Kota Matsuki

Metformin restores impaired HDL-mediated cholesterol efflux due to glycation

High-density lipoprotein (HDL) mediates cholesterol efflux, which is the initial and rate-limiting step of reverse cholesterol transport. The present study was undertaken to evaluate the effect, on macrophage cholesterol efflux, of functional modification of HDL by its glycation. We also investigated the effects of the glycation-inhibitors metformin (MF) and aminoguanidine (AG) on glycated HDL-mediated cholesterol efflux. Human plasma HDL (5mg protein/mL) was glycated by incubation with 3-deoxyglucosone (3-DG). Glycation was monitored by measuring carboxymethyl-lysine (CML). HDL-mediated cholesterol efflux was determined using human THP-1-derived macrophages pre-labeled with [(3)H]-cholesterol. To measure expression of potential factors related to the efflux in the macrophages, ATP-binding cassette transporter (ABC) G1 was analyzed by real-time quantitative RT-PCR and Western blot. Glycation of HDL significantly reduced the HDL-mediated cholesterol efflux from THP-1-derived macrophages (87.7+/-4.2% of control, n=9, p<0.0001). In the presence of metformin or aminoguanidine (100mM), glycated HDL-mediated cholesterol efflux was restored to 97.5+/-4.3% and 96.9+/-3.1%, respectively. Exogenous HDL reduced ABCG1 mRNA and protein expression in THP-1-derived macrophages, but glycation deprived HDL of this effect. We conclude that glycated HDL particles are ineffective as acceptors of ABCG1-mediated cholesterol efflux; and this may explain, at least in part, accelerated atherosclerosis in diabetic patients. Metformin serves as a possible candidate to restore impaired cholesterol efflux and reverse cholesterol transport.

Effects of combined PPARγ and PPARα agonist therapy on reverse cholesterol transport in the Zucker diabetic fatty rat

Aim:  We investigated the effects of the combined therapy of PPARγ and PPARα agonists on HDL metabolism, especially concerning reverse cholesterol transport (RCT), using Zucker diabetic fatty rats (ZDF/Crl‐Leprfa rats) that are the rodent model for type 2 diabetes with obesity, hyperlipidaemia and insulin resistance.

Association between Higher Serum Cortisol Levels and Decreased Insulin Secretion in a General Population

Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03–1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population.

Association between serum prolactin levels and insulin resistance in non-diabetic men

Prolactin (PRL) has roles in various physiological functions. Although experimental studies showed that PRL has both beneficial and adverse effects on type 2 diabetes mellitus, clinical findings in subjects with hyperprolactinemia indicate adverse effects on glucose metabolism. However, effects of PRL within the physiological range in human are controversial. A population-based study of 370 Japanese men enrolled in the 2014 Iwaki study (aged 52.0 ± 14.8 years). In this cross-sectional study, associations between serum PRL levels and homeostatic model assessment (HOMA) indices representing glucose metabolism in a physiological setting were examined using multivariable regression analysis. Although univariate linear regression analyses showed significant associations between serum PRL levels and HOMA indices, adjustment with multiple factors made the association with HOMA-ß (insulin secretion) insignificant, while those with HOMA-R (insulin resistance) remained significant (ß = 0.084, p = 0.035). Non-linear regression analyses showed a regression curve with a peak at serum PRL level, 12.4 ng/mL and a positive association of serum PRL level with HOMA-R below the peak (ß = 0.119, p = 0.004). Higher serum PRL levels within the physiological range seem to be associated with insulin resistance in men.

Reduced cellular cholesterol efflux and low plasma high-density lipoprotein cholesterol in a patient with type B Niemann-Pick disease because of a novel SMPD-1 mutation

BACKGROUND Type A or B Niemann-Pick disease (NPD) is characterized by the accumulation of sphingomyelin in the lysosomes and cell membranes. This accumulation results because of a mutation in the sphingomyelin phosphodiesterase-1 (SMPD-1) gene that causes a deficit in the acid sphingomyelinase (ASM). OBJECTIVE Herein, we report on a new point mutation in the SMPD-1 gene that was discovered in a patient with type B NPD. METHODS AND RESULTS A culture of the patients fibroblasts demonstrated that the observed clinical symptoms and reduced plasma high-density lipoprotein cholesterol (HDL-C) were associated with a reduced efflux of cholesterol. Examination of the skin fibroblasts demonstrated that ASM activity was reduced to approximately 60% of that observed in control cells, and a newly identified point mutation was found in codon 494 [Gly (GGT) → Cys (TGT)] in the SMPD-1 gene. Furthermore, repeated measurements of the plasma HDL-C levels remained low (17.5-20.5 mg/dL), and the Apo A-I- or HDL-mediated cholesterol efflux from the patients fibroblasts was significantly reduced as compared with control fibroblasts. CONCLUSION In summary, we identified a unique point mutation in a patient with type B NPD that was associated with various clinical findings, including a low plasma HDL-C level. This reduced cellular cholesterol efflux may be implicated, at least in part, in low plasma HDL levels.

Dominance of the hypothalamus-pituitary-adrenal axis over the renin-angiotensin-aldosterone system is a risk factor for decreased insulin secretion

How the association between the hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin-aldosterone system (RAAS) affects glucose metabolism were not well examined in a general population. Participants of the population-based 2015 Iwaki study were enrolled (n: 1,016; age: 54.4 ± 15.1 years). Principal component (PC) analysis identified two PCs: PC1 represented levels of the HPA axis (serum cortisol) and the RAAS (plasma aldosterone) as a whole, and PC2 represented the HPA axis relative to the RAAS (HPA axis dominance). We examined the association between these PCs and glucose metabolism using homeostasis model assessment indices of reduced insulin sensitivity (HOMA-R) and secretion (HOMA-β). Univariate linear regression analyses showed a correlation between PC2 and HOMA-β (β = −0.248, p < 0.0001), but not between PC1 and HOMA-β (β = −0.004, p = 0.9048). The correration between PC2 and HOMA-β persisted after adjustment for multiple factors (β = −0.101, p = 0.0003). No correlations were found between the PCs and HOMA-R. When subjects were tertiled based on PC2, the highest tertile was at greater risk of decreased insulin secretion (defined as the lower one third of HOMA-β (≤68.9)) than the lowest tertile after adjustment for multiple factors (odds ratio, 2.00; 95% confidence interval, 1.35–2.97). The HPA axis dominance is associated with decreased insulin secretion in a Japanese population.