N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study.

BACKGROUND: Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia. METHODS: This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c) < 8.0%, LDL-C < 120 mg/dL, and fasting triglyceride ≥150 mg/dL. After a 12-week observation period, they were treated with 4 g/day n-3 PUFAs for 12 weeks. Lipoprotein particle sizes, concentrations, lipoprotein insulin resistance (LPIR) scores, lipid profiles, HbA1c, and fasting plasma glucose (FPG) were measured before and after treatment. Lipoprotein profiles were measured by nuclear magnetic resonance spectroscopy. Data were analyzed using Wilcoxon signed-rank tests. RESULTS: Concentrations of total cholesterol (P < 0.001), LDL-C (P = 0.003), and triglyceride (P < 0.001) decreased following n-3 PUFA administration. N-3 PUFAs decreased the size of very low-density lipoprotein (VLDL; P < 0.001) particles, but did not affect LDL or high-density lipoprotein (HDL) particles. The concentration of large LDL increased, whereas small LDL decreased, causing the large to small LDL ratio to increase significantly (P = 0.042). Large VLDL and chylomicron concentrations significantly decreased, as did the large to small VLDL ratio (all P < 0.001). FPG levels unchanged, whereas HbA1c levels slightly increased. LPIR scores improved significantly (P = 0.001). CONCLUSIONS: N-3 PUFAs partly improved atherogenic lipoprotein particle size and concentration, and produced less atherogenic lipoprotein subclass ratios in patients that achieved target LDL-C levels and glycemic control. These results suggest that n-3 PUFAs may reduce residual cardiovascular risk factors in statin-treated patients with type 2 diabetes and hypertriglyceridemia. TRIAL REGISTRATION: The study was registered at UMIN-ID: UMIN000013776 .

CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration.

OBJECTIVE: CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels. METHODS AND RESULTS: We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-beta did not affect the growth inhibitory effect of CCN3. Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3. CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice. CONCLUSIONS: CCN3 suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of CCN3 in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.

Favorable Effects of 24-Week Whole-Body Vibration on Glycemic Control and Comprehensive Diabetes Therapy in Elderly Patients with Type 2 Diabetes.

BACKGROUND: Elderly patients with type 2 diabetes (T2DM) are vulnerable to treatment-inducible hypoglycemia, falls, and depressive symptoms. Although it is challenging for elderly patients to adhere to regular exercise, its positive effect on functional ability, glycemic control, and mental wellness offers comprehensive diabetes treatment. In the present study, we aimed to investigate a novel exercise approach for the elderly, focusing on whole-body vibration (WBV). METHODS: This retrospective cohort study was conducted in a primary-care setting at a medical fitness center affiliated with the incorporated medical institution of THY (TOTAL HEALTH YARD). Fourteen (WBV group) and 12 (control group) elderly patients with T2DM undergoing and not undergoing our WBV program, respectively, for > 6 months were analyzed. Primary endpoints were the functional ability changes, evaluated by Timed Up and Go (TUG), Sit-to-Stand test (SST), gait length, and grip test. Secondary endpoints were global glycemic control and questionnaires, namely the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Geriatric Depression Scale (GDS). All records of exercise adherence and any adverse events were followed. RESULTS: Significant improvements in TUG and SST were found only in the WBV group [TUG: 7.1 ± 0.9, 7.1 ± 0.8 to 7.0 ± 1.0, 6.6 ± 0.9 (s), P = 0.63, 0.01; SST: 10.4 ± 1.9, 11.3 ± 2.4 to 9.7 ± 2.3, 9.5 ± 2.1 (s), P = 0.62, P < 0.01, control vs. WBV group, respectively]. The WBV group demonstrated significant improvement of hemoglobin A1C levels (7.2 ± 0.8 to 6.9 ± 0.5, P < 0.01) and DTSQ and GDS scores, while the control group did not. There were no hypoglycemic events during the study. The WBV program adherence was 93.3 ± 8.0%. CONCLUSION: We demonstrated the favorable effect of WBV training on balance, diabetes treatment, and mood. Therefore, WBV training can be proposed as comprehensive therapy in a safe manner and potentially has a positive effect on health-related quality of life in elderly patients with T2DM.

Influence of C-peptide on early glomerular changes in diabetic mice.

BACKGROUND: C-peptide has been shown to ameliorate diabetes-induced functional and structural renal changes in animal models as well as in patients with type 1 diabetes. This study aims to examine the molecular effects of C-peptide on early glomerular changes in a mouse model of type 1 diabetes. METHODS: Fourteen days after induction of diabetes by streptozotocin (STZ), the animals received rat C-peptide for either 24 h or 7 days. Urinary albumin excretion was measured by ELISA. Glomerular mRNA expression of the transforming growth factor (TGF)-beta(1) and type IV collagen was quantified by real-time PCR. The effect of C-peptide on type IV collagen gene expression in cultured murine podocytes was also examined. RESULTS: C-peptide decreased urinary albumin excretion from 0.29 to 0.18 microg/min (-40.7%, P < 0.01). The transcript level of (alpha3)IV collagen in glomeruli was up-regulated 2.2-fold in diabetic mice and was inhibited by 45-70% (P < 0.05) upon C-peptide treatment. C-peptide suppressed glomerular expression of TGF-beta(1) by 36.6% after 7 days (P < 0.05) but not 24 h after injection. In vitro studies using cultured podocytes revealed that C-peptide dose-dependently inhibited TGF-beta-induced up-regulation of type IV collagen. Moreover, both pertussis toxin (PTX) and a specific inhibitor for extracellular signal-regulated kinase (ERK) pathway reversed the inhibitory effect of C-peptide on TGF-beta. Finally, C-peptide was shown to up-regulate the activity of ERK in podocytes. CONCLUSIONS: These findings indicate that C-peptide suppresses specific aspects of early glomerular changes in a mouse model of diabetes and that the effect is at least in part mediated via interaction with the TGF-beta signal in glomerular podocytes.