Jutaro Tanabe

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.

Time course of pain sensation in rat models of insulin resistance, type 2 diabetes, and exogenous hyperinsulinaemia

Small sensory fibre dysfunction has been recently recognized as a component of impaired glucose tolerance and insulin resistance (IR) syndrome. However, few studies have investigated whether small sensory fibre dysfunction develops in normoglycaemic or pre‐diabetic animal models of IR and/or hyperinsulinaemia. In addition, scant information is available on the metabolic features of IR in relation to small sensory fibre dysfunction due to the progressive failure of beta cells to compensate for IR during the development of frank diabetes.

Influence of apolipoprotein E genotype on the response to caloric restriction in type 2 diabetic patients with hyperlipidaemia

Aims:  Hyperlipidaemia is a major predisposing factor to atherosclerosis in patients with type 2 diabetes. Apolipoprotein (apo) E polymorphism influences lipoprotein metabolism, and the present study was undertaken to explore the relation, in type 2 diabetics, between apo E genotype and the plasma lipid response to dietary therapy.

A case of multiple endocrine neoplasia type II accompanied by thyroid medullary carcinoma and pheochromocytomas expressing corticotropin-releasing factor and urocortins.

A 38-year-old woman with RET gene mutation presented with tumors in her thyroid and bilateral adrenal glands. I-metaiodobenzylguanidine scintigraphy revealed accumulation of the radioisotope in both adrenal glands. Both plasma adrenaline and noradrenaline levels were elevated. The circadian rhythms for plasma adrenocorticotropic hormone (ACTH) and cortisol levels were disturbed. Plasma ACTH and cortisol levels failed to be suppressed by an overnight dexamethasone test, suggesting autonomic secretion of ACTH and cortisol, although the patient had no typical Cushingoid features, hypertension, or impaired glucose tolerance. Pathological examination showed that these tumors were pheochromocytoma and thyroid medullary carcinoma, respectively, both of which highly expressed corticotropin-releasing factor, urocortin1, and urocortin3. Together with the endocrinological and pathological observations, the patient was diagnosed as multiple endocrine neoplasia type II with corticotropin-releasing factor- and urocortin-producing tumors that stimulated ACTH and glucocorticoid secretion.

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.

Lower serum calcium levels are a risk factor for a decrease in eGFR in a general non-chronic kidney disease population

Association between serum calcium (Ca) levels and kidney dysfunction progression in a non-chronic kidney disease (CKD) population has not been well elucidated, especially in consideration for classical metabolic risk conditions such as hypertension, dyslipidemia, and diabetes, and those related to Ca metabolism. Among participants of the population-based Iwaki study of Japanese people, those with an estimated glomerular filtration rate (eGFR) ≧60 ml/min/1.73 m2 and age ≧40 years, and who attended the study consecutively in 2014 and 2015 were enrolled (gender (M/F): 218/380; age: 58.9 ± 10.2). Regression analysis showed a significant correlation between serum Ca levels and a change in eGFR in the 1-year period (∆eGFR) after adjustment with multiple factors including those related to Ca metabolism (β = 0.184, p < 0.001). When subjects were stratified into tertiles based on their serum Ca levels (higher >9.6 mg/dL, middle 9.4–9.6 mg/dL, lower <9.4 mg/dL), lower serum Ca levels were a significant risk for a rapid decliner of eGFR designated as the lower one third of ∆eGFR (<−4.40 ml/min/1.73 m2) (odds ratio 2.41, 95% confidence interval 1.47–3.94). Lower serum Ca levels are a significant risk for rapid decrease in eGFR, independent of previously reported metabolic risk factors in this general population with non-CKD, or eGFR ≧60 ml/min/1.73 m2.

Association between insomnia and coping style in Japanese patients with type 2 diabetes mellitus

Purpose Insomnia, which is associated with type 2 diabetes mellitus (DM), results in a low quality of life, and several relationships exist between insomnia and coping style. Thus, we clarified the association between some coping styles and insomnia among Japanese type 2 DM patients. Subjects and methods The subjects included 503 type 2 DM patients (mean age 63.9±12.5 years). Sleep disturbance and personality traits were evaluated using the Japanese version of the Pittsburgh Sleep Quality Index and the Brief Scale for Coping Profile, respectively. Lifestyle factors, glycated hemoglobin A1c (HbA1c) levels, and the depression statuses of the patients were also included in the analyses. Results Among the 503 subjects with type 2 DM, 141 (28.0%) subjects exhibited probable insomnia. After adjusting for confounders, being female, living alone, and using “avoidance and suppression” were significantly correlated with current insomnia. No other relationships were found between insomnia and HbA1c or lifestyle factors, such as smoking, drinking alcohol, and exercise frequency. Conclusion The prevalence of insomnia in individuals with type 2 DM was high, and the protective factors included some emotion-focused coping styles. Future prospective studies are required to confirm the therapeutic effects of behavioral interventions on insomnia in patients with type 2 DM.