Low-Density Lipoprotein Cholesterol Is Associated With Insulin Secretion

Corinna Dannecker; Robert Wagner; Andreas Peter; Julia Hummel; Andreas Vosseler; Hans-Ulrich Häring; Andreas Fritsche; Andreas L. Birkenfeld; Norbert Stefan; Martin Heni

Disclosures

J Clin Endocrinol Metab. 2021;106(6):1576-1584. 

In This Article

Results

Low-density Lipoprotein Receptor Expression in Human Pancreatic Islets

The basis for a possible effect of LDL cholesterol levels on human islets is the expression of LDLRs in pancreatic tissue. We therefore sought single-cell data from Enge et al.[21] and observed LDLR expression in all major endocrine cells types of the pancreas (Figure 2).

Figure 2.

Low-density lipoprotein receptor (LDLR) expression across pancreatic cells. Recently published single-cell expression profiles21 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.

Association Between Low-density Lipoprotein Cholesterol Levels and Glucagon Concentrations

Because LDLR expression was present in α cells, we first analyzed possible links to glucagon secretion at fasting as well as during an OGTT. There was no association between LDL cholesterol and fasting glucagon levels (P = .7, β = –.01 adjusted for sex, age, and BMI, P = .04, β = .09 unadjusted, respectively). There was also no significant association between fasting LDL and glucagon secretion during the OGTT (P = .2, β = –.07 adjusted for sex, age, and BMI, P = .4, β = .05 unadjusted, respectively) (see Table 2). We detected no significant interaction with BMI (all P ≥ .5).

Association Between Low-density Lipoprotein Cholesterol Levels and Insulin Secretion

We next analyzed the relation of LDL with insulin secretion from pancreatic β cells and detected statistically significant positive associations of LDL cholesterol and C-peptide–based indices of insulin secretion (AUCC-Peptide(0–30min)/AUCGlucose(0–30min): P < .001, β = .06; AUCC-Peptide(0–120min)/AUCGlucose(0–120min):P < .001, β = .08; see Figure 1). This remained significant after adjustment of LDL cholesterol for HDL cholesterol (AUCC-Peptide(0–30min)/AUCGlucose(0–30min): P < .001, β = .06; AUCC-Peptide(0–120min)/AUCGlucose(0–120min): P < .001, β = .08) (see Table 2) or for triglyceride levels, though the association was only at the trend level for AUCC-Peptide(0–30min)/AUCGlucose(0–30min) (P = .09, β = .03; AUCC-Peptide(0–120min)/AUCGlucose(0–120min):P = .005, β = .05), respectively.[22]

Adjusting LDL cholesterol for fasting blood glucose levels or the area under the blood glucose curve during the OGTT revealed comparable association (all P ≤ .002).[22] Additionally we found a significant interaction between LDL cholesterol and glucose tolerance on insulin secretion (AUCC-Peptide(0–30min)/AUCGlucose(0–30min)and AUCC-Peptide(0–120min)/AUCGlucose(0–120min), P = .004, β = –1.28 and P = .03, β = –.97, respectively). This interaction remained significant after adjusting for sex, age, BMI, and insulin sensitivity, at least for AUCC-Peptide(0–120min)/AUCGlucose(0–120min) (P = .02, β = –.79). Therefore, we stratified our cohort by glucose tolerance. Whereas C-peptide–based insulin secretion was not linked with LDL cholesterol in individuals with prediabetes or treatment-naive diabetes (all P ≥ .2), there was a significant association in those with normal glucose regulation AUCC-Peptide(0–30min)/AUCGlucose(0–30min): P < .001, β = .09; AUCC-Peptide(0–120min)/AUCGlucose(0–120min): P < .001, β = .1 adjusted for sex, age, BMI, and Matsuda ISI). No interaction with sex was present, however (AUCC-Peptide(0–30min)/AUCGlucose(0–30min): P = .9; AUCC-Peptide(0–120min)/AUCGlucose(0–120min): P = .3), indicating a comparable relation in both sexes. We also found no interaction with BMI (AUCC-Peptide(0–30min)/AUCGlucose(0–30min): P = .8; AUCC-Peptide(0–120min)/AUCGlucose(0–120min): P = .6). In contrast to the C-peptide–based indices, we found a negative association between LDL concentrations and insulin secretion when analyzing insulin-based insulin secretion indices (insulinogenic index [ISI]: P = .01, β = –.04; DI: P < .001, β = –.06; see Figure 2). This remained significant after adjustment for HDL cholesterol (ISI: P = .01, β = .04; DI: P = .001, β = –.06) (see Table 2). For the insulin-based ISIs, we detected no significant interaction with glucose tolerance, sex, or BMI (all P ≥ .1).

Association Between Low-density Lowering Cholesterol Levels and Insulin Clearance

After secretion into the portal vein, insulin undergoes hepatic extraction as well as peripheral clearance. In comparison, C-peptide is not extracted by the liver, but reaches the systemic circulation to a full extent before being cleared in the kidneys. Because insulin and C-peptide show different elimination kinetics, we next performed an analysis for estimates of fasting and post–load insulin clearance. LDL cholesterol levels were directly associated with fasting insulin clearance as well as clearance during the OGTT (P < .001, β = .09 and P < .001, β = .06, respectively) (see Table 2). This relationship did not interact with glucose tolerance (fasting insulin clearance: P = .06; clearance during OGTT: P = .9) or BMI (fasting insulin clearance: P = .8; clearance during OGTT: P = .96).

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