Nondiabetic Women Research Articles

Abstract 4121568: The Influence of Cardiovascular Health on Atherosclerotic Cardiovascular Disease Progression and Life Expectancy Among Individuals with Type 2 Diabetes

Objective: This study aims to evaluate whether cardiovascular health (CVH) plays a similar role in the transition from a healthy state to atherosclerotic cardiovascular disease (ASCVD) and subsequent mortality rates in diabetic patients compared to those without diabetes. It also evaluates the effectiveness of CVH in reducing diabetes-related ASCVD risks and enhancing ASCVD-free life expectancy. Research design and methods: This cohort study included 176,669 adults from the UK Biobank, among whom 10,109 (22.3%) were diagnosed with type 2 diabetes mellitus (T2DM). CVH was assessed using the Life's Essential 8 score, encompassing diet, physical activity, smoking, sleep, BMI, blood lipids, blood glucose, and blood pressure. CVH scores were categorized into low, moderate, and high levels based on their distribution among diabetic patients. The main outcomes were the transitions from no ASCVD to the onset of ASCVD and then to mortality, as well as the ASCVD-free life expectancy. Results: In patients with T2DM, high CVH levels were associated with lower ASCVD risk (HR: 0.55, 95% CI: 0.45-0.68 for women; HR: 0.57, 95% CI: 0.50-0.65 for men) and reduced mortality in those with ASCVD (HR: 0.62, 95% CI: 0.39-0.98 for women; HR: 0.62, 95% CI: 0.48-0.79 for men), compared to the low CVH group. No significant difference in CVH's effect on ASCVD and mortality was observed between diabetic and non-diabetic groups. When compared with non-diabetic individuals, no excess risk was observed in incident ASCVD and post-ASCVD mortality among diabetic patients with high CVH. At the age of 40, women with low CVH were expected to live 38.5 years (38.0-39.1) free from ASCVD, which increased to 42.9 years (42.4-43.5) for those with high CVH, while non-diabetic women were predicted to have an ASCVD-free life expectancy of 44.1 years (43.5-44.6). For men at the age of 40, those with low CVH had an ASCVD-free life expectancy of 32.0 years (31.3-32.6), which rose to 37.9 years (37.4-38.6) with high CVH. Non-diabetic men were expected to live 38.3 years (37.7-39.0) free from ASCVD. Notably, life expectancy with ASCVD did not increase with higher CVH levels in both genders. Conclusions: Our findings suggest that the American Heart Association’s recommendations for promoting CVH, initially designed for the general population, are also beneficial for individuals with T2DM. Adopting these guidelines can help mitigate ASCVD progression and enhance life expectancy in diabetic patients.

Perinatal outcomes in pregnancies achieved after fertility treatments with and without diet-controlled GDM.

To evaluate the rates of adverse perinatal outcomes among women who conceived after fertility treatments with and without diet-controlled GDM. In this retrospective population-based cohort study, all pregnancies of non-diabetic and diet-controlled GDM women who conceived after fertility treatments (in-vitro fertilization - IVF and ovulation induction - OI) and delivered between the years 1996-2016 in a tertiary medical center, were included. Pregnancies of women with pre-gestational diabetes mellitus, and those complicated with gestational diabetes mellitus A2, multiple pregnancies, congenital malformations and those lacking prenatal care, were excluded. Demographical, clinical, and obstetrical characteristics were recorded, and pregnancy complications and adverse perinatal outcomes were compared between the groups. Multivariate logistic regression models were used to control for confounders. Statistical analyses were performed using logistic regression to control for potential confounders. A p-value of < 0.05 was considered statistically significant. During the study period, 6254 deliveries met the inclusion criteria, 10.23% of them (n = 640) had diet-controlled GDM. Pregnancies with diet-controlled GDM were found to be associated with significantly higher rates of hypertensive disorders of pregnancy (15.6% vs. 9.8%, p < 0.001), polyhydramnios (5.9% vs. 2.7%, p < 0.001), and cesarean deliveries (40.8% vs. 31.9%, p < 0.001). Diet-controlled GDM was also found to be an independent protective factor against perinatal mortality (aOR = 0.22, 95% Cl 0.05-0.92, P = 0.04) possibly due to the more intensive monitoring and management typically provided to women undergoing fertility treatments. This close care may mitigate some of the risks associated with ART, leading to improved perinatal outcomes. Among pregnancies achieved after fertility treatments, diet-controlled GDM was associated with reduced perinatal mortality and higher rates of certain pregnancy complications. These findings highlight the importance of close monitoring and careful management of women with diet-controlled GDM, as it may help mitigate risks associated with ART pregnancies. Further research is needed to understand the mechanisms behind these outcomes and to optimize management strategies for this specific population.

