Vascular alterations are the most common causes of morbidity and mortality in diabetic patients. Despite the impact of endothelial dysfunction on microcirculatory properties, little is known about the endothelial cell alteration during the development of diabetes and its correlation to the metabolic situation. For that reason we continuously monitored in vivo functional and morphological alterations of the microvasculature in hyperglycemic and hyperinsulinemic transgenic UCP1/DTA mice with brown fat deficiency, using a dorsal skin-fold chamber preparation and fluorescence microscopy. UCP1/DTA mice showed a dramatic decrease in vascular density due to a remarkable reduction of small vessels. Vascular permeability and leukocyte endothelial interactions (LEIs) significantly increased. The extent of vascular alteration correlated with the extent of metabolic dysfunction. Decreased tissue perfusion observed in UCP1/DTA mice might play a role in impaired wound healing observed in diabetes. The increased permeability in subcutaneous tissue may serve as predictor of vascular changes in early stages of diabetes. The increased LEI and serum tumor necrosis factor-␣ levels, which mirror the inflammatory process, support the growing evidence of the inflammatory component of diabetic disease. The results suggest that anti-inflammatory strategies might be able to prevent vascular deterioration in early stages of diabetes. Further investigations are required to evaluate the benefit of such therapeutic strategies. Diabetes 52:542-549, 2003 V ascular alterations are the most common causes of morbidity and mortality in diabetic patients. The microcirculation not only governs the efficacy of substrate delivery but also mediates adaptations to changing local requirements and metabolic conditions. Functional alterations of the microcirculation precede morphological changes and determine the resultant vascular morphology (1). Microvascular disease has been shown to have a high prevalence in diabetes (2,3). Several studies described endothelial dysfunction and functional alterations in the microcirculation of diabetic patients. Animal models of diabetes show increased vascular permeability (4), alterations in erythrocyte velocity (5), sequestration of leukocytes in the microcirculation (5-7), and morphological alterations such as altered vascular density (5). These alterations are mainly described as the result of hyperglycemia and advanced glycation end products (8,9) and develop sequentially. Functional alterations, such as increased microvascular permeability and increased entrapment of leukocytes, have been described as an early event in diabetes and in animal models and could be partially observed after only a few hours of hyperglycemia (4,7). Morphological alterations, such as altered microvascular density and diameter, appear later (5,10). However, mechanisms that lead to microangiopathies in diabetic patients remain only partially understood.Monitoring of microcirculatory alterations in patients is limited by the invasive chara...

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Microvascular complications are an important cause of morbidity in diabetic patients and can be detected in a significant number of patients at the time of diabetes diagnosis. However, little is known about the alterations in the microvasculature previous to the clinical manifestation of diabetes mellitus type 2. To obtain more insights into the early microvascular deterioration resulting from prediabetes, morphological and functional microvascular parameters were monitored using intravital fluorescence microscopy through a dorsal skin-fold chamber preparation in the uncoupling promotor-driven diphtheria toxin A chain (UCP1/DTA) mice. At the age of 12 weeks, the UCP1/DTA-mice were characterized by impaired glucose tolerance with concurrent unchanged fasting glucose, as well as dyslipidemia, hyperinsulinemia, hypertension and obesity. Prediabetic mice displayed combined hypertriglyceridemia and hypercholesterinemia. Associated with these prediabetic metabolic alterations, we demonstrate that microvascular density showed a dramatic decrease due to a reduction in perfused small vessels. A reduction in vascular density combined with unaltered blood flow in single vessels resulted in impaired tissue perfusion. Endothelial dysfunction with subsequently increased microvascular permeability and leukocyte-endothelium interactions were found. Our results of profound microvascular alterations at stages of normal fasting glucose underline the importance of early screening for prediabetes and associated microvascular complications.

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