Currently, obesity has become a global health issue and is referred to as an epidemic. Dysfunctional obese adipose tissue plays a pivotal role in the development of insulin resistance. However, the mechanism of how dysfunctional obese-adipose tissue develops insulin-resistant circumstances remains poorly understood. Therefore, this review attempts to highlight the potential mechanisms behind obesity-associated insulin resistance. Multiple risk factors are directly or indirectly associated with the increased risk of obesity; among them, environmental factors, genetics, aging, gut microbiota, and diets are prominent. Once an individual becomes obese, adipocytes increase in their size; therefore, adipose tissues become larger and dysfunctional, recruit macrophages, and then these polarize to pro-inflammatory states. Enlarged adipose tissues release excess free fatty acids (FFAs), reactive oxygen species (ROS), and pro-inflammatory cytokines. Excess systemic FFAs and dietary lipids enter inside the cells of non-adipose organs such as the liver, muscle, and pancreas, and are deposited as ectopic fat, generating lipotoxicity. Toxic lipids dysregulate cellular organelles, e.g., mitochondria, endoplasmic reticulum, and lysosomes. Dysregulated organelles release excess ROS and pro-inflammation, resulting in systemic inflammation. Long term low-grade systemic inflammation prevents insulin from its action in the insulin signaling pathway, disrupts glucose homeostasis, and results in systemic dysregulation. Overall, long-term obesity and overnutrition develop into insulin resistance and chronic low-grade systemic inflammation through lipotoxicity, creating the circumstances to develop clinical conditions. This review also shows that the liver is the most sensitive organ undergoing insulin impairment faster than other organs, and thus, hepatic insulin resistance is the primary event that leads to the subsequent development of peripheral tissue insulin resistance.

Vascular aging encompasses structural and functional changes in the vasculature, significantly contributing to cardiovascular diseases, which are the leading cause of death globally. The incidence and prevalence of these diseases increase with age, with most morbidity and mortality attributed to myocardial infarction and stroke. Diagnosing and intervening in vascular aging while understanding the mechanisms behind age-induced vascular phenotypic and pathophysiological alterations offers the potential for delaying and preventing cardiovascular mortality in an aging population. This review delves into various aspects of vascular aging by examining age-related changes in arterial health at the cellular level, including endothelial dysfunction, cellular senescence, and vascular smooth muscle cell transdifferentiation, as well as at the structural level, including arterial stiffness and changes in wall thickness and diameter. We also explore aging-related changes in perivascular adipose tissue deposition, arterial collateralization, and calcification, providing insights into the physiological and pathological implications. Overall, aging induces phenotypic changes that augment the vascular system’s susceptibility to disease, even in the absence of traditional risk factors, such as hypertension, diabetes, obesity, and smoking. Overall, age-related modifications in cellular phenotype and molecular homeostasis increase the vulnerability of the arterial vasculature to structural and functional alterations, thereby accelerating cardiovascular risk. Increasing our understanding of these modifications is crucial for success in delaying or preventing cardiovascular diseases. Non-invasive techniques, such as measuring carotid intima-media thickness, pulse wave velocity, and flow-mediated dilation, as well as detecting vascular calcifications, can be used for the early detection of vascular aging. Targeting specific pathological mechanisms, such as cellular senescence and enhancing angiogenesis, holds promise for innovative therapeutic approaches.

