Microvascular Homeostasis Is Compromised in Pancreatic Islets in a Mouse Model of β-Cell Loss and Low-Grade Inflammation

Vascular dysfunction is considered a consequence of diabetes. However, in pancreatic islets, some hemodynamic changes occur before the onset of symptoms. The underlying mechanisms driving islet vascular abnormalities have not been fully characterized, but islet pericyte dysfunction seems to be an early event in the pathogenesis of type 1 diabetes 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 β-cell toxin streptozotocin (STZ; 50 mg/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 blood flow and compromised islet vascular integrity, because large fluorescent dextrans (500 kDa) could leak from peripheral islet vessels in the exteriorized pancreas of STZ-treated mice. Our study supports that the 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 β-cell mass and inflammation. ARTICLE HIGHLIGHTS: Pericyte dysfunction is an early event in type 1 diabetes in humans, but how it affects islet microvascular homeostasis in vivo is unknown. We sought to determine whether vascular integrity and blood flow regulation in islets were impaired in a model of partial β-cell loss and inflammation. Islet capillaries lost functional pericyte coverage shortly after low-dose streptozotocin, compromising vascular stability and local control of blood flow. Strategies that preserve vascular niches in islets could be of important therapeutic potential.