Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor.

Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.

Optimal home SBP targets for preventing the progression of diabetic nephropathy in patients with type 2 diabetes mellitus.

OBJECTIVES: Home blood pressure control can reduce the risk of increased urinary albumin excretion in patients with diabetes mellitus. However, the optimal home blood pressure targets to prevent the onset or progression of diabetic nephropathy are not well defined. METHODS: We performed a retrospective cohort study of 851 patients with type 2 diabetes mellitus. Logistic regression models were used to evaluate the correlations of home SBP levels with progression of diabetic nephropathy. RESULTS: During the follow-up of 2 years, 86 patients had progression of diabetic nephropathy. Adjusted odds ratios (95% confidence interval) for progression of diabetic nephropathy in patients with morning SBP of 120-129  mmHg [2.725 (1.074-6.917), P = 0.035], 130-139  mmHg [3.703 (1.519-9.031), P = 0.004] and in those with morning SBP equal or more than 140  mmHg [2.994 (1.182-7.581), P = 0.021] were significantly higher than that in those with morning SBP less than 120  mmHg in multiple logistic analyses. CONCLUSION: The preferable morning SBP targets might be less than 120  mmHg for preventing the onset or progression of diabetic nephropathy in patients with type 2 diabetes mellitus.

[Contribution of clinical laboratory to the diabetes care team: efforts in physiological laboratory].

A large number of clinical laboratory technologists are qualified as diabetes educators; however, few of them actually participate in teaching patients. This is partially because it is difficult to balance their routine laboratory tasks and the work of a diabetes educator. We have introduced ultrasonic examinations of the ophthalmic artery, inspection of the R-R interval and current perceptual-threshold inspection for the early diagnosis of diabetic complications, and we have been contributing to the good medical care for diabetes. Furthermore, to care for diabetic foot lesions, clinical laboratory technologists have participated in checking diabetic patients' feet since 2007. In concrete terms, we examine the feet of diabetic patients, take digital pictures of the feet, and write a report, while preparing for thermographic examination of the patient. At the same time, we give simple guidance about foot care. Technologists cannot perform medical treatment; however, this has been accepted by medical staff because we only check foot lesions. We make use of existing medical imaging and reporting systems in the physiological laboratory, so doctors and nurses on the diabetic care team can always obtain information about the patients. Such actions have a good reputation not only among medical staff but also among diabetic patients.

Orally administered selective TRPV1 antagonist, JTS-653, attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain.

Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1-inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain.

Inhibition of CCL20 increases mortality in models of mouse sepsis with intestinal apoptosis.

BACKGROUND: CC chemokine ligand 20 (CCL20) and CC chemokine receptor 6 are believed to stimulate the recruitment of neutrophils and activation of macrophages against bacterial pathogens through the activation of T helper cells. We analyzed the role of CCL20 in the acute phase of sepsis. METHODS: The effect of a neutralizing, anti-mouse CCL20 monoclonal antibody (mAb) was examined in 2 murine models of sepsis: Cecal ligation and puncture (CLP) and Escherichia coli peritonitis. Immune cell migration, bacterial clearance, and expression of 17 cytokines and 5 chemokines were quantified in E coli-induced peritonitis. Expression of CCL20 in various tissues was determined, and apoptotic cells in jejunum were measured. RESULTS: Anti-CCL20 mAb increased mortality in CLP and E coli peritonitis (P = .029 and .024, respectively by Kaplan-Meier method and log-rank test). The 48-hour survival rate in anti-CCL20 mAb- and control immunoglobulin (Ig)G-treated mice was 37% (11/30) vs 62% (18/29) in CLP and 28% (11/40) vs 48% (19/40) in bacterial peritonitis. Neutralization of CCL20 showed no effect on leukocyte infiltration into the peritoneal cavity or bacterial clearance at 24 hours. CCL20 was induced strongly and predominantly in jejunum after bacterial infection, and neutralizing CCL20 increased apoptosis of epithelial cells in jejunum crypt. Inhibition of CCL20 increased serum tumor necrosis factor (TNF)-α (3.3-fold greater than control mice) and decreased serum interleukin (IL)-1α and IL-6. CONCLUSION: Neutralization of CCL20 before induction of sepsis increased mortality during sepsis accompanied with increasing epithelial apoptosis in the jejunum and augmenting serum TNF-α.

