Sex Specific Incidence Rates of Type 2 Diabetes and Its Risk Factors over 9 Years of Follow-Up: Tehran Lipid and Glucose Study

Objective

To investigate the population-based incidence of type 2 diabetes and its potential risk factors in a sex-split cohort of Iranian population.

Materials and Methods

A total of 8400 non-diabetic participants, aged ≥20 years (3620 men and 4780 women) entered the study. Crude and age standardized incidence rates per 1000 person-years were calculated for whole population and each sex separately. Cox proportional hazard models were used to evaluate hazard ratios (HR) and 95% confidence intervals for all potential risk factors in both uni-variable and multivariable models.

Results

During a median follow-up of 9.5 years, 736 new cases of diabetes were identified, including 433 women and 303 men. The annual crude and age-standardized incidence rates (95% CI) of diabetes in the total population were 10.6 (9.92–11.4) and 9.94 (7.39–13.6) per 1000 person-years of follow-up and the corresponding sex specific rates were 10.2 (9.13–11.4) and 9.36 (5.84–14.92) in men and 11.0 (9.99–12.0) and 10.1 (7.24–13.9) in women, respectively. In the multivariable model, the risk for incident diabetes was significantly associated with fasting and 2 hour post challenge plasma glucose as well as family history of diabetes in both men and women. However, among women, only the contribution of wrist circumference to incident diabetes achieved statistical significance [HR: 1.16 (1.03–1.31)] with waist/height ratio being marginally significant [HR: 1.02 (0.99–1.04)]; while among men, only body mass index was a significant predictor [HR: 1.12 (1.02–1.22)]. Additionally, low education level conferred a higher risk for incident diabetes only among men [HR: 1.80 (1.23–2.36); P for interaction with sex = 0.003].

Conclusion

Overall, sex did not significantly modify the impact of risk factors associated with diabetes among Iranian adults; however, among modifiable risk factors, the independent role of lower education and general adiposity in men and central adiposity in women might require different preventive strategies.     

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c-Myc axis on panobinostat cytotoxicity

Although the identification of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of many cancer types including chronic myeloid leukemia (CML), still adjustment of neoplastic cells to cytotoxic effects of anticancer drugs is a serious challenge. In the area of drug resistance, epigenetic alterations are at the center of attention and the present study aimed to evaluate whether blockage of epigenetics mechanisms using a pan-histone deacetylase (HDAC) inhibitor induces cell death in CML-derived K562 cells. We found that the abrogation of HDACs using panobinostat resulted in a reduction in survival of the K562 cell line through p27-mediated cell cycle arrest. Noteworthy, the results of the synergistic experiments revealed that HDAC suppression could be recruited as a way to potentiate cytotoxicity of Imatinib and to enhance the therapeutic efficacy of CML. Here, we proposed for the first time that the inhibitory effect of panobinostat was overshadowed, at least partially, through the aberrant activation of the phosphoinositide 3-kinase (PI3K)/c-Myc axis. Meanwhile, we found that upon blockage of autophagy and the proteasome pathway, as the main axis involved in the activation of autophagy, the anti-leukemic property of the HDAC inhibitor was potentiated. Taken together, our study suggests the beneficial application of HDAC inhibition in the treatment strategies of CML; however, further in vivo studies are needed to determine the efficacy of this inhibitor, either as a single agent or in combination with small molecule inhibitors of PI3K and/or c-Myc in this malignancy.     

κ-casein gene (<Emphasis Type="Italic">CSN3</Emphasis>) allelic polymorphism in Russian cattle breeds and its information value as a genetic marker

The frequencies of the κ-casein gene (CSN3) alleles and genotypes have been determined in five Russian cattle breeds (Bestuzhev, Kalmyk, Russian Black Pied, Yaroslavl, and Yakut breeds) by means of PCR-RFLP analysis using two independent restriction nucleases (HinfI and TaqI) and by allele-specific PCR. Typing alleles A and B of CSN3 is of practical importance, because allele B is correlated with commercially valuable parameters of milk productivity (protein content and milk yield) and improves the cheese yielding capacity. The frequencies of the B allele of CSN3 in the breeds studied vary from 0.16 to 0.50; and those of the AB and BB genotypes, from 0.27 to 0.60 and from 0.02 to 0.23, respectively. The Yaroslavl breed had the highest frequencies of CSN3 allele B and genotype BB (0.50 and 0.23, respectively). The frequencies of the B allele and BB genotype in other breeds studied varied from 0.25 to 0.32 and from 0.03 to 0.09, respectively. In none of the breeds studied have the observed and expected heterozygosities been found to differ from each other significantly. However, the observed genotype distributions significantly differ from the expected one in some herds (in most such cases, an excess of heterozygotes is observed). Two herds of the Yaroslavl breed dramatically differ from each other in the heterozygosity level: a deficit (D = ?0.14) and an excess (D = 0.20) of heterozygotes have been observed at the Mikhailovskoe and Gorshikha farms, respectively. In general, however, the heterozygosity of the Yaroslavl breed corresponds to the expected level (D = 0.04). Analysis of breeds for homogeneity with the use of Kulback’s test has shown that all cattle breeds studied are heterogeneous, the CSN3 diversity within breeds being higher than that among different breeds, which is confirmed by low F _st values (0.0025–0.0431). Thus, a DNA marker based on CSN3 gene polymorphism is extremely important for breeding practice as a marker of milk quality; however, it is inapplicable to marking differences between breeds or phylogenetic relationships between cattle breeds because of the high diversity with respect to this locus within breeds.     