Unveiling Macrosomia Risks of Non-Diabetic Women: Insights from Second Trimester Maternal Lipid Profiles.

Macrosomia, characterized by excessive fetal growth, is common in infants born to women with pre-gestational diabetes and gestational diabetes mellitus (GDM). However, macrosomia, which leads to birth-related maternal and fetal complications and metabolic complications in the adolescence of the affected fetuses, also occurs in the pregnancies of non-diabetic women. This study aims to identify the association between second-trimester lipid profiles and macrosomia in non-diabetic pregnant women to aid in early diagnosis. This retrospective cohort study included 8,956 patients who delivered at a tertiary care center between 2017 and 2019. Exclusion criteria encompassed pre-existing diabetes, GDM, preeclampsia (PE), intrahepatic cholestasis of pregnancy, obesity, fetal chromosomal or genetic abnormalities, tobacco, alcohol, or drug use affecting lipid metabolism. Participants were divided into two groups: 621 with macrosomia and 873 controls. Second trimester maternal lipid profiles and demographic variables such as age, pregnancy week, and gender were assessed. In the study cohort, maternal age (P=0.002), gestational week (P=0.003), and cesarean section rate (P<0.001) were higher in the macrosomic group. High-density lipoprotein-cholesterol (HDL-C) was significantly lower, while total cholesterol (TC), triglycerides (TG), and low-density lipoprotein-cholesterol (LDL-C) were significantly higher in the macrosomic group (P<0.001). Univariate analysis revealed positive associations between second-trimester TG (OR 1.023, 95% CI: 1.020‒1.033, P<0.001), TC (OR 1.023, 95% CI: 1.016‒1.030, P<0.001) and LDL-C (OR 1.036, 95% CI: 1.018-1.054, P<0.001) with macrosomia and a negative association with HDL-C (OR 0.954, 95% CI: 0.923‒0.976, P<0.001). However, after adjusted multivariable logistic analysis, only TG remained statistically significantly associated with macrosomia (OR 1.054, 95% CI: 1.033‒1.076, P<0.001). Our study emphasizes the importance of early recognition and prevention of macrosomia. Structured prospective studies are needed to enhance macrosomia prediction and implement preventive measures, such as dietary modifications. These strategies will be crucial in preventing birth-related complications and long-term health risks, including diabetes, obesity, and cardiovascular diseases, associated with macrosomia.

Histological Change of Placenta in Diabetic Pregnant Women in Comparison to Normal Pregnant Women

Background: The placenta is a foeto-maternal organ and its alterations is directly related to the disease’s length and severity. The human placenta experiences a number of functional and structural pathologic alterations when complicated by metabolic disorder such as diabetes mellitus. Methods: This cross-sectional comparative study was conducted over a period of threeyears from January 2019 to December 2021 at the Department of Anatomy, Rajshahi Medical College, Rajshahi, in collaboration with the Department of Obstetrics and Gynaecology, Rajshahi Medical College Hospital and Diabetic Hospital Rajshahi, Bangladesh. The study was carried out on 70 pregnant women, among them 35 diabetics and 35 non-diabetics. The fibrinoid necrosis, syncytial knot and immature villi of the placenta were studied in diabetic and non-diabetic pregnant women. SPSS software, version-24 was used for data analysis, with a p-value &lt; 0.05 indicating statistically significance for all tests. Results: The diabetic and non-diabetic pregnant women groups were almost identical in terms of attachment of umbilical cord to placenta with marginal attachment being more often found in either group (p = 0.829). Histological examination of placenta showed that fibrinoid necrosis was common in placenta of diabetic mothers than that of the normal mothers (p &lt; 0.001). Syncytial knot and immature villi were higher in the former group than those in the latter group, here p values were also less than .001. Conclusion: Histological findings (fibrinoid necrosis, syncytial knot and immature villi) were more in placenta of diabetic mother and they were highly significant different between the groups. EWMCJ Vol. 12, No. 1&amp;2, January-July 2024: 27-33