JTS-653 blocks afferent nerve firing and attenuates bladder overactivity without affecting normal voiding function.

PURPOSE: We evaluated the role of TRPV1 in bladder overactivity based on afferent nerve firing and urodynamic parameters using the selective TRPV1 antagonist JTS-653. MATERIALS AND METHODS: We evaluated the effects of JTS-653 on the increased pelvic nerve discharge and intravesical pressure induced by intravesical infusion of 100 µM capsaicin in anesthetized rats. The effects of JTS-653 on the urodynamic parameters of bladder overactivity induced by intravesical infusion of 30 nM resiniferatoxin or 0.2% acetic acid, or on normal bladder activity were evaluated by cystometry in conscious rats. The effects of JTS-653 on carbachol induced contraction were investigated using bladder muscle strips. RESULTS: JTS-653 significantly suppressed the capsaicin induced increase in nerve discharge and intravesical pressure. Intravesical infusion of resiniferatoxin or acetic acid decreased the intercontraction interval and voided volume. JTS-653 significantly increased the intercontraction interval and voided volume in rats with resiniferatoxin or acetic acid induced bladder overactivity without affecting maximal voiding pressure. The antimuscarinic agent propiverine significantly decreased maximal voiding pressure but did not affect the intercontraction interval or voided volume in rats with acetic acid induced bladder overactivity. In normal rats JTS-653 showed no significant effects on the intercontraction interval, voided volume or maximal voiding pressure. JTS-653 did not affect carbachol induced contraction of the bladder muscle. CONCLUSIONS: Our findings suggest that TRPV1 is involved in bladder overactivity via afferent nerve activation but it is not associated with normal voiding function. A TRPV1 antagonist would be a useful drug for bladder overactivity with a different pharmacological profile than antimuscarinic agents.

Pharmacological characterization of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel transient receptor potential vanilloid 1 antagonist.

Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [(3)H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA(2) values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC(50) values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC(50) values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation.

Five-item version of the international index of erectile function correlated with albuminuria and subclinical atherosclerosis in men with type 2 diabetes.

AIM: There is increasing evidence of a strong link between erectile dysfunction and atherosclerosis. The aim of this study was to evaluate the relationships between the 5-item version of the International Index of Erectile Function (IIEF-5) score and albuminuria as well as markers of subclinical atherosclerosis in men with type 2 diabetes. METHODS: We evaluated the relationship of the IIEF-5 score with the degree of urinary albumin excretion, pulse wave velocity, ankle-brachial index or toe-brachial index (n = 125) as well as with major cardiovascular risk factors, including age, blood pressure, serum lipid concentration and hemoglobin A1c, body mass index, severity of diabetic retinopathy or nephropathy, and presence of neuropathy or cardiovascular disease in 197 men with type 2 diabetes. RESULTS: The mean IIEF-5 score was 10.0 ± 6.9. The IIEF-5 score was inversely correlated with age or duration of diabetes, and positively correlated with diastolic blood pressure or serum total cholesterol concentration. The IIEF-5 score inversely correlated with log (urinary albumin excretion; r =-0.190, p =0.0078) or pulse wave velocity (r =-0.255, p =0.0003), and positively correlated with the toe-brachial index (r = 0.379, p < 0.0001). The IIEF-5 score was lower in patients with proliferative diabetic retinopathy than in patients with no diabetic retinopathy, and in patients with macroalbuminuria than in patients with normoalbuminuria. The IIEF-5 score was also lower in patients with neuropathy or cardiovascular disease than without. CONCLUSIONS: The IIEF-5 score correlated with diabetic micro- and macroangiopathy in men with type 2 diabetes.

Uncontrolled home blood pressure in the morning is associated with nephropathy in Japanese type 2 diabetes.

