Glucose metabolism in heterozygous familial hypercholesterolemia with a founder effect and a high diabetes prevalence: a cross-sectional study.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is typically associated with a lower prevalence of type 2 diabetes mellitus (T2DM). However, individuals carrying the p.[Tyr400_Phe402del]LDLR mutation, which is prevalent in Gran Canaria, exhibit an unexpectedly high prevalence of T2DM. This study aimed to investigate whether the p.[Tyr400_Phe402del] LDLR mutation co-segregates with T2DM and other glucose metabolism abnormalities. METHODS: A total of 226 individuals were recruited, with 196 included in the final analysis. This included 90 HeFH patients from Gran Canaria (HeFH-GC) carrying the p.[Tyr400_Phe402del]LDLR mutation, 76 first-degree relatives (non-HeFH), and 30 HeFH patients from Italy (HeFH-It) with other LDLR mutations. Clinical, anthropometric, biochemical, and hematological parameters, including insulin resistance and sensitivity, were assessed via oral glucose tolerance tests (OGTT), and indices such as HOMA-IR, HOMA-beta, QUICKI, and the triglyceride‒glucose ratio were measured. RESULTS: Among HeFH-GC participants, 20% had T2DM, similar to 18.4% in the non-HeFH group (p = NS). HOMA-beta was significantly greater in HeFH-GC patients (86.2 vs. 68.4; p = 0.046). Normoglycemic HeFH-GC individuals had elevated HOMA-IR [2.0 (1.3-2.9) vs. 1.3 (1.0-1.9); p = 0.008]. Compared with HeFH-It patients, HeFH-GC individuals had higher fasting glucose levels (99 vs. 92.5 mg/dL; p = 0.004) and lower 120-min post-OGTT glucose levels (115 vs. 136.5 mg/dL; p = 0.001). Lipid-lowering therapy, hypertension, hypertriglyceridemia, and increased waist circumference were associated with T2DM. CONCLUSIONS: HeFH patients from Gran Canaria exhibit a high prevalence of T2DM. The p.[Tyr400_Phe402del]LDLR mutation does not co-segregate with T2DM, but normoglycemic HeFH-GC individuals have greater insulin resistance. Additionally, lipid-lowering therapy, hypertension, hypertriglyceridemia, and increased waist circumference are factors associated with the prevalence of T2DM.