M Mode Assessment of Fetal Interventricular Septal Thickness in Third Trimester with Comparison Between Diabetic and Non-Diabetic Mothers

Background: Babies born to diabetic mothers face increased risks of illness and death despite advances in prenatal care. One common heart defect in these babies is interventricular septal hypertrophy. Objective: This study examines how gestational diabetes affects fetal interventricular septal thickness (IVST). Material &amp; Methods: The study took place at Sharda Hospital's Radiology Department over two months. Ninety pregnant women between 28 and 35 weeks of gestation were selected. The women were grouped based on oral glucose tolerance test (OGTT) results into non-diabetic (Subgroup A), controlled diabetic (Subgroup B), and uncontrolled diabetic (Subgroup C). IVST measurements were taken using M-mode during diastole. Results: The average age of participants was 26.41±3.18 years. In the 28-32 week group, the mean IVST was 3.76±0.23mm for non-diabetic women, 4.00±0.28mm for controlled diabetics, and 5.83±0.64mm for uncontrolled diabetics. In the 32-35 week group, the mean IVST was 4.25±0.29mm for non-diabetics, 4.75±0.43mm for controlled diabetics, and 6.84±0.34mm for uncontrolled diabetics. IVST was significantly higher in uncontrolled diabetics (p&lt;0.05), while non-diabetic and controlled diabetic groups had similar thicknesses. There was a significant positive correlation between OGTT levels and IVST (p&lt;0.05). Conclusion: Fetal IVST was notably higher in uncontrolled diabetic mothers. There is a strong association between OGTT results and IVST. M-mode measurement of IVST is simpler than fetal echocardiography and can be included in routine third-trimester scans for diabetic mothers to detect early signs of hypertrophic cardiomyopathy.

12518 Development Of A Four-compartment, Dynamic (In Vivo) Model For Insulin Disposition In Healthy Humans: Use Of Fick’s Law To Model Plasma-interstitial Insulin Flux

Abstract Disclosure: R.I. Dorin: None. C.R. Qualls: None. Introduction: Metabolic elimination of insulin (I) in vivo includes pathways mediated by high-affinity and potentially saturable insulin receptor binding; endogenous insulin secreted into the portal vein is subject to first pass elimination. The rate of insulin flux between vascular (Vp) and interstitial (Vi) compartments is often modeled by first order rate constants; here we analyzed an alternative approach using Fick’s law. Methods: The four-compartment, insulin (I) model is expressed by four differential equations that represent I flow (mass/time) in 4 volumes (V) (or compartments) having 3 corresponding elimination rate functions (α): (i) vascular plasma (Vp), (ii) interstitial (Vi, αi), (iii) hepatic (Vh, αh), and (iv) kidney (Vk, αk). Fick’s law was used to model diffusion of insulin between Vp and Vi; Michaelis-Menten like functions were used for saturable elimination functions (αh and αi); rates of hepatic (HPF) and renal (KPF) plasma flow were from literature. Realistic bounds for solved parameters (insulin permeability constant [k, L/min] and αi [min-[1]]) were developed by test bed analysis of published plasma (Ip) and interstitial (Ii) insulin concentration data. The inverse problem (estimating parameters) used Ip data from insulin-modified, frequently sampled iv glucose tolerance (IM-FSIVGT) studies performed in 40 healthy, non-diabetic women (1). Parameter solutions for individual subjects were obtained by iterative least squares method minimizing differences between model-predicted and measured Ip. Results: For infusion of exogenous I (ZI) at a constant rate (e.g., insulin clamp), reported steady state Ii/Ip data suggest that interstitial insulin elimination (αi) is conditionally saturable. Together with non-steady state data for Ip and Ii, initial estimates of k and αi were obtained. Steady state solutions give rise to four algebraic equations: (1) Ii/Ip = a, where a &amp;lt; 1 is consistent with experimental data, (2) Ih is a reduced version of a linear combination of Ip and endogenous insulin secretion (Zβ), where the factor of reduction (b) is &amp;lt;1, (3) Ik/Ip = d, where d&amp;lt;1, and (4) Ip is a linear combination of (i) ZI and (ii) the reduced (by factor b) Zβ. For Ip, this linear combination of ZI and reduced Zβ is also normalized by factor c (weighted sum of k, HPF, and KPF). Conclusions: (i) The proposed insulin flow model using Fick’s law was advantageous in providing realistic parameters and solutions that are tractable to physiologic interpretation, (ii) a simplified version of this model is generalizable to C-peptide, and (iii) since measurement of Ii is impractical in the clinical setting, the proposed prediction model may provide useful modeling adjunct to personalize pharmacokinetic and pharmacodynamic strategies for insulin administered by subcutaneous, iv, and hybrid closed-loop insulin pump routes. 1. Gower et al. Nutrition &amp; Metabolism (2016) 13:2 Presentation: 6/1/2024

