Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1␣ (HIF1␣) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1␣, we determined that HIF1␣ fails to induce the expected proangiogenic response. In contrast, we observed that HIF1␣ initiates adipose tissue fibrosis, with an associated increase in local inflammation. The dramatic rise in the prevalence of obesity has lead to increased efforts aimed at gaining a better understanding of the physiology and pathophysiology of adipose tissue and adipocytes. One of the more-surprising features of adipose tissue described over the past 10 years is the realization that adipose tissue in general and adipocytes in particular have the potential to be a rich source of a vast array of secretory proteins. Since infiltrating immune cells, most notably monocytes, are known to have a profound effect on adipocytes, interest in the stromal fraction of adipose tissue has increased considerably. These stromal components consist of fibroblastlike preadipocytes, endothelial cells, vascular smooth muscle cells, neurons, and immune cells. It is currently not established how these stromal components interact with adipocytes during adipose tissue expansion. The nature of the local endothelium, a key constituent of the vasculature, has received limited attention to date.Destruction of local endothelial cells results in a reduction in fat mass during times of excess caloric intake independent of food intake (2,30,38). Functioning through an as yet unidentified mechanism, such a reduction in fat mass results in decreased levels of steatosis in the liver and enhanced glucose tolerance. These metabolic improvements are somewhat surprising, considering that the forced reduction of fat mass in the context of lipodystrophies leads to a decrease rather than an increase in systemic insulin sensitivity (30,36). These observations highlight the need for a better understanding of the adipose tissue vasculature.During times of positive energy balance, adipose tissue absorbs the energy surplus by increasing both cell size and number. The ability of adipose tissue to expand critically depends on vascular outgrowth (4). At the same time, the increased adipocyte size requires oxygen to diffuse over longer distances prior to reaching adipocyte mitochondria; this is evident by a decreased partial oxygen pressure (20 mmHg versus 40 mmHg) in obese versus lean mice, respectively (20,37,53). Hypoxia in obese adipose tissue has been observed by several groups and results in the induction of the key hypoxia regulator, hypoxia-inducible factor 1 (HIF1) (20,37,49,53). HIF1 is a heterodimer consisting of the oxygen-regulated HIF1␣ subunit and the constitutively expressed HIF1␤ ...

Diabetes is a global endemic with rapidly increasing prevalence in both developing and developed countries. The American Diabetes Association has recommended glycated hemoglobin (HbA1c) as a possible substitute to fasting blood glucose for diagnosis of diabetes. HbA1c is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding two to three months. HbA1c not only provides a reliable measure of chronic hyperglycemia but also correlates well with the risk of long-term diabetes complications. Elevated HbA1c has also been regarded as an independent risk factor for coronary heart disease and stroke in subjects with or without diabetes. The valuable information provided by a single HbA1c test has rendered it as a reliable biomarker for the diagnosis and prognosis of diabetes. This review highlights the role of HbA1c in diagnosis and prognosis of diabetes patients.

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The mechanisms of lung microvascular complications and pulmonary hypertension known to be associated with idiopathic pulmonary fibrosis (IPF), a debilitating lung disease, are not known. Therefore, we investigated whether bleomycin, the widely used experimental IPF inducer, would be capable of activating phospholipase D (PLD) and generating the bioactive lipid signal-mediator phosphatidic acid (PA) in our established bovine lung microvascular endothelial cell (BLMVEC) model. Our results revealed that bleomycin induced the activation of PLD and generation of PA in a dose-dependent (5, 10, and 100 μg) and time-dependent (2-12 hours) fashion that were significantly attenuated by the PLD-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI). PLD activation and PA generation induced by bleomycin (5 μg) were significantly attenuated by the thiol protectant (N-acetyl-L-cysteine), antioxidants, and iron chelators suggesting the role of reactive oxygen species (ROS), lipid peroxidation, and iron therein. Furthermore, our study demonstrated the formation of ROS and loss of glutathione (GSH) in cells following bleomycin treatment, confirming oxidative stress as a key player in the bleomycin-induced PLD activation and PA generation in ECs. More noticeably, PLD activation and PA generation were observed to happen upstream of bleomycin-induced cytotoxicity in BLMVECs, which was protected by FIPI. This was also supported by our current findings that exposure of cells to exogenous PA led to internalization of PA and cytotoxicity in BLMVECs. For the first time, this study revealed novel mechanism of the bleomycin-induced redox-sensitive activation of PLD that led to the generation of PA, which was capable of inducing lung EC cytotoxicity, thus suggesting possible bioactive lipid-signaling mechanism/mechanisms of microvascular disorders encountered in IPF.