Adipose tissue is a significant producer of pro-inflammatory cytokines in obese and old individuals. However, there is no direct evidence of whether and how aged adipocytes enhance the production of pro-inflammatory markers. We aimed to investigate whether the aging adipocytes increase pro-inflammatory markers. Swiss mouse embryonic-tissue-derived 3T3-L1 cells were differentiated into adipocytes and maintained for 60 days in the conditioned medium or 35 days in the unconditioned medium. Additionally, 20-month-old male C57BL/6 mice were fed a standard chow diet for 37 weeks until they were extremely aged, when ~75% of mice died because of aging. Accumulated lipids, pro-inflammatory markers, and nuclear factor kappa B (NF-κB) pathway markers from differentiated adipocytes were analyzed. Pro-inflammatory markers and NF-κB pathway markers of epididymal white adipose tissues (EWATs) and adipocytes from EWATs were also analyzed. We found that the aging adipocytes chronologically accumulated lipids and increased pro-inflammatory markers interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α); at the same time, NF-κB p50 markers were also increased while IκBα protein was decreased significantly in conditioned medium. Similar results were observed when differentiated adipocytes were maintained in the unconditioned medium and the adipocytes from EWATs of aged mice. We demonstrated that aging augmented chronic inflammation through the NF-κB signaling pathway in adipocytes and adipose tissue.

Objectives: High prevalence of vitamin D deficiency (VDD) in children and adolescents with type 1 diabetes (T1D) was found in several epidemiological studies. The current study aimed to assess the Vitamin D status in children and adolescents with T1D and to examine the influence of the disease characteristics on vitamin D status in a specialized care centre in a tertiary hospital in Bangladesh.Methods: Participants were enrolled in the cross‐sectional study at the time of a regularly scheduled visit to the CDiC Paediatric Diabetes Center in BIRDEM 2(Bangladesh Institute of Research and Rehabilitation of Diabetes Endocrine and Metabolic Disorders), a tertiary care hospital in Bangladesh. The demographic and clinical data were collected through medical records with a structured questionnaire.Results: Among sixty study participants, most had inadequate levels of vitamin D: deficiency 31 (51.7%), insufficiency 14 (23.3%) and sufficiency 15 (25.0%). Participants with vitamin D deficiency (VDD) were significantly older compared to the sufficient and insufficient group (p = .029), and were residing in urban areas (p = .036) and from higher socioeconomic status (p = .014). BMI was significantly higher in VDD compared to the sufficient group (p = .040). Although we observed higher median values of daily insulin requirements and HbA1c values in patients with VDD compared to patients with vitamin D insufficiency or vitamin D sufficiency, these differences did not reach statistical significance.Conclusions: The present study revealed that the prevalence of vitamin D deficiency and insufficiency among T1 diabetes children was very high. Future studies in large sample are required to assess hypovitaminosis D in youth with T1D and also the possible relating factors of vitamin D deficiency.

The development of physiologically relevant in vitro colorectal cancer (CRC) models is vital for advancing understanding of tumor biology. Although CRC patient-derived xenografts (PDXs) recapitulate key patient tumor characteristics and demonstrate high concordance with clinical outcomes, the use of this in vivo model is costly and low-throughput. Here we report the establishment and in-depth characterization of an in vitro tissue-engineered CRC model using PDX cells. To form the 3D engineered CRC-PDX (3D-eCRC-PDX) tissues, CRC PDX tumors were expanded in vivo, dissociated, and the isolated cells encapsulated within PEG-fibrinogen hydrogels. Following PEG-fibrinogen encapsulation, cells remain viable and proliferate within 3D-eCRC-PDX tissues. Tumor cell subpopulations, including human cancer and mouse stromal cells, are maintained in long-term culture (29 days); cellular subpopulations increase ratiometrically over time. The 3D-eCRC-PDX tissues mimic the mechanical stiffness of originating tumors. Extracellular matrix protein production by cells in the 3D-eCRC-PDX tissues resulted in approximately 57% of proteins observed in the CRC-PDX tumors also being present in the 3D-eCRC-PDX tissues on day 22. Furthermore, we show congruence in enriched gene ontology molecular functions and Hallmark gene sets in 3D-eCRC-PDX tissues and CRC-PDX tumors compared to normal colon tissue, while prognostic Kaplan–Meier plots for overall and relapse free survival did not reveal significant differences between CRC-PDX tumors and 3D-eCRC-PDX tissues. Our results demonstrate high batch-to-batch consistency and strong correlation between our in vitro tissue-engineered PDX-CRC model and the originating in vivo PDX tumors, providing a foundation for future studies of disease progression and tumorigenic mechanisms.