Effect of aging on insulin secretory function and expression of beta cell function-related genes of islets

Recently, the glucose-stimulated insulin release of isolated human islets has been shown to deteriorate progressively with advancing donor age. This decline in beta cell function with aging may contribute to the increasing development of IGT and type 2 diabetes and also to the progressive nature of the disease. This study was to see whether there is any change in expression of beta cell function-related genes in islets with aging. Islets were isolated from young (2-month old) and old (22-24-month old) LETO rats and C57BL/6N mice. The in vitro GSIR index was significantly lower in islets from old mice compared with young mice. In real-time RT-PCR, PDX-1, insulin, GLUT2 and prohormone convertase 1/3 gene expression in islets was markedly lower in old rats (33%, 13%, 20% and 34%, respectively) and old mice (56%, 42%, 28% and 22%, respectively) compared with young animals. On the other hand, genes not specifically related to beta cell-specific function, such as caspase 3, superoxide dismutase 2 and glycerol kinase were not significantly different in expression in islets according to age. In conclusion, with increasing age, insulin secretory function of islets deteriorates accompanied with a decrease in expression of beta cell-specific genes including PDX-1.     

Depressive mood in pre-dialytic chronic kidney disease: Statistical parametric mapping analysis of Tc-99m ECD brain SPECT

The purpose of this study was to investigate depression-related regions in pre-dialytic patients with chronic kidney disease (CKD) patients. Participants comprised 33 patients with stage 4 and 5 CKD (age, 55 [42–63]) and 32 healthy volunteers (age, 53.5 [49.5–57]). Depressed mood was assessed in the patients, and both groups underwent Tc-99m-labeled ethylcysteinate dimer (Tc-99m ECD) single photon emission computed tomograpy (SPECT). Statistical parametric mapping identified 18 areas of hypoperfusion in the patients in comparison with the normal controls. The largest clusters were areas including left precentral gyrus, right superior and middle temporal gyrus, both cerebellar posterior lobes, both inferior frontal gyrus, right superior and middle frontal gyrus, right cuneus, right inferior parietal lobule, and right putamen. However, there were no specific hypoperfusion areas in CKD patients with depression compared with CKD patients without depression. Interestingly, several hypoperfusion areas in CKD patients (inferior frontal gyrus [BA46], superior temporal gyrus [BA42], anterior cingulate gyrus [BA24]) were concordant with hypoperfusion areas found in patients with major depression who were free of kidney disease. In conclusion, this study did not demonstrate specific depression-related cerebral hypoperfusion areas. However, the cerebral blood flow pattern in CKD patients was similar to that of patients with major depression in some areas. Although further investigations are needed in the future, we suggest that the causes of the higher prevalence of depression in CKD might be associated with this finding.     

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized,double-blind,active-controlled,multicenter phase 3 trial

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.     

Can gamma-glutamyltransferase be an additional marker of arterial stiffness?

BACKGROUND: It has been recently suggested that gamma-glutamyltransferase (GGT) is independently associated with cardiovascular mortality and atherosclerosis, so the present study evaluated whether GGT is an additional marker of arterial stiffness, independent of other risk factors, in screening cohorts. METHODS AND RESULTS: The 1,387 individuals (741 men, 646 women) who underwent brachial - ankle pulse wave velocity (baPWV) measurement had their serum levels of GGT, creatinine, uric acid, C-reactive protein, lipids, fasting glucose and insulin, and their hepatitis profiles checked. There were statistically significant increments of baPWV according to quartile of GGT, which was statistically significant in women, but not in men. In logistic regression analysis, age, diabetes mellitus, GGT, heart rate, history of hypertension, triglyceride, and systolic blood pressure were significant variables that influenced increased pulse wave velocity (PWV). After age-and blood pressure-adjustment, GGT, homeostatic model assessment-insulin resistance, heart rate, history of hypertension, and metabolic syndrome were significant variables in men, and in women metabolic syndrome and history of hypertension were significant contributors to increased PWV. CONCLUSION: The present study results suggest that serum GGT may be an additional marker of arterial stiffness, especially in men, though the relationship with arterial stiffness was very weak. Further studies are needed to elucidate the mechanism of GGT's contribution to arteriosclerosis and to confirm the current results.     

Relationship of low-density lipoprotein (LDL) particle size to thyroid function status in Koreans

Objective  Dyslipidaemia is a well-known manifestation of thyroid dysfunction. Recently, small low-density lipoprotein (LDL) particle size has been linked with development of cardiovascular disease. To better understand the effects of thyroid dysfunction on the development of cardiovascular disease, we examined LDL particle size and lipid profiles in subjects with different thyroid function.
Methods  Included were 46 patients with overt hypothyroidism, 57 patients with subclinical hypothyroidism, 46 patients with overt hyperthyroidism, 51 patients with subclinical hyperthyroidism, and 110 age- and sex-matched healthy control subjects. We measured LDL particle size and lipid profiles in these subjects.
Results  No significant differences were found in LDL particle size between the groups with different thyroid function. Serum total cholesterol and LDL-cholesterol levels were significantly higher in the cases of hypothyroidism than in the cases of hyperthyroidism and the healthy control subjects. Serum triglyceride levels were higher in subjects with overt hypothyroidism than in those with overt hyperthyroidism or healthy control subjects.
Conclusions  LDL particle size, the emerging risk factor for atherosclerosis, did not appear to be significantly affected by the degree of thyroid dysfunction. Increased risk of atherosclerosis in hypothyroidism does not appear to be associated with LDL particle size, the non-traditional cardiovascular risk factor.     