Phytochemical attributes of endemic endangered primrose (Primula heterochroma Stapf.) accessions grown in Iran

Primula heterochroma is indigenous to Caspian coast forests in the north of Iran. Total phenols, total flavnoids, total carotenoids and antioxidant capacity of 50 P. heterochroma accessions were investigated. The highest total phenol (1272.31 mg GA equivalent/100 g fresh weight) and total flavonoids (615 mg catechin/100 g fresh weight) were observed in G5 accession from Saravan. The highest antioxidant activity was observed in G14 accession (73.03 %) from Kacha, followed by G2 accession (69.75 %) and G5 accession (66.84 %) from Saravan. The results of HPLC analysis showed that quercetin-3-glucoside was the major phenolic compound widely found in these accessions followed by chlorogenic acid. There was a linear relationship between the antioxidant capacities and the total phenols and total flavonoid. Inversely, there was no statistically significant correlation between total carotenoid and antioxidant activity. Based on the path coefficient analysis, the maximum direct effect on antioxidant was observed in total phenols (0.908). In addition, the cluster analysis based on Euclidean distance with Unweighted pair-group method using arithmetic average (UPGMA) method separated the accessions into four main groups. Our results supported that Iranian wild primrose accessions possess valuable antioxidant properties for therapeutic and potential medicinal use.

Electronic supplementary material

The online version of this article (doi:10.1007/s12298-015-0328-9) contains supplementary material, which is available to authorized users.     

Prehypertension Tsunami: A Decade Follow-Up of an Iranian Adult Population

ObjectivePrehypertension is associated with cardiovascular disease (CVD). There is no study to examine the incidence and risk factors of prehypertension in a sex stratified setting. The aim of this study was to examine the effect modification of sex for different risk factors which predicts the progression from normotension to prehypertension in a Middle East population-based cohort, during a median follow-up of 9.2 years.MethodsA multivariate Cox analysis was performed among 1466 and 2131 Iranian men and women, respectively, who were free of prehypertension, hypertension, CVD and diabetes at baseline and free of incident hypertension without preceding prehypertension at follow-up. Incident prehypertension at follow-up was defined as systolic blood pressure (SBP) of 120–139 mmHg and/or diastolic blood pressure (DBP) of 80–89 mmHg.ResultsOverall, 1440 new cases of prehypertension were identified resulting in an incidence rate of 593/10000 person-years; the corresponding values for women and men were 489/10000 and 764/10000person-years, respectively. There were significant interactions between gender with age, DBP, waist-to-hip-ratio (WHpR) and estimated glomerular filtration rate (eGFR) (all P-values <0.05) in multivariate analysis. Strong associations were found between age, body mass index (BMI) and SBP with incident prehypertension in both genders. However, the effect of DBP and WHpR was significant among women and 2-hour post challenge plasma glucose (2h-PCPG)was an independent risk factor for men. In the sex-adjusted analysis, glomerular hyperfiltration [Hazard ratio (HR) and 95%CI: 1.01 (1.00–1.01), P-value = 0.02], age, BMI, WHpR, SBP and DBP had higher risks while being female [HR (95%CI): 0.81(0.69–0.94), P-value = 0.01] had a lower risk for incident prehypertension.ConclusionAccording to this study results, among Iranian population with high incidence of prehypertension, general adiposity and glomerular hyperfiltration in total, 2h-PCPG in men and central adiposity in women should be emphasized as risk factors for prehypertension.     

Protective effects of Withania somnifera root on inflammatory markers and insulin resistance in fructose-fed rats

Background:

We investigated the effects of Withania somnifera root (WS) on insulin resistance, tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6) in fructose-fed rats.

Methods:

Forty-eight Wistar-Albino male rats were randomly divided into four groups (n=12); Group I as control, Group II as sham-treated with WS by 62.5mg/g per diet, Group III fructose-fed rats received 10%W/V fructose, and Group IV fructose- and WS-fed rats. After eight weeks blood samples were collected to measure glucose, insulin, IL-6, and TNF-α levels in sera.

Results:

Blood glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-R), IL-6, and TNF-α levels were all significantly greater in the fructose-fed rats than in the controls. Treatment with WS significantly (P < 0.05) inhibited the fructose-induced increases in glucose, insulin, HOMA-R, IL-6, and TNF-α.

Conclusion:

Our data suggest that WS normalizes hyperglycemia in fructose-fed rats by reducing inflammatory markers and improving insulin sensitivity.Key Words: Withania somnifera, Insulin resistance, IL-6, TNF- α     

Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3‐kinase (PI3K) pathway using pan‐PI3K inhibitor BKM120 exerted a cytotoxic effect against CML‐derived K562 cells through both the induction of p21‐mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro‐apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy‐related genes might serve as a compensatory pathway to cease the anti‐leukemic effect of BKM120 in K562; since we found a reinforced anti‐survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined‐modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies.