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


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

In This Article

Abstract and Introduction


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.


Dyslipidemia is characterized by low levels of high-density lipoproteins (HDLs), hypertriglyceridemia, high total and low-density lipoprotein (LDL) cholesterol concentrations, as well as an increased proportion of small dense lipoproteins. Changes in lipoprotein particles and their concentrations, especially increased levels of proatherogenic LDL particles, play an important role in the development of cardiovascular diseases. It is well established that statin treatment is very effective in lowering LDL cholesterol levels and therefore in preventing cardiovascular events.[1–3]

Statins inhibit hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), the key enzyme for cholesterol synthesis in the liver.[4] Despite the beneficial effects on the cardiovascular system, statin therapy is unfortunately linked to an increased risk for type 2 diabetes, especially in individuals prone to the disease.[5,6] Recently, data from several meta-analyses of randomized, controlled trials with statins and population-based studies of patients taking statins were summarized. In these studies, incidence rates for new-onset diabetes mellitus range from 28% to 43%.[7] Another review reported a range of 9% to 12% in 2 meta-analyses of statin trials and of 18% to 99% in 5 population-based studies.[8] Swerdlow et al tested whether the observed effects are a consequence of the mode of action of statins—the inhibition of HMG-CoA reductase.[9] Single-nucleotide variations (formerly single-nucleotide polymorphisms) in the HMG-CoA reductase gene were therefore used as proxies for its inhibition by statins and were indeed associated with a higher risk for type 2 diabetes.[9] This associative study, however, cannot differentiate between the effects of lower LDL and the consequences of altered enzyme activity.

Other genetic studies detected loss-of-function mutations in PCSK9, the gene encoding proprotein convertase subtilisin/kexin type 9. These variants are associated with lower LDL cholesterol levels and protect against coronary heart disease[10] but were also linked to higher fasting glucose concentrations and an increased risk of type 2 diabetes in a mendelian randomization study.[11] Accordingly, short-term PCSK9 inhibitor therapy was found to be related to a significant elevation of plasma glucose levels and glycated haemoglobin.[12] Finally, cross-sectional data from the Netherlands demonstrate that patients with familial hypercholesterolemia show a significantly higher prevalence of type 2 diabetes than their unaffected relatives, with variability by mutation type.[13]

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion from pancreatic β cells. Insulin resistance alone is insufficient to cause type 2 diabetes, as long as the β cell remains able to compensate for the increased demand for insulin. Once this compensatory mechanism reaches its physiological limits, glucose levels increase and patients progress toward overt type 2 diabetes.

Mechanistic studies suggest an impact of LDL cholesterol on the structure and function of pancreatic islets;[14–16] however, this has not yet been comprehensively studied in humans. LDL cholesterol and diabetes risk might either be directly linked at the molecular level, for example, in the pancreatic islets, or this might be coincidence in a metabolic state that goes along with both lower LDL cholesterol and higher diabetes risk.

We therefore aimed to investigate the association between LDL cholesterol concentrations and the key pathogenic mechanism of type 2 diabetes, insulin secretion, in a cohort with increased risk for the disease.