The purposes of this study were to investigate the state of blood pressure control level and to investigate the relationship between blood pressure control level and nephropathy in Japanese type 2 diabetes. We measured clinic and home blood pressure in 923 type 2 diabetic patients. According to the criteria for hypertension in the Japanese Society of Hypertension Guidelines 2009, patients were classified into four groups by clinic systolic blood pressure (130 mmHg) and morning systolic blood pressure (125 mmHg), as follows: controlled hypertension (CH), white-coat hypertension (WCH), masked hypertension (MH), and sustained hypertension (SH). Of all patients, 13.9, 12.6, 13.3, and 60.2% were identified as having CH, WCH, MH, and SH, respectively. The average number of drugs prescribed was 1.8. We assessed the association between blood pressure control level and nephropathy in diabetic patients. The degree of urinary albumin excretion and the prevalence of nephropathy in diabetic patients were higher in MH and SH groups than those in the CH group. The majority of patients had poor blood pressure control, regardless of ongoing conventional antihypertensive therapy, and diabetic patients with MH and SH were associated with nephropathy. It is suggested that more aggressive antihypertensive treatment is recommended to prevent nephropathy in diabetic patients.

Effect of pioglitazone on various parameters of insulin resistance including lipoprotein subclass according to particle size by a gel-permeation high-performance liquid chromatography in newly diagnosed patients with type 2 diabetes.

Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. The aim of this study was to obtain a better understanding of the mechanism involved in the insulin sensitizing effect of pioglitazone. A total of 50 newly diagnosed patients with type 2 diabetes were enrolled in this study and divided into two groups, 25 of who were treated with 15 mg/day pioglitazone and 25 with 500 mg/day metformin for 12 weeks. Changes in various parameters of insulin resistance including lipoprotein subclass according to particle size determined by high performance liquid chromatography, as well as glucose metabolism, were monitored to determine the relationship between lipoprotein subclass and other insulin resistance parameters. Both pioglitazone and metformin treatment were associated with significant reductions in hyperglycemia, HOMA-IR and HbA1c levels. Pioglitazone treatment, but not metformin treatment resulted in significant reductions in serum large very low-density lipoprotein (VLDL: 44.5-64.0 nm) and increases in serum adiponectin levels (both <0.001). In the pioglitazone group, the change in large VLDL levels correlated positively with changes in HbA1c (r=0.468, P=0.0174), HOMA-IR (r=0.593, P=0.0014), very small LDL (r=0.714, P<0.0001) and net electronegative charged modified-LDL (r=0.412, P=0.0399), and inversely with changes in adiponectin level (r=-0.526, P=0.0061). The results in this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone may have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and by increasing adiponectin.

Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection.

It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-1 receptor, IL-4, IL-4Ralpha and IL-10 in 330 H. pylori-infected noncardia patients with GC and 190 H. pylori-infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal-type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09-2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal-type GC. The frequency of an IL-10-592AA homozygote showing concomitant carriage of the HLA DRB1*0405-DQB1*0401 haplotype was significantly higher in patients with intestinal-type GC (chi(2) = 6.369, p = 0.0116, p(c) = 0.0464, OR = 2.43, 95% CI = 1.21-4.48). Our results suggest that the HLA class II and IL-10-592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori-infected individuals in the Japanese population.

Association between serum estradiol concentrations and carotid atherosclerosis in men with type 2 diabetes mellitus.

The aim of this study was to evaluate relationships between serum estradiol concentration and carotid atherosclerosis in addition to major cardiovascular risk factors in men with type 2 diabetes mellitus because previous reports concerning the role of estrogen on atherosclerosis in men are conflicting. Serum estradiol concentrations were measured in 305 consecutive men with type 2 diabetes mellitus. Relationships were evaluated between serum estradiol concentration and carotid atherosclerosis, as determined by ultrasonographically evaluated intima-media thickness (IMT) and plaque score, in a subgroup of 144 diabetic patients, as well as major cardiovascular risk factors, including age, blood pressure, and lipid concentrations. An inverse correlation was found between serum estradiol concentration and IMT (r = -0.174, P = .0369), but no correlation was found between serum estradiol concentration and plaque score. Patients with serum estradiol concentrations in the lowest tertile displayed significantly higher IMT compared with patients in the highest tertile (P = .0083). Serum estradiol concentration was not a determinant of IMT (beta = -.121, P = .1396) in the multiple regression analysis. An inverse correlation was found between serum estradiol concentration and triglyceride concentration (r = -0.136, P = .0186). In conclusion, serum estradiol concentration is inversely associated with carotid atherosclerosis as determined by ultrasonographically evaluated IMT in men with type 2 diabetes mellitus.

Hypereosinophilic syndrome accompanied by Buerger's disease-like femoral arterial occlusions.