Efficacy and Safety of 30-Mg Fimasartan for the Treatment of Patients With Mild to Moderate Hypertension: An 8-Week,Multicenter, Randomized,Double-Blind,Phase III Clinical Study

Purpose

The standard 60-mg dose of fimasartan, a newly developed selective angiotensin II receptor blocker, is effective and safe for use in patients with mild to moderate hypertension. This study aimed to compare the efficacy and safety of low-dose (30 mg) fimasartan and placebo or valsartan (80 mg) for 8 weeks in patients with mild to moderate hypertension.

Methods

In this randomized trial, 293 patients (219 men; mean age, 54.24 [9.77] years) with mild to moderate hypertension were enrolled. After randomization to receive 30-mg fimasartan (n = 115), placebo (n = 117), or 80-mg valsartan (n = 61), the treatment dose was kept constant without dose escalation for 8 weeks. The primary end point was improvement in sitting diastolic blood pressure (SiDBP) from baseline to 8 weeks that was compared between treatments with low-dose fimasartan and placebo. The secondary end point was the overall efficacy and safety of low-dose fimasartan compared with that of placebo or valsartan.

Findings

At week 8, SiDBP changed by –9.93 (8.86) mm Hg in the fimasartan group and by –2.08 (9.47) mm Hg in the placebo group, which indicated significant antihypertensive efficacy (P < 0.0001). Efficacy was shown at week 4 as measured by SiDBP (–9.96 [7.73] vs –2.27 [7.85] mm Hg; P < 0.0001) or sitting systolic blood pressure (SiSBP) (–16.18 [14.44] vs –1.95 [13.48] mmHg; P < 0.0001) and at week 8 as determined by SiSBP (–15.35 [16.63] vs –2.30 [14.91] mm Hg; P < 0.0001). The fimasartan group exhibited more potent antihypertensive efficacy than the valsartan group both at week 4 (SiDBP, –9.96 [7.73] vs –6.53 [9.58] mm Hg [P = 0.0123]; SiSBP, –16.18 [14.4] vs –7.65 [12.89] mm Hg [P = 0.0002]) and at week 8 (SiDBP, –9.93 [8.86] vs –5.47 [8.96] mm Hg [P = 0.0021]; SiSBP, –15.35 [16.63] vs –7.49 [13.68] mm Hg [P = 0.0021]). Most treatment-emergent adverse events (TEAEs) were mild (89 of 95), and there were no serious TEAEs. The incidence of TEAEs was 19.1% in the fimasartan group, 22.6% in the placebo group, and 13.6% in the valsartan group, with no significant differences.

Implications

Low-dose fimasartan (30 mg) was well tolerated during the study period with no significant TEAEs. Low-dose fimasartan had an effective blood pressure–lowering effect that was greater than that of 80-mg valsartan in patients with mild to moderate hypertension. ClinicalTrials.gov identifier: NCT01672476.     

Urinary Cystatin C and Tubular Proteinuria Predict Progression of Diabetic Nephropathy

OBJECTIVE

The aim of this study was to evaluate the association of urinary cystatin C, a tubular damage marker, with the progression of type 2 diabetic nephropathy.

RESERCH DESIGN AND METHODS

The baseline values of serum and urinary cystatin C were measured as primary parameters and those of urinary nonalbumin protein (NAP) were measured as secondary parameters. In this prospective observational study, a total of 237 type 2 diabetic patients were followed up for 29 months (13–44 months).

RESULTS

Both the urinary cystatin C-to-creatinine ratio (CCR) and NAP-to-creatinine ratio (NAPCR) were significantly different according to the degree of albuminuria. Both markers had strongly positive correlations at baseline. After adjusting for several clinical factors, both urinary CCR and NAPCR had significant associations with the decline of the estimated glomerular filtration rate (eGFR) (r = 0.160, P = 0.021; r = 0.412, P < 0.001, respectively). Urinary CCR had positive correlations with the decline of eGFR in the subpopulation of patients with eGFR ≥60 mL/min/1.73 m². In patients with eGFR ≥60 mL/min/1.73 m² and normoalbuminuria, only urinary NAPCR showed a significant association with the decline of eGFR; urinary CCR did not. In multivariate regression analysis, the number of patients who progressed to chronic kidney disease stage 3 or greater was higher in those in the upper tertiles of both the urinary levels of cystatin C and NAP than in those in the lower tertiles.

