Aims/Introduction
To determine the efficacy and safety of ipragliflozin in combination with metformin in Asian patients with type 2 diabetes mellitus.
Materials and Methods
This phase 3, multicenter, ...placebo‐controlled, double‐blind, parallel‐group study was carried out at 18 sites in Korea and 12 sites in Taiwan. After an 8‐week washout period for patients using drugs other than metformin and a 2‐week run‐in period, patients were randomized to either 50 mg ipragliflozin or a placebo for 24 weeks while continuing metformin. Efficacy outcomes included the changes in hemoglobin A1c, fasting plasma glucose (FPG) and bodyweight from baseline to the end of treatment (with last observation carried forward). Safety outcomes included treatment‐emergent adverse events.
Results
Between November 2011 and January 2013, 171 patients were randomized to and administered ipragliflozin (n = 87) or a placebo (n = 83). The mean changes (standard deviation) in hemoglobin A1c were −0.94% (0.75%) and −0.47% (0.81%) in the ipragliflozin and placebo groups, respectively (between‐group difference −0.46%, P < 0.001). The changes in fasting plasma glucose and bodyweight were also significantly greater in the ipragliflozin group, with between‐group differences of −14.1 mg/dL and −1.24 kg, respectively (both P < 0.001). The most common treatment‐emergent adverse events (ipragliflozin vs placebo) were upper respiratory tract infection (9.2% vs 12.0%) and urinary tract infection (6.9% vs 2.4%).
Conclusions
These results show that ipragliflozin is effective and well tolerated when used in combination with metformin in Asian patients with type 2 diabetes mellitus.
Ipragliflozin is effective and well tolerated when used in combination with metformin in Taiwanese and Korean patients with type 2 diabetes mellitus. The results of this study are consistent with those of an earlier study in Japanese patients.
Vasculitic peripheral neuropathy (VPN) arises from an inflammatory obstruction in the blood vessels supplying peripheral nerves and subsequent ischaemic insults, which exhibits the clinical features ...of neuropathic pain and impaired peripheral nerve function. VPN induced by ischaemia–reperfusion (IR) has been reported to involve nuclear factor‐κB (NF‐κB)‐mediated neuroinflammation. Recent studies have suggested that endoplasmic reticulum (ER) stress has been implicated in the development of peripheral neuropathies. Resveratrol possesses a potent anti‐inflammatory capacity. We hypothesized that resveratrol may exert a protective effect against VPN through modulating the interrelated ER stress and NF‐κB pathways. Male Sprague‐Dawley rats were allocated into five groups: sham, sham + resveratrol 40 mg/kg (R40), IR, IR + R20 and IR + R40. VPN was induced by occluding the right femoral artery for 4 hours followed by reperfusion. Our data have shown that VPN induced by IR led to hind paw mechanical allodynia, heat hyperalgaesia, and impaired motor nerve conduction velocity (MNCV). With resveratrol intervention, the behavioural parameters were improved in a dose‐dependent manner and the MNCV levels were increased as well. The molecular data revealed that VPN induced by IR significantly increased the expression of NF‐κB as well as the ER stress sensor proteins, protein kinase RNA‐like endoplasmic reticulum kinase, inositol‐requiring enzyme 1 and activating transcription factor 6 in the sciatic nerves. More importantly, resveratrol significantly attenuated the expression of NF‐κB and the ER stress sensor proteins after IR. In conclusion, resveratrol alleviates VPN induced by IR. The mechanisms may involve modulating NF‐κB‐mediated neuroinflammation via suppressing ER stress.