A case of hypereosinophilic syndrome (HES) with a rare complication of Buerger's disease-like large arterial occlusion (AO) was successfully treated with emergent percutaneous transluminal angioplasty and anticoagulants plus corticosteroid. By reviewing 15 reported cases of HES with AO including the present case, we found man predominance but no other consistent characteristics in HES with AO, such as age, smoking history, eosinophil counts or previous treatments, thus, predicting AO in HES patients appears to be difficult. Vessel intervention should be considered as a treatment option, since treatment delay in some patients has resulted in the amputation of extremities.

Low serum testosterone concentration in middle-aged men with type 2 diabetes.

Low concentrations of endogenous androgens have been linked with insulin resistance and atherosclerosis. Men with diabetes have been reported to have lower serum testosterone concentration than non-diabetic men; however, there has never been a large study. The aim of this study was to investigate if endogenous androgen concentration is certainly lower in a relatively large number of Japanese patients with type 2 diabetes compared with healthy men, and to identify what factors may be associated with low serum testosterone concentrations in men with type 2 diabetes. Serum free testosterone concentrations were measured in 524 healthy men and in 331 consecutive Japanese men with type 2 diabetes between 40 and 69 years old. In addition, we investigated the relationships between serum free testosterone concentration and luteinizing hormone (LH) concentration as well as major cardiovascular risk factors including age, blood pressure, plasma lipid concentration, glycemic control (HbA(1c)), and BMI. Serum free testosterone concentrations were lower in men with type 2 diabetes than in healthy men in the 40-49 years group (10.9 +/- 3.3 vs. 14.0 +/- 3.6 pg/ml, P<0.0001), in the 50-59 years group (10.4 +/- 3.2 vs. 12.1 +/- 2.9 pg/ml, P<0.0001), and in the 60-69 years group (9.5 +/- 2.6 vs. 10.5 +/- 2.9 pg/ml, P = 0.0104). A negative correlation was found between serum free testosterone and LH concentrations (r = -0.326, P<0.0001). In conclusion, serum free testosterone concentration is certainly lower in a relatively large number of Japanese patients with type 2 diabetes compared with healthy men with each decade of life between 40 and 69 years old.

Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus.

The aim of this study was to evaluate the relationship between arterial stiffness determined by pulse wave velocity (PWV) and serum endogenous androgen concentrations as well as major cardiovascular risk factors in men with type 2 diabetes mellitus. Serum free testosterone and dehydroepiandrosterone sulfate (DHEA-S) concentrations were measured in 268 men with type 2 diabetes mellitus. Relationships between PWV and serum endogenous androgen concentrations as well as major cardiovascular risk factors, including age, blood pressure, serum lipid concentration, glycemic control (hemoglobin A(1c)), body mass index, and degree of albuminuria, were evaluated. Positive correlations were found between PWV and age (r = 0.491, P < .0001), duration of diabetes (r = 0.320, P < .0001), systolic blood pressure (r = 0.292, P < .0001), and log (urinary albumin excretion) (r = 0.269, P < .0001). Inverse correlations were found between serum free testosterone concentration and PWV (r = -0.228, P = .0003) and between serum DHEA-S concentration and PWV (r = -0.252, P = .0002) in men with type 2 diabetes mellitus. Pulse wave velocity was significantly greater in patients with lower concentrations of free testosterone (<10 pg/mL) than in patients with higher concentrations of free testosterone (1864 +/- 359 vs 1736 +/- 327 cm/s; P = .0053). Pulse wave velocity also was significantly greater in patients with lower concentrations of DHEA-S (<1000 ng/mL) than in patients with higher concentrations of DHEA-S (1843 +/- 371 vs 1686 +/- 298 cm/s; P = .0008). Multiple regression analysis identified both serum free testosterone concentration (beta = -.151, P = .0150) and serum DHEA-S concentration (beta = -.200, P = .0017) as independent determinants of PWV. In conclusion, serum endogenous androgen concentrations are inversely associated with arterial stiffness determined by PWV in men with type 2 diabetes mellitus, which is true for men in general based on other works.

Role of endogenous androgen against insulin resistance and athero- sclerosis in men with type 2 diabetes.