Gender differences in the relationship between the triglyceride-glucose index and serum Klotho concentrations among the middle-aged and elderly: a cross-sectional analysis

BackgroundThe triglyceride-glucose (TyG) index is recognized as a robust indicator for evaluating insulin resistance (IR). Despite the well-documented anti-aging biological functions of Klotho protein, its correlation with the TyG index remains unexplored.MethodsA cross-sectional analysis was conducted involving participants from the National Health and Nutrition Examination Surveys (NHANES) 2007–2016. The TyG index was computed using laboratory data, while serum Klotho concentrations was determined using ELISA kit. After adjusting potential confounding variables, multivariate regression models were employed to evaluate the association between the TyG index and Klotho protein levels among middle-aged and elderly females and males separately. Additionally, smooth curve fitting and segmented regression model were applied to investigate potential threshold effects and identify the inflection point.ResultsA total of 6,573 adults qualified for inclusion, comprising 3,147 (47.88%) males and 3,426 (52.12%) females. Multivariate regression analysis revealed that females with a higher TyG index exhibited significantly lower serum Klotho concentrations (β=-83.41, 95% CI: -124.23 to -42.60, P < 0.0001). This association was not statistically significant in males (β = 15.40, 95% CI: -19.16 to 49.95, P = 0.3827). Subgroup analyses revealed a significant interaction effect by diabetes status in females (P-interaction = 0.0121), where non-diabetic females showed a stronger negative association between TyG index and serum Klotho levels compared to diabetic females. In the female group, when TyG index was divided into quartiles, individuals in the highest quartile of TyG index exhibited reduced levels of Klotho protein (Q4: -88.77 pg/ml) compared to those in the lowest quartile (Q1) after full adjustment (P = 0.0041). Segmented regression analysis indicated a turning point value of 9.4 in females. Notably, a 1-unit increase in TyG index was significantly associated with a decrease in Klotho levels by -111.43 pg/ml (95% CI: -157.34 to -65.52, P < 0.0001) when TyG index was below 9.4, while above this threshold, the association was not significant (Log likelihood ratio test: 0.009).ConclusionsThe findings highlight a non-linear correlation between the TyG index and serum Klotho concentrations among females, indicative of a saturation effect. This relationship was particularly pronounced in non-diabetic women. In contrast, no statistically significant association was observed in male participants.

Relation between serum sclerostin and CTRP3 levels and bone mineral density in diabetic postmenopausal women

