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Background <p>Heterozygous familial hypercholesterolemia (HeFH) is typically associated with a lower prevalence of type 2 diabetes mellitus (T2DM). However, individuals carrying the <i>p.[Tyr400_Phe402del]LDLR</i> mutation, which is prevalent in Gran Canaria, exhibit an unexpectedly high prevalence of T2DM. This study aimed to investigate whether the <i>p.[Tyr400_Phe402del] LDLR</i> mutation co-segregates with T2DM and other glucose metabolism abnormalities.</p> Methods <p>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 <i>p.[Tyr400_Phe402del]LDLR</i> mutation, 76 first-degree relatives (non-HeFH), and 30 HeFH patients from Italy (HeFH-It) with other <i>LDLR</i> mutations. Clinical, anthropometric, biochemical, and hematological parameters, including insulin resistance and sensitivity<b>,</b> were assessed via oral glucose tolerance tests (OGTT), and indices such as HOMA-IR, HOMA-beta, QUICKI, and the triglyceride‒glucose ratio were measured.</p> Results <p>Among HeFH-GC participants, 20% had T2DM, similar to 18.4% in the non-HeFH group (<i>p</i> = NS). HOMA-beta was significantly greater in HeFH-GC patients (86.2 vs. 68.4; <i>p</i> = 0.046). Normoglycemic HeFH-GC individuals had elevated HOMA-IR [2.0 (1.3–2.9) vs. 1.3 (1.0–1.9); <i>p</i> = 0.008]. Compared with HeFH-It patients, HeFH-GC individuals had higher fasting glucose levels (99 vs. 92.5&#xa0;mg/dL; <i>p</i> = 0.004) and lower 120-min post-OGTT glucose levels (115 vs. 136.5&#xa0;mg/dL; <i>p</i> = 0.001). Lipid-lowering therapy, hypertension, hypertriglyceridemia, and increased waist circumference were associated with T2DM.</p> Conclusions <p>HeFH patients from Gran Canaria exhibit a high prevalence of T2DM. The <i>p.[Tyr400_Phe402del]LDLR</i> 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.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月6日

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  • Ana María González-Lleó,
  • Yeray Brito-Casillas,
  • Virginia Martín-Santana,
  • Yaiza Gil-Quintana,
  • Antonio Tugores,
  • Roberto Scicali,
  • Marta Riaño,
  • Luisa Hernández-Baraza,
  • Roberto Jiménez-Monzón,
  • Josefa Girona,
  • Francesco Di Giacomo Barbagallo,
  • Luis Masana,
  • Mauro Boronat,
  • Ana M. Wägner,
  • Rosa M. Sánchez-Hernández

摘要

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.

Graphical abstract