Impaired Glucose Metabolism in People with Extremely Elevated High-Density Lipoprotein Cholesterol and Low Alcohol Consumption: Results of the Kanagawa Investigation of Total Checkup Data from the National Database-3 (KITCHEN-3)

Abstract

Background: Recently, we have shown that extremely high high-density lipoprotein cholesterol (HDL-C), which was observed mostly in heavy drinkers, was associated with the incidence of diabetes. However, the observed association was influenced by the consumption of alcohol. Furthermore, it is unknown whether impaired glucose metabolism exists in people with extremely high HDL-C, regardless of their alcohol consumption. Therefore, we addressed this issue in people who did not have a habit of drinking alcohol. Methods: In this community-based cross-sectional study, we included 177,034 participants (40–74 years old) who reported being nondrinkers. We investigated levels of HbA1c, fasting plasma glucose (FPG), HDL-C, and clinical parameters according to 11 levels of HDL-C concentration from 20 to 120 mg/dL or over. Results: A total of 6112 participants with HDL-C ≥ 100 mg/dL (3.5%) showed a better lipid profile, higher prevalence amongst women, more habitual exercise, a lower prevalence of smoking, and lower body mass index (BMI). Compared with an HDL-C of 70–79 mg/dL, HDL-C ≤ 69 mg/dL (except an HDL-C of 20–29 mg/dL) and HDL-C ≥ 90 mg/dL were significantly associated with a high HbA1c of ≥6.0%, independently of confounding factors. This finding was distinctly demonstrated in women. Similar trends were observed when high HbA1c was replaced with high FPG (≥110 mg/dL). Conclusions: Our study demonstrated that impaired glucose metabolism may exist in people with extremely high HDL-C and who hardly drink alcohol.

Association between extremely high high-density lipoprotein-cholesterol and hypertensive retinopathy: results of a cross-sectional study from Kanagawa Investigation of Total Checkup Data from the National Database-6 (KITCHEN-6)

“…Alternatively, as we previously proposed, 9 another mechanism may exist for the association. Catecholamines, which are over-secreted in pheochromocytoma and paragangliomas, can cause hypertension, diabetes and weight loss.…”

“…[1][2][3] Consistently, cohort studies in recent years have shown that higher mortality rates associated with CVD are observed in individuals with HDL-C levels above 80-100 mg/dL. [4][5][6][7] In addition, we recently demonstrated that people with extremely high HDL-C (EH-HDL; ≥110 mg/dL) have increased risks for diabetes 8 and impaired glucose metabolism equivalent to pre-diabetes, 9 compared with HDL-C 80-89 and 70-79 mg/dL, respectively, which showed a J-shaped or U-shaped association between the levels of HDL-C and impaired glucose metabolism.…”

“… 29 Some of their features, such as diabetes and low BMI, were applicable to the features of subjects with EH-HDL in our previous studies. 9 10 Consistently, Gosk-Przybyłek et al 30 recently showed that excessive secretion of catecholamine was related to retinal artery thickening, independently of blood pressure. However, elevated blood pressure, including paroxysmal hypertension, is often difficult to detect in patients with pheochromocytoma, 31 which may hamper clarification of the characteristics of individuals with latent hypertension.…”

Is it time to reconcile HDL with cardiovascular diseases and beyond? An update on a paradigm shift

“…This observation could account for the negative results of trials of entities that enhance HDL-C levels. Further studies of this parabolic relationship have revealed that extremely 3 high HDL-C levels (> 100 mg/dL) are associated with endothelial dysfunction [19,20*], impaired glucose metabolism [21] and an impaired capacity of HDL to acquire free cholesterol from triglyceride-rich lipoprotein lipolysis [22]. Alternatively, extremely high HDL-C levels may be attributed to particular lifestyles such as excessive alcohol consumption, or genomic factors such as loss-of-function mutations in key HDL metabolism-regulating genes [23].…”