BackgroundOsteoporosis (OP) is a common finding in diabetic patients especially high-risk populations such as postmenopausal women. Sclerostin is a glycoprotein chiefly secreted by mature osteocytes and is considered a main regulator of bone formation. The C1q/TNF-Related Protein 3 (CTRP3) was found to be significantly associated with OP in postmenopausal women. The effect of type 2 diabetes mellitus (T2DM) on sclerostin and CTRP3 levels in postmenopausal women is rarely investigated. The present study aimed to assess the impact of T2DM on sclerostin and CTRP3 levels and their relation to OP in postmenopausal women.MethodsThe study included 60 postmenopausal women with T2DM and 60 age-matched postmenopausal non-diabetic women. Bone mineral density (BMD) was assessed using dual energy X-ray absorptiometry (DEXA). Serum levels of sclerostin and CTRP3 were assessed using enzyme-linked immunosorbent assay (ELISA) technique.ResultsDiabetic group expressed significantly higher serum levels of sclerostin when compared with non-diabetic group (110.0 ± 29.0 versus 51.5 ± 23.2 ng; p < 0.001). Oppositely, CTRP3 were significantly lower in the diabetic group (3.5 ± 3.5 versus 9.9 ± 3.7 ng/ml, p < 0.001). Multivariate logistic regression analysis identified HbA1c levels [OR (95% CI): 0.49 (0.26–0.93), p = 0.028], sclerotin levels [OR (95% CI): 1.06 (1.0-1.012), p = 0.041] and CTRP3 levels [OR (95%) CI: 1.64 (1.0-2.68), p = 0.047] as significant predictors of OP in diabetic patients.ConclusionsSclerostin and CTRP3 levels are involved in OP in postmenopausal diabetic patients.

Exploring Gender Differences in the Association Between TyG Index and COPD: A Cross-Sectional Study from NHANES 1999-2018.

This study examined gender differences in the association of Triglyceride-Glucose (TyG) index with the prevalence of chronic obstructive pulmonary disease (COPD), particularly in a non-diabetic population. The study leveraged data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2018, with a cohort of 23,456 participants. Logistic regression and restricted cubic spline analyses were employed to explore the relationship between the TyG index and COPD prevalence. Statistical analyses revealed a significant positive association between the TyG index and COPD prevalence among non-diabetic women after adjustment for all covariates (OR=1.50; 95% CI, 1.08-2.08), supported by a linear relationship (P for non-linearity=0.298). No equivalent significant association was found in non-diabetic men (OR=1.00; 95% CI, 0.67-1.48). Within the diabetic group, the TyG index did not show a significant association with COPD prevalence, regardless of gender. Our study reveals a significant positive correlation between the TyG index and COPD prevalence in the non-diabetic population, marked by notable gender differences.

A randomized controlled study of neoadjuvant metformin with chemotherapy in nondiabetic breast cancer women: The METNEO study.

Clinical data demonstrate that metformin exhibits antiproliferative, proapoptotic and antimetastatic actions. Here, correlative molecular studies were undertaken to determine the roles of transmembrane tumour necrosis factor-related apoptosis-inducing ligand death receptors (DRs) and CD133, a glycoprotein biomarker of breast cancer (BC) stem cells, in the advantageous action of metformin on pathological and clinical outcomes in BC patients on neoadjuvant chemotherapy. We randomly assigned 70 nondiabetic BC patients in a 1:1 ratio to either neoadjuvant AC-T chemotherapy (4cycles of adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2, followed by 12 cycles of weekly paclitaxel 80 mg/m2) or AC-T with adjunct metformin (850 mg twice/day). The expressions of DR4, DR5 and CD133 were quantified in excised tissue samples with residual tumour cells. The overall clinical response (odds ratio: 22.67 [2.77-185.18], P= .004), breast-conserving surgery (odds ratio: 3.67 [1.303-10.321], P= .014) and pathological complete response (β =2.49 ±1.13 [0.274-4.712], P= .028) rates were significantly improved in the metformin arm. Tissues obtained from the metformin arm had upregulated mRNA expression of DR4 (Mean delta cycle thresholds ± standard error of the mean: 2.68 ±0.25 vs. 4.87 ±0.53, P= .0003) and DR5 (0.21 ±0.25 vs. 4.29 ±0.95, P= .0004) compared to control arm. The enhanced DR expression negatively correlated with that of CD133 + BC stem cells, which was significantly reduced by metformin at both cytoplasmic/membranous (43.48 vs. 100.00%, P< .0001) and nuclear sites (4.35 vs. 95.00%, P< .0001). Metformin improves clinical and pathological responses to neoadjuvant AC-T chemotherapy in BC via prompting directionally opposite changes in DRs (increments) and CD133 + (decrements) expressions. This study was registered in ClinicalTrials.gov (registration number: NCT04170465, https://clinicaltrials.gov/ct2/show/NCT04170465).

