and glucagon levels in 3,039 individuals without cholesterol-lowering therapy, but with increased risk for diabetes, who underwent routine blood tests and a 5-point oral glucose tolerance test (OGTT). The researchers derived glucagon concentrations, insulin secretion, and insulin clearance indices from the OGTT.

LDL-C was not associated with fasting glucagon (p=0.7; β, –0.01) or postglucose load glucagon levels (p=0.7; β, –0.07) but significantly correlated with C-peptide–based indices of insulin secretion (area under the curve [AUC]_{C-Peptide(0-30min)/}AUC_{Glucose(0-30min)}: p<0.001; β, 0.06; AUC_{C-Peptide(0-120min)} /AUC_{Glucose(0-120min)}: p<0.001; β, –0.08). [J Clin Endocrinol Metab 2021;106:1576-1584]

On the other hand, LDL-C levels showed a negative association with insulin-based insulin secretion indices (insulinogenic index: p=0.01; β, –0.04; disposition index: p<0.001; β, –0.06) but correlated positively with insulin clearance assessed from C-peptide and insulin concentrations, both in the fasting state (p<0.001; β, 0.09) and postglucose load (p<0.001; β, 0.06).

“Our results indicate that higher LDL-C levels could promote insulin secretion from pancreatic β cells,” the researchers said. “This link could explain the observations in various clinical studies in which lowering of LDL levels by statin therapy results in a deterioration of glucose control.” [Lancet 2010;375:735-742; Postgrad Med 2017;129:430-435; Curr Diab Rep 2017;17:10]

In contrast, a study by Natali and colleagues found no relation between LDL-C and insulin secretion. This analysis, however, had a smaller sample size and did not include individuals with higher cholesterol concentrations. [Metabolism 2017;69:33-42]

“Of note, potential LDL effects on insulin secretion appear to be affected by glucose control and seem to be blunted in prediabetes and diabetes. Thus, LDL-lowering therapy might raise diabetes risk especially in still-metabolically healthy individuals,” the researchers said.

“In case of already impaired glycaemia, other pathomechanisms might superimpose LDL effects on pancreatic β cells,” they added.

High-density lipoprotein cholesterol and triglycerides also correlated with insulin secretion, but the link between LDL-C levels and insulin secretion was independent of these potential confounders in the present analysis. [Dryad Dataset 2021;doi:10.5061/dryad.2547d7wpt]

“Taken together, our present results demonstrate that all major endocrine cells show log-transformed LDL receptor expression in the pancreas,” the researchers said.

“A detailed understanding of the underlying complex biology will aid the way to novel approaches to preserve β-cell function and prevent diabetes in patients who require LDL cholesterol–lowering therapy,” they added.