Cellular Cholesterol Uptake: A Role in the Pathogenesis of Diabetes Mellitus? | Journal Scan

Study Questions:

What is the prevalence of type 2 diabetes between patients with familial hypercholesterolemia and their unaffected relatives?

Methods:

This was a cross-sectional study with the source population derived from the familial hypercholesterolemia screening program registry in the Netherlands. All individuals who underwent DNA testing for familial hypercholesterolemia between 1994 and 2014 were eligible. Those with homozygous familial hypercholesterolemia were excluded. The presence of type 2 diabetes (self-reported) was the primary outcome. The authors investigated the possibility of a dose-response relationship between the severity of familial hypercholesterolemia mutations and prevalence of type 2 diabetes. Those who were carriers of mutations in the gene for apolipoprotein B gene (APOB) constituted a less severe phenotype than carriers of the low-density lipoprotein (LDL) receptor mutation; and, receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations.

Results:

A total of 63,318 individuals were included in the primary analysis. The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25,137) vs. 2.93% in unaffected relatives (n = 1,119/38,183) for an odds ratio (OR) of 0.62 (95% confidence interval [CI], 0.55-0.69; p < 0.001). The prevalence of type 2 diabetes was lower in carriers of APOB mutations compared with unaffected relatives (adjusted OR, 0.65; 95% CI, 0.48-0.88; p < 0.001); the difference was greater in those with LDL receptor mutations, compared to unaffected relatives (adjusted OR, 0.45; 95% CI, 0.38-0.54; p < 0.001).

Conclusions:

In a Dutch cross-sectional analysis of those who underwent DNA testing for familial hypercholesterolemia, those with familial hypercholesterolemia had a significantly lower prevalence of type 2 diabetes mellitus, compared to unaffected relatives. There was variability by mutation type with an inverse dose-response relationship between the severity of familial hypercholesterolemia causing mutation and prevalence of type 2 diabetes.

Perspective:

This is an intriguing article that offers some insight on the pathogenesis of type 2 diabetes mellitus. Though a cross-sectional study design does not establish causality, the findings suggest that cellular cholesterol uptake, a common pathway in familial hypercholesterolemia and statin therapy, plays a role in the development of type 2 diabetes. The authors had hypothesized that patients with familial hypercholesterolemia had pancreatic beta cells with decreased cholesterol uptake and improved function and survival. Conservative estimates suggest that statin therapy may increase the risk of developing diabetes by 9% (primarily in those with pre-existing impairment of glucose tolerance). As the authors acknowledge, the findings from this analysis need to be confirmed longitudinally, but may ‘provide support for development of new approaches to the prevention and treatment of type 2 diabetes by improving function and survival of pancreatic beta cells.’

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Primary Hyperlipidemia

Keywords: Hypercholesterolemia, Diabetes Mellitus, Type 2, Apolipoproteins B, Hyperlipoproteinemia Type II, Receptors, LDL, Cholesterol, LDL, Mutation, Phenotype, DNA, Heterozygote, Registries, Prevalence, Metabolic Syndrome X


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