Predictors of subclinical atherosclerosis in asymptomatic healthy non-diabetic postmenopausal women

Predictors of subclinical atherosclerosis in asymptomatic healthy non-diabetic postmenopausal women

Low muscle mass is associated with low insulin sensitivity, impaired pancreatic β cell function, and high glucose excursion in nondiabetic nonobese Japanese women

AimWe tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic β-cell function, and postglucose glycemia. MethodsAppendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c ≦ 5.5 %. ResultsIn two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized β: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized β: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM. ConclusionLow skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic β-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.

Sustained metabolic dysregulation and the emergence of diabetes: associations between HbA1c and metabolic syndrome components in Tunisian diabetic and nondiabetic groups

IntroductionMetabolic Syndrome (MetS), diabetes, and other noncommunicable diseases (NCDs) have been a major focus of research in recent decades as the prevalence of these conditions continues to rapidly increase globally. However, the timing and patterns of development from metabolic risk factors to disease states are less well understood and are especially critical to understand in low- and middle-income countries (LMICs) and populations undergoing epidemiological transitions.MethodsNationally representative sociodemographic, anthropometric, and point-of-care biomarker data from the 2016 Tunisian Health Examination Survey (n = 8170) were used to determine the prevalence of diabetes and MetS components in Tunisia and to investigate associations between glycated hemoglobin (HbA1c) and MetS components (blood pressure [BP], HDL cholesterol [HDL], triglycerides [TG], and waist circumference [WC]) in participants aged 15-97 years old. To better understand how sustained metabolic dysregulation and disease states impact these associations, diabetic and nondiabetic groups were analyzed separately.ResultsThe overall prevalence of diabetes based on measured HbA1c was 18.2%. The diabetic groups had a higher prevalence of each individual MetS component, and significantly higher (BP, TG, WC, and HbA1c) and lower (HDL) values than the nondiabetic groups. Yet, there were a higher number of significant associations between HbA1c and MetS components found in nondiabetic women and men when compared to diabetic women and men. HbA1c was positively associated with the cumulative number of MetS components, irrespective of diabetes status in men and women.ConclusionsThe prevalence of both diabetes and MetS components (particularly low HDL cholesterol and elevated TG) is high among the Tunisian population. More MetS components were associated with HbA1c in nondiabetic individuals, showing a strong connection between the development of MetS components and diabetes. However, once the diabetes disease state manifests, there is more variability in the relationships. These results show the potential for HbA1c to be an indicator of metabolic health below clinical disease cutoffs, which may allow insights into the physiological changes that precipitate the emergence of diabetes.

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Impact of Diabetes in Pregnancy on Stage II Lactogenesis among Postpartum Diabetic Women Compared to Non-Diabetics

Abstract Background Diabetes in pregnancy -whether preexisting or gestational can have negative impact on pregnancy, labor and lactation. Infants of diabetic mothers benefit most from early establishment of breastfeeding as it helps them regulate their blood glucose levels on the short term and decrease their risk of developing diabetes later on life. Aim of the Work This study aims to compare diabetic and non-diabetic pregnant women regarding the onset of stage II lactogenesis at 72 hours postpartum and to associate the degree of diabetes control in antepartum period with the delay in stage II of lactogenesis. Subjects and Methods This study is an observational prospective cohort study, carried out on 203 pregnant women aged from 18 to 40 years old during their routine antenatal care visits in the third trimester of pregnancy at Ain-Shams University Maternity hospital outpatient clinic from December 2020 to August 2021, Cairo, Egypt. Results We found that Diabetes in pregnancy can cause a delay in the onset of Lactogenesis stage II regardless of the degree of control. We can also say that diabetes can affect lactation directly and indirectly. For example, Diabetes can cause higher rates of cesarean section, infant separation from mother and delayed initiation of first breastfeed which was found to cause DOLII. And early initiation of lactation can be a modifiable risk factor to protect from DOLII especially in Diabetic mothers. Conclusion Diabetes can cause series of unfortunate events in pregnancy, labor, and lactation. Many of diabetes implications on peripartum health can affect lactation directly and indirectly. For example, Diabetes can cause higher rates of cesarean section, infant separation from mother, delayed initiation of first breastfeed and other birth complications. All these can cause DOL II. Diabetes itself is a risk factor for delayed onset of lactogenesis II which can cause further neonatal hypoglycemia and/or early introduction of infant formula. The cascade of these events can hinder the breastfeeding establishment when it is most needed. The control of diabetes was not found to have impact on DOL II. Further research needs to be done in this regard. Early initiation of lactation can be a modifiable risk factor to protect from DOLII especially in Diabetic mothers.