The objective of this nationwide case‐control study was to evaluate the risk of specific malignancy in diabetic patients who received thiazolidinediones (TZDs). A total of 606,583 type 2 diabetic ...patients, age 30 years and above, without a history of cancer were identified from the Taiwan National Health Insurance claims database during the period between January 1 2000 and December 31 2000. As of December 31 2007, patients with incident cancer of liver, colorectal, lung, and urinary bladder were included as cases and up to four age‐ and sex‐matched controls were selected by risk‐set sampling. Logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) between TZDs and cancer incidence. A total of 10,741 liver cancer cases, 7,200 colorectal cancer cases, and 70,559 diabetic controls were included. A significantly lower risk of liver cancer incidence was found for any use of rosiglitazone (OR: 0.73, 95% CI: 0.65‐0.81) or pioglitazone (OR: 0.83, 95% CI: 0.72‐0.95), respectively. The protective effects were stronger for higher cumulative dosage and longer duration. For colorectal cancer, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk (OR: 0.86; 95% CI: 0.76‐0.96). TZDs were not associated with lung and bladder cancer incidence, although a potential increased risk for bladder cancer with pioglitazone use ≥3 years could not be excluded (OR: 1.56; 95% CI: 0.51‐4.74). Conclusion: The use of pioglitazone and rosiglitazone is associated with a decreased liver cancer incidence in diabetic patients. The effects on occurrence of specific cancer types may be different for pioglitazone and rosiglitazone. (HEPATOLOGY 2012;)
The electron band structure and phonon energy dispersion of the silicon nanowires (SiNWs) embedded in SiGe 0.3 (SiNW-SiGe 0.3 composite) are simulated by using the effective mass Schrödinger equation ...and the elastodynamic wave equation, respectively. Then, the TE properties of the SiNW-SiGe 0.3 composite are investigated by the Landauer approach. The simulation shows the contribution from electrons/holes on both electrical conductance and thermal conductance increases few times by introducing SiNWs, but on the other hand, lattice thermal conductance reduces around two orders. These results are consistent with the experimental measurement and indicates that much lower lattice thermal conductance dominates the TE performance of the SiNW-SiGe 0.3 composite.
OBJECTIVE Stereotactic radiosurgery (SRS) is an important alternative management option for patients with small- and medium-sized vestibular schwannomas (VSs). Its use in the treatment of large ...tumors, however, is still being debated. The authors reviewed their recent experience to assess the potential role of SRS in larger-sized VSs. METHODS Between 2000 and 2014, 35 patients with large VSs, defined as having both a single dimension > 3 cm and a volume > 10 cm
, underwent Gamma Knife radiosurgery (GKRS). Nine patients (25.7%) had previously undergone resection. The median total volume covered in this group of patients was 14.8 cm
(range 10.3-24.5 cm
). The median tumor margin dose was 11 Gy (range 10-12 Gy). RESULTS The median follow-up duration was 48 months (range 6-156 months). All 35 patients had regular MRI follow-up examinations. Twenty tumors (57.1%) had a volume reduction of greater than 50%, 5 (14.3%) had a volume reduction of 15%-50%, 5 (14.3%) were stable in size (volume change < 15%), and 5 (14.3%) had larger volumes (all of these lesions were eventually resected). Four patients (11.4%) underwent resection within 9 months to 6 years because of progressive symptoms. One patient (2.9%) had open surgery for new-onset intractable trigeminal neuralgia at 48 months after GKRS. Two patients (5.7%) who developed a symptomatic cyst underwent placement of a cystoperitoneal shunt. Eight (66%) of 12 patients with pre-GKRS trigeminal sensory dysfunction had hypoesthesia relief. One hemifacial spasm completely resolved 3 years after treatment. Seven patients with facial weakness experienced no deterioration after GKRS. Two of 3 patients with serviceable hearing before GKRS deteriorated while 1 patient retained the same level of hearing. Two patients improved from severe hearing loss to pure tone audiometry less than 50 dB. The authors found borderline statistical significance for post-GKRS tumor enlargement for later resection (p = 0.05, HR 9.97, CI 0.99-100.00). A tumor volume ≥ 15 cm
was a significant factor predictive of GKRS failure (p = 0.005). No difference in outcome was observed based on indication for GKRS (p = 0.0761). CONCLUSIONS Although microsurgical resection remains the primary management choice in patients with VSs, most VSs that are defined as having both a single dimension > 3 cm and a volume > 10 cm
and tolerable mass effect can be managed satisfactorily with GKRS. Tumor volume ≥ 15 cm
is a significant factor predicting poor tumor control following GKRS.
Immunization is recommended for people with diabetes mellitus (DM), but little information is available on their seropositivity rates. To determine the impact of glucose tolerance state on ...seropositivity rate after hepatitis B vaccination, we included 7645 adult participants from the National Health and Nutrition Examination Survey 2005-2016 who reported three doses of hepatitis B vaccine and were seropositive for anti-hepatitis B surface antibody (≥ 12.0 mIU/mL), after exclusion of those positive for anti-hepatitis B core antibody and/or hepatitis B surface antigen. We classified the states of glucose tolerance as normal glucose tolerance (NGT, 61.68%), abnormal glucose tolerance (AGT, 26.02%), or DM (13.30%). We observed a stepwise decline in hepatitis B seropositivity rate from NGT (53.64%) to AGT (45.52%) to DM (28.84%) (P < 0.0001). We confirmed these results after standardization for age and BMI (P < 0.0001 for all subgroup analyses) and in subgroup analyses by gender and racial/ethnic group. Dysregulated glucose metabolism is associated with a decreased seropositivity rate after hepatitis B vaccination. Our observations suggest that regular follow-up screening for anti-hepatitis B surface antibody, with additional booster vaccination as necessary, is especially important in patients with DM. Whether a similar phenomenon exits for other vaccines, especially COVID-19, remains to be investigated.
