Effect of Serum Cholesterol on Insulin Secretory Capacity: Shimane CoHRE Study

<div><p>Objectives</p><p>Previous studies indicate that, in addition to the blood glucose level, the lipid level in the blood may affect functions of pancreatic beta cells. In this study, we aimed to examine whether there was a relationship between the serum level of total cholesterol (TC) and the insulin secretory capacity in healthy subjects.</p><p>Subjects and Methods</p><p>In participants of health examinations conducted from 2006 to 2010, we analyzed data from a total of 2,499 subjects (1,057 men and 1,442 women) after exclusion of individuals with dyslipidemia, thyroid dysfunction, diabetes, HbA1c≥6.5%, or fasting blood glucose≥126 mg/dL. Homeostasis model assessment for beta cell function (HOMA-beta) was utilized as a model representing the pancreatic beta cell function.</p><p>Results</p><p>Although the serum TC level had a positive correlation with HOMA-beta in a univariate correlation analysis, after adjustment by confounding factors in a multiple regression analysis, HOMA-beta had a negative correlation with TC. This was further confirmed in a multiple logistic regression analysis, showing that higher TC was an independent risk factor for decreased insulin secretory capacity (defined as HOMA-beta≤30%) together with higher age, lower BMI, lower TG, male sex and regular alcohol intake. After the participants were stratified by BMI into three groups, the effect of TC on HOMA-beta increased along with the increase in BMI, and it was highly significant in the highest tertile.</p><p>Conclusion</p><p>This cross-sectional study indicated that increased serum TC level might be related to the decrease of insulin secretory capacity in aged healthy population and that reduction of TC is more necessary in obese subjects to prevent diabetes.</p></div

Multiple logistic regression analysis on impairment in insulin secretory capacity.

<p>OR: odds ratio, CI: confidence interval.</p

Multiple linear regression analysis on HOMA-beta with various parameters.

<p>SE: standard error, std beta: standardized regression coefficient.</p

Multiple linear regression analysis on HOMA-IR with various parameters.

<p>SBP: systolic blood pressure, SE: standard error, std beta: standardized regression coefficient.</p

Demographic data.

<p>BMI: body mass index, FPG: fasting plasma glucose, FIRI: fasting immunoreactive insulin, BP: blood pressure, TG: triglyceride, TC: total cholesterol, LDLC: low density lipoprotein cholesterol, HDLC: high density lipoprotein cholesterol, non-HDLC: non-high density lipoprotein cholesterol, HOMA-IR: homeostasis model assessment for insulin resistance, HOMA-beta: homeostasis model assessment for beta cell function</p

Multiple linear regression analysis on HOMA-beta in stratified tertile groups by BMI.

<p>SE: standard error, std beta: standardized regression coefficient.</p

Correlation of TC with parameters concerning the diabetic status.

<p>Correlation of TC with parameters concerning the diabetic status.</p

p38 activation and IL-6 formation in fibroblasts from Gaucher’s disease patients harboring GBA1^L444P/L444P.

<p><b>A.</b> Human fibroblasts were stimulated with 100 nM PMA or 25 ng/ml TNF-α for 30 min. Proteins were subjected to immunoblot analysis with antibodies specific for phospho/active-p38 (p-p38) and β-actin. Equal amounts of protein were loaded in each lane, and the representative results are shown. <b>B.</b> After 6 h stimulation, levels of IL-6 in culture supernatants were measured using ELISA system. IL-6 values in control, PMA and TNF-α are expressed as percentage relative to those of healthy subject, respectively. Data represent mean ± S.E. (n = 3). *, <i>p</i> < 0.001; **, <i>p</i> < 0.02; ***, <i>p</i> < 0.002.</p

p38 activation and IL-6 formation in a Gaucher’s disease mouse model.

<p>Proteins were extracted from tissues (brain, lung, and liver) of wild type mice or Gaucher disease mouse models (V394L, D409H, and V394L/PS-NA) and then subjected to immunoblot analysis with antibodies specific for phospho- p38 and β-actin. Equal amounts of protein were loaded in each lane, and the representative results of brain tissues are shown (<b>A</b>). Amounts of active/phospho-p38 were estimated by measuring the density of bands of phospho-p38 and expressed as arbitrary units (<b>B</b>). The data represent mean ± S.E. (n = 4–7). *, <i>p</i> < 0.02; **, <i>p</i> < 0.05. (<b>C</b>) mRNA was extracted from brain tissues from wild type and neuropathic Gaucher disease model V394L/PS-NA mice, and mRNAs of p38 isoforms and IL-6 were determined by the quantitative real time PCR. The data represent mean ± S.E. (n = 5). TNF-α, <i>p</i> < 0.0006 (*). (<b>D</b>) Serum IL-6 levels from wild type mice or Gaucher disease mouse models (V394L, D409H, and V394L/PS-NA) were determined by the ELISA system. The data represent mean ± S.E. Wild type, n = 21; V394L, n = 10; D409H, n = 7; V394L/PS-NA, n = 7. Wt <i>vs</i> V394L, <i>p</i> < 0.0006 (*); Wt <i>vs</i> D409, <i>p</i> < 0.03 (**); Wt <i>vs</i> V394L/PS-NA, <i>p</i> < 0.05 (***).</p

p38 activation and IL-6 formation in Gaucher’s disease mouse fibroblasts.

<p><b>A.</b> Fibroblasts from wild type mouse or V394L/PS-NA mouse were stimulated with 25 ng/ml TNF-α for 30 min, and then proteins were extracted. Proteins were subjected to immunoblot analysis with antibodies specific for phospho-p38 (p-p38) and β-actin. Equal amounts of protein were loaded in each lane, and the representative results are shown. <b>B.</b> After 6 h stimulation, levels of IL-6 in culture supernatants were measured using ELISA system. The data represent mean ± S.E. (n = 3).</p