Insulin Blood Levels in Gestational Diabetes Mellitus in Relation to Ethnicity and Age in the Kingdom of Bahrain: A Cross-Sectional Study.

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy. It may be attributed to certain placental hormones during pregnancy which render insulin less effective. Our study aimed to focus on the levels of insulin in gestational diabetic women in the Kingdom of Bahrain as compared with non-diabetic pregnant women. Furthermore, we studied the correlation between insulin levels by ethnicity and age of the pregnant women. Methods: A cross-sectional study was conducted on 75 pregnant participants: 41 with GDM (test group) and 34 without GDM (control group). Insulin levels were determined in patients with GDM and compared to non-diabetic pregnant women. A comparison between Bahraini and non-Bahraini women was carried out in two different age groups: below and above 30 years of age. P values < 0.05 were considered significant. The results showed higher mean values of fasting blood glucose (FBG), random blood glucose (RBG), and insulin levels in the test group when compared to the control group. There was no significant difference in FBG, RBG, and insulin levels among Bahraini women with GDM and non-Bahraini women (Indian, Pakistani. Bengali, and Filipino) with GDM. Age, less than 30 vs more than 30 years, had no significant effect on women with GDM. Insulin levels were higher in pregnant women with GDM irrespective of their ethnicity or age. The lack of blood glucose control in GDM even in the presence of high insulin secretion may suggest loss of insulin effectiveness due to other factors such as stress and lactogenic placental hormones.

Sex-dependent intra-islet structural rearrangements affecting alpha-to-beta cell interactions lead to adaptive enhancements of Ca2+ dynamics in prediabetic beta cells

Aims/hypothesisPrediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells’ functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes.MethodsIslets from male and female transgenic Ins1CreERT2-GCaMP3 mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca2+]i) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca2+]i dynamics in line with single beta cell [Ca2+]i analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca2+]idynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca2+]i dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10.ResultsMice fed a WD for 1 month displayed increased beta cell [Ca2+]i dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca2+]i dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes.Conclusions/interpretationWe identified increased coordination of [Ca2+]i dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca2+]i dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca2+]i dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca2+]i dynamics may thus serve as an early marker for beta cell failure in prediabetes.Graphical

An analysis of urodynamic parameters in diabetic and nondiabetic women.

Diabetes is highly prevalent worldwide, with an estimated 536 million living with diabetes in 2021, and that number projected to increase to 783 million by 2045. Diabetic bladder dysfunction is thought to affect up to 60%-90% of individuals with diabetes and can significantly impact quality of life. Despite the prevalence of diabetic bladder dysfunction, the exact pathophysiological mechanism, and resulting clinical presentation, remains debated. Our objective was to compare urodynamic parameters between diabetic and nondiabetic women, assessing the impact of various markers of diabetes severity on bladder function. A retrospective chart review was conducted on female patients aged 18 and above who underwent urodynamic studies at a single tertiary care university hospital system from 2014 to 2020. Patients were categorized based on diabetes status, and diabetes severity including duration of disease, hemoglobin A1c levels, insulin dependence, and markers of end-organ dysfunction. Urodynamic variables, including compliance, bladder voided efficiency, bladder contractility index, postvoid residual, maximum flow rate, capacity, voided volume, and detrusor overactivity, were assessed by two independent reviewers. Statistical analyses were performed to assess the impact of diabetes and diabetic severity on urodynamic parameters. A total of 652 female patients were included in the study, of which, 152 (23.3%) had diabetes, with an average duration of diagnosis of 82.3 months. Diabetic women were older and had higher body mass index compared to nondiabetic women. Diabetic retinopathy and neuropathy were present in 18% and 54.6% of diabetic patients, respectively. Significant differences in urodynamic parameters were observed between diabetic and nondiabetic women, with diabetic women showing higher rates of detrusor overactivity (p = 0.01), particularly associated with increasing BMI (p = 0.03). However, classic markers of diabetes severity including duration, as well as markers of end-organ damage, showed mixed associations with urodynamic changes. Despite the prevalence of diabetic bladder dysfunction and its impact on patient quality of life, the exact mechanisms and clinical presentation remain elusive. Our study highlights the significant differences in urodynamic parameters between diabetic and nondiabetic women, emphasizing the need for further research into the relationship between diabetes and diabetic bladder dysfunction.