In the diagnosis of diabetes mellitus, hemoglobin A1c (HbA1c) is sometimes measured to determine the need of an oral glucose tolerance test (OGTT). However, HbA1c does not accurately reflect glycemic ...status in certain conditions. This study was performed to test the possibility that measurement of serum glycated albumin (GA) better assesses the need for OGTT. From 2006 to 2012, 1559 subjects not known to have diabetes or to use anti-diabetic medications were enrolled. Serum GA was measured, and a 75-g OGTT was then performed to diagnose diabetes. Serum GA correlated significantly to age (r = 0.27, p<0.001), serum albumin (r = -0.1179, age-adjusted p = 0.001), body mass index (r = -0.24, age-adjusted p<0.001), waist circumference (r = -0.16, age-adjusted p<0.001), and plasma GA (r = 0.999, p<0.001), but was unaffected by diet (p = 0.8). Using serum GA at 15% for diagnosis of diabetes, the sensitivity, specificity, and area under the receiver-operating characteristic curve were 74%, 85%, and 0.86, respectively. Applying a fasting plasma glucose (FPG) value of < 100 mg/dL to exclude diabetes and of ≥ 126 mg/dL to diagnose diabetes, 14.4% of the study population require an OGTT (OGTT%) with a sensitivity of 78.8% and a specificity of 100%. When serum GA value of 14% and 17% were used to exclude and diagnose diabetes, respectively, the sensitivity improved to 83.3%, with a slightly decrease in specificity (98.2%), but a significant increase in OGTT% (35%). Using combined FPG and serum GA cutoff values (FPG < 100 mg/dL plus serum GA < 15% to exclude diabetes and FPG ≥ 126 mg/dL or serum GA ≥ 17% to diagnose diabetes), the OGTT% was reduced to 22.5% and the sensitivity increased to 85.6% with no change in specificity (98.2%). In the diagnosis of diabetes, serum GA measurements can be used to determine the need of an OGTT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Pooled efficacy studies suggest that glycaemic responses to dipeptidyl‐peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha‐glucosidase ...inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy.
Materials and methods
TECOS enrolled 14 671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48–64 mmol/mol (6.5%‐8.0%), and randomized them, double‐blind, to sitagliptin or placebo. There were 3265 patients (22.3%) from Asian countries. Background glucose‐lowering therapies were unaltered for the first 4 months post randomization unless clinically essential, facilitating comparison of sitagliptin‐associated effects in self‐identified East Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups.
Results
Median baseline HbA1c by race was 54 to 57 mmol/mol (7.1%‐7.4%). Mean 4‐month reduction in placebo‐adjusted HbA1c was greatest in East Asians (−6.6 mmol/mol −0.60% vs ≤6.0 mmol/mol ≤0.55% in other groups), with significantly greater reduction vs the 2 largest groups (White Caucasians, Other Asians; P < .0001) after adjustment for covariates. After the first 4 months, East and Other Asians were more likely to initiate additional oral therapy (metformin and/or sulfonylureas) than insulin vs White Caucasians (P < .0001). Acarbose use increased in the Asian patients, but no glycaemic interaction with allocated study medication was observed (adjusted P = .12).
Conclusions
The greatest initial reduction in HbA1c with sitagliptin in the TECOS population was in East Asians. No enhanced glycaemic effect was seen when sitagliptin was given with acarbose.
Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms ...in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.
Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.
The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.
Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive ...therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity.
Display omitted
•Adipose-specific Naa10p depletion prevents diet-induced obesity•Naa10p depletion increases Ucp1 expression and thermogenesis in beige adipocytes•N-terminal acetylation of Pgc1α by Naa10p suppresses thermogenic gene expression•Higher NAA10 expression correlates with human obesity
Lee et al. reveal that Naa10p-mediated N-terminal acetylation of Pgc1α inhibits beige thermogenesis and promotes diet-induced obesity (DIO) in mice. Together with the fact that NAA10 expression positively correlates with human obesity, their results suggest that inhibiting the enzymatic activity of Naa10p in adipose tissues may suppress DIO.
PDF
