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

Discussion

Lowering LDL cholesterol levels has beneficial effects on the cardiovascular system but is unfortunately linked to increased risk for type 2 diabetes. Based on previous experimental data,[14–16] we hypothesized that LDL cholesterol is linked via its receptor to pancreatic islet function. Therefore, we now investigated the relevance for humans and addressed whether LDL cholesterol levels are linked to insulin secretion from pancreatic β cells or to α-cell function. Such a relationship could contribute to the widely observed association between LDL cholesterol–lowering and diabetes risk.

All cells in the islets of Langerhans express LDL receptors. Whereas glucagon levels were unrelated to LDL cholesterol, we observed significant associations with insulin secretion. Notably, C-peptide–based indices were positively but insulin-based ones were negatively associated with LDL cholesterol. This was due to an association of LDL cholesterol with insulin clearance.

In 1997 Grupping et al showed that human islet β cells isolated from donor pancreas express LDL-binding sites that fulfill the properties of LDLRs.[23] In 2017 Enge et al. provided single-cell data from human pancreatic cells.[21] Using this data set, we identified LDLR expression in all major endocrine cells. α Cells secrete glucagon, which works antagonistically to insulin. Additionally, postchallenge changes in glucagon contribute to glycemia after an OGTT and are therefore important in regulating postprandial glucose metabolism.[18] Because the hormone affects blood glucose levels and single-cell data showed LDLR expression on α cells, we first investigated the association between LDL cholesterol levels and glucagon secretion. As we did not find links between LDL cholesterol and glucagon, this hormone is most likely not involved in increased diabetes risk in the case of LDL-lowering therapy. The function of LDLRs on α-cell biology, however, remains to be determined.

Insulin is synthesized and released from pancreatic β cells. When glucose levels rise, insulin and its cleavage fragment C-peptide are released in equimolar amounts. The ability to secret sufficient amounts of insulin is the most important component for physiological control of glucose concentrations in the body. We detected a significant, positive association between fasting LDL concentrations and C-peptide–based estimates for insulin secretion. As these indices reflect insulin secretion independent of hepatic clearance, they are the superior estimates of insulin secretion in our present setting. Our results indicate that higher LDL cholesterol levels could promote insulin secretion from pancreatic β cells. 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.[5–8] Natali and colleagues detected no link between LDL cholesterol and insulin secretion.[24] This study is not, however, entirely comparable to our present analysis because the sample size was smaller and individuals with higher cholesterol concentrations were excluded. 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. In case of already impaired glycemia, other pathomechanisms might superimpose LDL effects on pancreatic β cells.

Recently, Klimentidis et al. identified 31 genetic loci that are associated with lower circulating LDL cholesterol and increased diabetes risk. The identified variants are linked with genes that affect de novo fatty acid synthesis, hepatic lipid uptake, and export and insulin action. Of note, 5 of the identified loci were associated with insulin secretion, including SLC2A2.[25] This gene encodes the glucose transporter 2, which is essential for postload hepatic glucose uptake that will subsequently enter hepatic de novo lipogenesis. Further genetic loci like C2CD4A/B, MICAL3, HNF1A-OASL, and GIPR were previously described to be associated with insulin secretion[26–30] and have now been linked to circulating LDL cholesterol.[25] Molecular mechanisms that mediate this association remain unknown.

While HDL cholesterol and triglycerides are also associated with insulin secretion, the link between LDL cholesterol and insulin secretion was independent of these potential confounders in our present analysis.[22]

Although our data on LDL cholesterol and C-peptide–based analyses of insulin secretion are well in line with previous findings on diabetes risk, we unexpectedly detected an inverse correlation for the tested insulin-based estimates of insulin secretion (IGI and DI). Thus, our results at first glance appear controversial. As insulin and C-peptide undergo different elimination mechanisms with a high hepatic first-pass clearance of insulin,[31] we next investigated possible links between LDL cholesterol and insulin clearance that could potentially explain these contrary results. Indeed, fasting and stimulated insulin clearance both were directly associated with LDL concentrations. Accordingly, with increasing LDL cholesterol concentrations, more insulin is extracted by the liver, explaining the inverse correlation of insulin-based and C-peptide–based estimates for insulin secretion. In humans, the liver is the most LDLR-abundant organ and accounts for more than 70% of the total LDL clearance from plasma.[32] We therefore hypothesize that hepatic mechanisms that decrease circulating LDL cholesterol levels concurrently enhance the liver's insulin clearance capacity. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein, could possibly link LDL cholesterol levels and insulin clearance. Animal research suggests a link between CEACAM1, a key component of hepatic insulin clearance, and lipid metabolism in the liver. However, the detailed molecular pathways and their potential link to LDL metabolism remain elusive.[33,34]

Among the limitations of this study is the use of estimates for insulin secretion and clearance. Both physiological processes are complex and influenced by several further components, and insulin secretion and clearance can be overestimated or underestimated. Furthermore, the results are based only on a cross-sectional analysis and did not apply the gold-standard measurements of insulin secretion, using well-established estimates from the OGTT. Further prospective analyses are necessary in an experimental setting, in which LDL cholesterol levels are actively decreased by cholesterol-lowering drugs. Additionally, only White individuals were included in this analysis, and we cannot rule out that ethnicity affects the described associations. Nevertheless, the observed effects are not likely to outweigh the benefits of LDL-lowering strategies in patients with increased LDL cholesterol levels. On the other hand, our data may suggest that benefits and risks in patients with reduced insulin secretory capacity should be carefully evaluated before commencing an LDL-lowering strategy.

Taken together, our present results demonstrate that all major endocrine cells show LDLR expression in the pancreas. While we did not find an association between LDL cholesterol levels and glucagon secretion from pancreatic α cells, a positive association was observed for LDL concentrations and C-peptide–based estimates for insulin secretion. Decreased insulin secretion in case of lower LDL cholesterol could underlie the observation of deteriorated glycemic control in response to LDL-lowering drugs. The observed inverse correlation of LDL cholesterol concentrations and insulin-based estimates for insulin secretion is a result of enhanced insulin clearance in case of higher LDL levels. CEACAM1 as a key component of hepatic insulin clearance could possibly link hepatic insulin clearance and LDL metabolism in the liver, for which molecular mechanisms are not identified so far. Accordingly, our data suggest that LDL cholesterol levels and insulin secretion and clearance might be directly linked. 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.

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