Charcot Neuro-Osteoarthropathy With Superimposed Osteomyelitis in a Nondiabetic Patient, as a Consequence of Cancer Chemotherapy: A MR-Monitored Case Report.

Charcot neuro-osteoarthropathy (CNO) is a manifestation of peripheral neuropathy as a chronic complication of diabetes mellitus but, less frequently, can be associated to other conditions such as alcoholism or neurotoxic therapies. An increasingly emerging cause of CNO is the use of oncological drugs which can cause neuropathic damage. The use of these therapies dramatically increased in recent years. CNO leads to a progressive degeneration of the foot's joints and to bone destruction and resorption which ends in deformities. These alterations in the foot's anatomy determine a high risk of ulceration, infection, and osteomyelitis. The superimposition of osteomyelitis on CNO increases the risk of major amputation, already high in patients suffering either from only CNO or osteomyelitis alone. We report the case of a 61-year old nondiabetic woman affected by CNO as a consequence of antiblastic therapy for breast cancer and the subsequent overlap of osteomyelitis, confirmed by magnetic resonance imaging. This case underlines how it is necessary to consider CNO as a possible complication of antiblastic therapy in the view of the severe consequences of missing its diagnosis.

Neglected cardiometabolic risk factors and subclinical target organ damage in post-menopausal women with normal glucose tolerance.

Menopausal transition is a crucial step in the women's cardiovascular health, and the risk stratification in apparently health post-menopausal females has been rarely assessed. Heart ultrasonography, unusually performed in such subjects, would be able to detect initial signs of organ damage. We described the cardiovascular risk profile of non-diabetic post-menopausal women, evaluating how easily computed, biochemistry-derived scores were related to ultrasonographic measures of target organ damage. We analyzed the characteristics of a cohort of two-hundred and seventy-three women consecutively referring to a prevention program of Azienda Ospedaliero-Universitaria Pisana (years 2017-2022) who underwent clinical evaluation, complete routine biochemical analyses with proxies of insulin resistance, heart and carotid ultrasonography. The cohort was further divided into four groups according to presence of isolated hypercholesterolemia (HC, 37%), isolated hypertension (HT, 5%), both HC/HT (38%), or none of them. In HC and HC/HT, LDL cholesterol was sharply above the recommended values (149 [134-171] mg/dL and 141 [123-159] mg/dL, respectively). E/e' ratio and left atrium size were augmented in HT women and further worsened in HT/HC, with an independent effect of hypertension (E/e' ß=0.055, P=0.013, left atrium volume ß=0.059, P=0.003). Presence of carotid plaques was independently linked to hypertension (ß=0.474, P=0.003). In HC and HC/HT, the Triglycerides-Glucose Index, a surrogate of insulin resistance, was higher than in the other classes (P=0.0013), and it was associated with E/A in HC and HT/HC, with a significative interaction (P=0.0004) with hypertension. Past hormone replacement therapy did not influence clinical, biochemical or echocardiographic parameters. Postmenopausal women display a high cardiovascular risk burden; a simple clinical and biochemistry screening would be advisable to identify and treat those more at risk. Cardiac ultrasonographic parameters were worse in hypertensive, hypercholesterolemic and insulin-resistant subjects, who may also deserve a deep and early instrumental characterization, especially when these conditions are associated.