Unexplained reciprocal regulation of diabetes and lipoproteins

Higuchi, Shunichi; Izquierdo, María C.; Haeusler, Rebecca A.

doi:10.1097/mol.0000000000000521

Cited by 17 publications

(11 citation statements)

References 98 publications

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“…Previous research into loci that jointly alter the risk for LDL-C and T2D has focused on the genomic targets of lipid-lowering medications, in the hope that these analyses will give specific insights into associated T2D risk. Our analyses confirmed that variants in HMGCR (36) and NPC1L1 (19) are associated with lower LDL-C and increased T2D risk. On the other hand, our analyses did not identify variants at PCSK9 .…”

Section: Discussionsupporting

confidence: 76%

Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

Klimentidis

Arora

Newell

et al. 2019

Preprint

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21Although hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), 22 evidence has emerged from statin trials and candidate gene investigations suggesting that lower 23 LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and 24 genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that 25 LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), 26 despite positive associations of LDL-C with HbA1c and BMI. We then performed the first 27 genome-wide exploration of variants simultaneously associated with lower LDL-C and increased 28 T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium 29 (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci 30 associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven 31 of these loci have previously been identified for this phenotype, and 9 have previously been 32 implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization 33 analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging 34 due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among 35 individuals with low LDL-C, and of the underlying mechanisms, including those underlying the 36 diabetogenic effect of LDL-C-lowering medications. 38Rates of cardiovascular disease (CVD) and type-2 diabetes (T2D) are among the most 39 pressing health concerns worldwide. These two diseases share many risk factors, and tend to co-40 occur; T2D carries a 2-4 fold increase in risk for CVD, and more than 70% of patients with T2D 41 will die from cardiovascular complications (1). Yet, there remains controversy over whether all 42 risk factors exert similar effects on the risk of these two conditions. Low-density lipoprotein 43 cholesterol (LDL-C) is a class of highly atherogenic particles, and circulating levels of LDL-C 44 are a causal risk factor for CVD across the lifespan (2). Lipid lowering medications, in particular 45 from the statin drug class, are effective at lowering levels of LDL-C which has a dose-response 46 relationship with a reduction in adverse cardiovascular events (3). The perception of a strong 47 inter-relationship of T2D with hyperlipidemia, in particular higher LDL-C, has led to a standard 48 of care in which lipid-lowering medications are a common therapeutic option for T2D. For 49 example, the American Diabetes Association (ADA) recommends high intensity statin use for 50 individuals with diabetes with prevalent atherosclerotic cardiovascular disease (ASCVD) or a 51 greater than 20% 10-year risk of ASCVD until they reach recommended stringent targets of 52 LDL-C < 70mg/dL. The ADA further recommends moderate-intensity statin use for T2D 53 patients 40 years and older without ASCVD (4). 54A recent analysis of national registry data from Scotland showed that 83.6% and 71.1% 55 of T2D patients with and...

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Section: Discussionsupporting

confidence: 76%

Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

Klimentidis

Arora

Newell

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous research into loci that jointly alter the risk for circulating LDL-C and T2D has focused on the genomic targets of lipid-lowering medications in the hope that these analyses will give specific insights into associated T2D risk. On one hand, our analyses confirmed that variants in HMGCR ( 41 ) and NPC1L1 ( 14 ) are associated with lower circulating LDL-C and increased T2D risk. On the other hand, our analyses did not identify variants at PCSK9 .…”

Section: Discussionsupporting

confidence: 68%

Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank

et al. 2020

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Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA 1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n 5 431,167) and the Global Lipids Genetics Consortium (n 5 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (n 5 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.

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“…Furthermore, various inhibitors of dipeptidyl peptidase-4 have additional effects on the lipid profile; for instance, anagliptin has a greater LDL cholesterol-lowering effect than sitagliptin (14). Incretin-based therapies lower TG levels (15), whereas inhibitors of sodium-glucose transport protein 2 may slightly increase both HDL and LDL cholesterol (15). Regardless, both glucagon like peptide 1 receptor agonists and oral sodium-glucose transport protein 2 inhibitors clearly reduce ASCVD outcomes via numerous incompletely defined mechanisms (16).…”

Section: Effect Of Nonlipid Interventions On Diabetic Dyslipidemiamentioning

confidence: 99%