Young capillary vessels rejuvenate aged pancreatic islets

Abstract

Pancreatic islets secrete hormones that play a key role in regulating blood glucose levels (glycemia). Age-dependent impairment of islet function and concomitant dysregulation of glycemia are major health threats in aged populations. However, the major causes of the age-dependent decline of islet function are still disputed. Here we demonstrate that aging of pancreatic islets in mice and humans is notably associated with inflammation and fibrosis of islet blood vessels but does not affect glucose sensing and the insulin secretory capacity of islet beta cells. Accordingly, when transplanted into the anterior chamber of the eye of young mice with diabetes, islets from old mice are revascularized with healthy blood vessels, show strong islet cell proliferation, and fully restore control of glycemia. Our results indicate that beta cell function does not decline with age and suggest that islet function is threatened by an age-dependent impairment of islet vascular function. Strategies to mitigate age-dependent dysregulation in glycemia should therefore target systemic and/or local inflammation and fibrosis of the aged islet vasculature.A ging leads to progressive decline of various homeostatic processes in mammals, including a deteriorating regulation of blood glucose levels. Pancreatic islets are small organs composed of endocrine cells that secrete the major hormones insulin, glucagon, and somatostatin, which play a key role in regulating blood glucose levels. Age-dependent dysfunction of islets and the concomitant dysregulation of blood glucose levels increase the risk for type 2 diabetes (1), which in turn contributes to other age-related chronic diseases. In general, it has been assumed that aging causes an intrinsic dysfunction of the insulin-secreting beta cells through reduced proliferative capacity and/or defective insulin secretion (1-9). However, there have been numerous reports that age-dependent impairment of glucose homeostasis is not just a result of intrinsic, age-dependent dysfunction of islets but is also caused by systemic factors. For example, islet function may be compromised by age-related increases in adiposity (10, 11) and by bloodborne factors (12), or it could be affected indirectly by agerelated deficiencies in vascular remodeling (13). Thus, the replicative decline of old pancreatic beta cells can be attributed to systemic factors (12). Recent studies identified factors present in young blood that reverse age-related cognitive impairments and induce vascular remodeling and regeneration in the brain and skeletal muscle (14-16), but so far it has not been feasible to discriminate systemic influences from aging factors intrinsic to islet endocrine cells. Here we address the long-standing question of whether the age-dependent impairment of glucose homeostasis is caused by intrinsic, age-dependent dysfunction of islets or by systemic aging factors.Our strategy to discern age-related intrinsic changes in islet function was to study islets from young mature (2 mo) and aged (18 mo) mice and to fol...

Label-free fast 3D coherent imaging reveals pancreatic islet micro-vascularization and dynamic blood flow

“…7(c)). This percentage of vascularization is in the range of what was observed in islets in situ and is comparable to the vessel density measured by Almaça et al [7] in ACE islets after an intravenous injection of fluorescent labeled dextran.…”

“…Using functional optical coherence imaging (FOCI), we found that there is a strong correlation between the increasing inflammation of the islets and the density of their vascular network [6]. In addition, there are indications that the glucose intolerance observed in aged mice is due to a vascular impairment rather than β-cell defect [7]. The deep localization of these islets inside the pancreas in the abdominal cavity and their heterogeneous distribution throughout this organ renders imaging their vascularization challenging.…”

Liraglutide Compromises Pancreatic β Cell Function in a Humanized Mouse Model

“…Mice have also been used to study natural processes such as aging (Demetrius, 2006; Vanhooren and Libert, 2013). Our recent findings have shown that aged mice have pancreatic islets with hallmarks consistent with human islets from aged individuals (Almaca et al, 2014). This further supported the notion that the human islets in our mouse model are likely to be exposed to a systemic aging process during a prolonged liraglutide treatment of ≥250 days as in situ islets in the human pancreas during long-term multi-year use of incretin mimetic therapy (Flurkey et al, 2007; Jucker et al, 1994).…”

Endothelium-derived essential signals involved in pancreas organogenesis

“…The key to prevention or reversal of diabetes may rest in the recently emphasized role of endothelium in beta-cell differentiation and maturation in vitro [52,53] . In addition, it has been suggested that EC pathology can lead to islet dysfunction suggesting that ECs are essential to maintain islet function in adults [97] .…”