Age-related decline in serum testosterone and dehydroepiandrosterone sulfate concentrations occur in men. Low concentrations of these endogenous androgens have been linked with insulin resistance, which is an important upstream driver for metabolic abnormalities such as hyperglycemia, hypertension, or hyperlipidemia, and increased cardiovascular risk. Moreover, men with diabetes have significantly less circulating androgen than nondiabetic men. Here, we summarize how androgen affects insulin resistance and atherosclerosis in men with type 2 diabetes. Low serum concentrations of endogenous androgens are associated with visceral fat accumulation. Androgen deprivation by castration to treat prostate cancer increases insulin resistance, while testosterone administration in type 2 diabetic men with androgen deficiency improves glucose homeostasis and decreases visceral fat, in addition to alleviating symptoms of androgen deficiency including erectile dysfunction. Androgen correlates inversely with severity of atherosclerosis and has beneficial effects upon vascular reactivity, inflammatory cytokine, adhesion molecules, insulin resistance, serum lipids, and hemostatic factors. Because men with type 2 diabetes have relative hypogonadism, testosterone supplementation could decrease both insulin resistance and atherosclerosis.

Low serum dehydroepiandrosterone sulfate concentration is a predictor for deterioration of urinary albumin excretion in male patients with type 2 diabetes.

We recently found that serum dehydroepiandrosterone sulfate (DHEA-S) concentration correlated inversely with the degree of urinary albumin excretion in a cross-sectional study. We therefore performed an observational study to investigate the relationship between serum DHEA-S concentrations and changes in urinary albumin excretion in male patients with type 2 diabetes to answer the question as to whether DHEA is a causal rather than simply coincidental intermediate linking urinary albumin excretion to cardiovascular disease (CVD). The relationship between serum DHEA-S concentration and changes in urinary albumin excretion was investigated in 207 consecutive male patients with type 2 diabetes. Baseline serum DHEA-S concentration and urinary albumin excretion were measured in 2003. After 12 months, urinary albumin excretion was measured and any changes in urinary albumin excretion were calculated. Patients were divided into tertiles according to DHEA-S concentration. Greater changes in urinary albumin excretion were seen in patients with low DHEA-S concentration (29.6+/-7.6mg/g creatinine) than in patients with high DHEA-S concentration (5.1+/-3.6mg/g creatinine, P=0.0091). An inverse correlation was observed between serum DHEA-S concentration and changes in urinary albumin excretion (r=-0.193, P=0.0052). Multiple regression analysis demonstrated that HbA1c (beta=0.241, P=0.0009), and serum DHEA-S concentration (beta=-0.195, P=0.0054) were independent determinants of changes in urinary albumin excretion. In conclusion, serum DHEA-S concentration was inversely correlated with changes in urinary albumin excretion, which may indicate causality in the increased CVD mortality in male patients with type 2 diabetes and low DHEA-S concentration.

Efficacy of glimepiride in patients with poorly controlled insulin-treated type 2 diabetes mellitus.

We retrospectively investigated the effects of adding glimepiride in patients with type 2 diabetes showing suboptimal control by insulin therapy. Of 63 patients with poorly controlled insulin-treated type 2 diabetes (baseline HbA1c, 8.4 +/- 0.6%), 32 were treated with insulin alone and 31 were given glimepiride in addition to insulin. HbA1c values, daily insulin dose, body weight, blood pressure, plasma lipid concentrations, and the number of hypoglycemic events were recorded at weeks 0, 12, 24, 36, 48, 60, and 72. HbA1c decreased by 1.1%, from 8.5 +/- 0.6% to 7.4 +/- 0.8% (P<0.0001) in patients treated with insulin plus glimepiride at 12 weeks, and improved glycemic control continued throughout the study. Required insulin dose was reduced significantly in patients treated with insulin plus glimepiride (from 29.4 +/- 14.5 to 22.3 +/- 12.1 units/day, P = 0.0187). Body weight increased significantly in patients treated with insulin plus glimepiride (from 57.0 +/- 8.7 to 59.5 +/- 9.2 kg, P = 0.0232). Adding glimepiride showed little effect on blood pressure, plasma total cholesterol, triglyceride, or HDL-cholesterol. Serum C peptide concentrations increased significantly in patients treated with insulin plus glimepiride (from 1.01 +/- 0.71 to 1.28 +/- 0.65 ng/ml, P = 0.0367). The number of hypoglycemic events did not differ between groups. Adding glimepiride to insulin therapy resulted in sustained improvement of glycemic control in patients with poorly controlled type 2 diabetes.