Editorial
Intestinal Cholesterol Absorption in Diabetes Mellitus
2023 Volume 30 Issue 7 Pages 733-734
Details
2023 Volume 30 Issue 7 Pages 733-734
See article vol. 30: 735-753
The number of patients with diabetes mellitus (DM) in Japan is increasing rapidly along with changing lifestyles and social environments. DM is a risk factor for cardiovascular disease (CVD). Among various glycemic agents, biguanide, an alpha-glucosidase inhibitor, peroxisome proliferator-activated receptor gamma agonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 analogs have shown preventive effects against CVD1-6).
Intestinal cholesterol absorption has been linked to CVD, leading to a paradigm shift with the advent of ezetimibe, an inhibitor of Niemann-Pick C1 Like 1 (NPC1L1), which, in addition to simvastatin, effectively reduced low-density lipoprotein (LDL-C) levels and improved CVD outcomes in patients with stable LDL-C levels after acute coronary syndrome7).
With regard to DM and intestinal cholesterol absorption, Malhotra reported that high glucose levels enhanced NPC1L1 promoter activity in enterocytes8). In addition, Lally found that NPC1L1 gene expression was increased in a biopsy sample of the duodenum in patients with type 2 DM compared with controls9).
Based on these studies, one could hypothesize that increased intestinal cholesterol absorption contributes to hypercholesterolemia and increases atherogenicity in patients with DM. However, Matsumura et al. disproved this hypothesis in this issue of the Journal of Atherosclerosis and Thrombosis10). They reported that campesterol and campesterol/lanosterol ratios were reduced in Japanese patients with DM, independent of several clinical parameters, including age, chronic kidney disease, body mass index, and dyslipidemia. These markers were found to be negatively associated with plasma glucose (PG) and glycated hemoglobin (HbA1c) levels using restricted cubic spline analysis.
Based on the findings of Matsumura et al., prolonged increases in blood glucose levels would inhibit intestinal cholesterol absorption. This article is crucial because they tested markers of intestinal absorption and synthesis of cholesterol using a large Japanese diabetic cohort (CACHE study). Indeed, their findings are consistent with some previous studies. Ooi et al. reported that cholesterol absorption markers were reduced in male patients with metabolic syndrome and type 2 DM11). Furthermore, two articles have reported decreased cholesterol absorption in type 2 DM12, 13), and insulin resistance has been associated with decreased cholesterol absorption14).
However, this study has certain limitations. First, the study has missing data for PG (26%) and HbA1c (15.7%). These insufficient data may be confounding factors. Second, the authors did not show unadjusted data for comparing cholesterol absorption markers, and adjusted factors may affect the association between cholesterol markers and PG or HbA1c. Third, as the authors have stated, the enrolled patients could not be divided into those with type 1 and type 2 DM. Previous articles have described that the type of DM differs in intestinal cholesterol metabolism. For example, Miettinen et al. reported that cholesterol absorption markers were higher, and the cholesterol synthesis marker was lower in type 1 DM than in type 2 DM15). Additionally, Semova et al. reported that insulin suppressed 12α-hydroxylated bile acids and cholesterol absorption in vivo, and cholesterol absorption markers were increased in patients with type 1 DM compared with normal subjects16). From these studies, the percentage of patients with type 1 DM among all patients would have a significant impact on their findings. Fourth, the cholesterol synthesis marker was not increased in the DM group compared with the non-DM group. In general, cholesterol synthesis increases proportional to the decrease in cholesterol absorption. It may have been necessary to discuss the explanation for this discrepancy.
Assessment of cholesterol absorption markers and insulin resistance or insulin insufficiency would provide detailed information in addition to the current findings. Thus, future studies measuring the homeostatic model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) are warranted.
In conclusion, this study showed decreased cholesterol absorption in DM using a large clinical study. These findings can help develop new therapeutic strategies in Japanese patients with DM.
All authors declared no Conflicts of Interest.