CONCLUSIONS

The results of this study suggest that urinary cystatin C and NAP may be predictors of the progression of type 2 diabetic nephropathy.Diabetic nephropathy is a complication with high morbidity and mortality as well as a major cause of end-stage renal disease. Although glomerular dysfunction is thought to be a major factor for the development and progression of diabetic nephropathy, tubulointerstitial damage may also play an important role in the pathogenesis of diabetic nephropathy (1–3). Recently, several studies have shown that some tubular damage markers have clinical implications as biomarkers for the development and progression of diabetic nephropathy (4–10).Cystatin C is a 13-kDa cysteine proteinase inhibitor and is produced by all nucleated cells at a constant rate (11). In healthy subjects, cystatin C is almost freely filtered by the renal glomeruli and almost entirely reabsorbed in the proximal tubule like other low molecular weight proteins; there is no tubular secretion of cystatin C (12–14). Similar to the serum cystatin C, the urinary cystatin C level is not affected by age or muscle mass in healthy subjects or in proteinuric patients without renal tubular damage (15). On the other hand, increased urinary cystatin C has been recognized as a marker of renal tubular dysfunction (16,17). In addition, urinary leakage of proteins other than albumin (nonalbumin protein [NAP]) can also indicate tubular damage rather than glomerular damage (18).The aims of this study were to evaluate the impact of urinary cystatin C on the progression of type 2 diabetic nephropathy and to determine whether urinary cystatin C has an association with the decline of the glomerular filtration rate (GFR) in type 2 diabetic patients. In addition, we also evaluated whether urinary NAP has any correlation with urinary cystatin C or has any effect on the decline in GFR.     

Sex-specific associations of obesity with exercise capacity and diastolic function in Koreans

Background and aimsWomen with obesity are highly predominant among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to elucidate sex-specific associations of obesity with exercise capacity and diastolic function.Methods and resultsHealthy individuals without known cardiovascular diseases undergoing cardiopulmonary exercise test and echocardiography (n = 736) were included and categorized into 4 groups according to their sex and obesity. Exercise capacity was lower in women than men. Obesity was associated with a lower exercise capacity in women (23.5 ± 7.3 vs. 21.3 ± 5.4 ml/kg/min, p < 0.05) but not in men (28.2 ± 7.8 vs. 28.0 ± 6.6 ml/kg/min, p > 0.10). Overall, women had a higher E/e′ than men. Women without obesity had a similar E/e′ to men with obesity (8.2 ± 1.8 vs. 8.4 ± 2.1, p > 0.10), and women with obesity had the highest E/e′. Among 5 risk factors (aging, obesity, elevated blood pressure, elevated heart rate, and elevated fasting glucose), obesity was a significant determinant of exercise intolerance in women but not men. Furthermore, obesity was associated with a greater risk of diastolic dysfunction in women than men (women, adjusted odds ratio 4.35 [95% confidence interval 2.44–7.74]; men, adjusted odds ratio 2.91 [95% confidence interval 1.42–5.95]).ConclusionObesity had a more deleterious effect on exercise capacity and diastolic function in women than men, even in a healthy cohort. These subclinical changes might contribute to the development of a female predominance among HFpEF patients, particularly among individuals with obesity.     

Direct comparison of an automated oscillometric device with an electronic auscultatory device for epidemiologic survey to evaluate the prevalence of hypertension

Mercury-free sphygmomanometers are gradually replacing the traditional sphygmomanometers in clinical settings and epidemiological surveys for measuring blood pressure (BP) due to mercury toxicity. No direct comparative studies have evaluated BP differences and statistical errors of automated oscillometric devices (ODs) against electronic auscultatory devices (ADs) for epidemiologic surveys. Herein, we evaluated the validity of ODs for the Korea National Health and Nutrition Examination Survey (KNHANES) using the Universal Standard for BP device validation through a direct comparison with ADs as the reference standard. Four trained observers performed validation on 278 volunteers aged ≥ 19 years with a standardized BP measurement protocol. Agreement between the BP measurements recorded with an OD against those recorded with an AD was assessed by Lin’s concordance correlation coefficient (CCC) and Bland–Altman’s limits of agreement. To evaluate the agreement for BP classification, weighted kappa values were estimated. To explore the factors associated with BP measurement differences between the 2 devices, multiple linear regression analysis was performed. The average BP differences (OD-AD) were 2.6 ± 6.2 mm Hg for systolic BP (SBP) and −5.1 ± 5.6 mm Hg for diastolic BP (DBP). Lin’s CCCs were 0.927 and 0.768 for the overall SBP and DBP, respectively. The cumulative percentage of absolute errors ≤10 mm Hg was 88.1% for SBP and 81.3% for DBP. The weighted kappa value for the Joint National Committee 7 BP classification was 0.75 (95% confidence interval: 0.68–0.81). An OD overestimated the prevalence of SBP (0.3%, P = .0222) and underestimated the prevalence of DBP (1.8%, P < .0001). Multivariate analysis to identify the risk factors for BP difference revealed the arm circumference (AC) to be negatively associated with BP difference. Male sex was positively associated, while age was negatively associated with SBP difference. OD-DBP was positively associated with DBP difference and negatively associated for DBP absolute error. ODs met the accuracy requirements of the Universal Standard criteria against ADs for SBP but not for DBP. Thus, the DBP values may be underestimated by ODs in the KNHANES.