<b>Microvascular homeostasis is compromised in pancreatic islets in a mouse model of beta cell loss and low-grade inflammation</b>

<p dir="ltr">Vascular dysfunction is considered a consequence of diabetes. However, in pancreatic islets, some haemodynamic changes occur before the onset of symptoms. The underlying mechanisms driving islet vascular abnormalities have not been fully characterized, but islet pericyte dysfunction appears to be an early event in the pathogenesis of type 1 diabetes (T1D) in humans. It remains to be investigated, however, how abnormal pericyte physiology affects their ability to regulate islet blood flow and vascular permeability. To address this issue, we treated mice with multiple subdiabetogenic doses of the beta cell toxin streptozotocin (STZ; 50mg/kg) and recorded islet vascular responses when animals developed glucose intolerance but were still not diabetic (average fed glycemia <200 mg/dL). At this stage, pericyte coverage of islet capillaries was abnormal, with capillaries either lacking pericytes or being covered by dysfunctional mural cells, which compromised islet vasomotor responses recorded ex vivo in living pancreas slices. These functional defects interfered with proper regulation of islet blood flow and compromised islet vascular integrity, as large fluorescent dextrans (500 kDa) could leak from vessels at the periphery of islets in the exteriorized pancreas of STZ-treated mice. Our study supports that loss of functional pericyte coverage of islet capillaries is part of a pathogenic process occurring in islets before diabetes onset, associated with a loss of functional beta cell mass and inflammation.</p>