Understanding how insulin secretion is regulated and how the β-cells and islets become dysfunctional is critical to understanding and treating diabetes. The islets of Langerhans are highly vascularized, receiving ∼10–20% of the pancreas blood flow (as measured by microbead accumulation) despite representing ∼1% of its volume (1). Proper vascularization of the islets is critical. For example, transplanted islets need to revascularize to receive the appropriate oxygenation and nutrient delivery required for survival and insulin production. Blood flow to the islets is extensively regulated by glucose, insulin, and other signaling molecules (2,3) and is altered in models of type 1 and type 2 diabetes (4–6). However, it is unknown whether this altered blood flow could contribute to pathogenesis.
The activity of contractile pericytes is tightly coupled to endothelial cells of the microvasculature, where pericytes alter blood flow via capillary constriction and dilation. Pericytes make up ∼3% of the islet cells and cover ∼40% of their capillaries (7). During metabolic stress, such as insulin resistance and obesity, islet pericytes and vascular density increase and capillaries dilate (8). Pericytes can directly influence the islet response to elevated glucose by influencing β-cell function or indirectly by modulating islet blood flow.
Islet pericytes directly support β-cells by secreting factors that bind their respective receptors on β-cells to regulate cell maturation and activity (9–12). Pericytic BMP4 regulates β-cell maturation and is required for glucose-stimulated insulin secretion (9). Additionally, pericytes secrete nerve growth factor (NGF) upon elevated glucose, which can stimulate insulin secretion (11). Genetic predisposition to type 2 diabetes, such as polymorphism in TCF7L2, influences the pericytic support of β-cell gene expression and function (10). Further, pericytes contribute to the islet basement membrane, which is essential for insulin secretion (12). Thus, pericytes directly modulate β-cell glucose-stimulated insulin secretion.
In parallel, pericytes have previously been suggested to contribute to glucose homeostasis by regulating islet blood flow. In 2018, Almaça et al. (7) proposed that pericytes directly regulate capillary diameter to alter islet blood flow. Thus, a short-term increase in glucose leads to pericyte relaxation and capillary dilation. Further, islet pericytes contract in response to the sympathetic neurotransmitter norepinephrine, suggesting neuronal regulation of islet pericyte-mediated capillary constriction (7).
These observations suggest that pericyte-mediated capillary dilation is a dynamic and highly regulated process that could allow fine-tuning of islet blood flow in response to increased demand.
However, how changes in pericyte-regulated islet blood flow influence insulin secretion and glucose homeostasis remained an open question. Specifically, it was unclear whether pericyte activation is sufficient to induce capillary constriction and whether this constriction affects glucose accessibility to the islets. Further, whether neuronally mediated pericyte activity influences glucose regulation remained to be determined. In this issue of Diabetes, Tamayo et al. (13) approach these questions to define the sympathetic regulation of pericyte activity and the potential role of pericyte-mediated capillary contractility on islet glucose responsiveness.
Tamayo et al. (13) used a deluge of novel techniques to analyze the effects and mechanisms involved in pericyte regulation of islet blood flow. Through confocal imaging, they built on previous studies presenting evidence that both isolated mouse islets and human islet slices are densely covered by pericytes, which are in convincing proximity to sympathetic nervous inputs (Fig. 1A). They then used a novel intraocular graft mouse model in which islets are implanted into the eye’s anterior chamber (Fig. 1A). This model allows for optogenetic stimulation of pericytes in the islets of freely moving mice and the evaluation of how pericyte constriction and the subsequent diminished blood flow to the islets impact systemic glucose homeostasis. Optogenetic stimulation of pericytes in the intraocular islet graft reduced glucose uptake within the islets, decreased plasma insulin, increased plasma glucagon, and elevated glucose levels compared with control animals during a glucose tolerance test (Fig. 1B). These findings demonstrate the previously unproven importance of islet blood flow regulation in normal glucose homeostasis.
Previously, the authors demonstrated that sympathetic activity stimulated pericyte constriction. Here, the authors demonstrated within the intraocular graft model that sympathetic agonists activated pericytes and decreased capillary diameter, which would decrease islet blood flow. Paralleling the effects of optogenetic stimulation of pericytes, plasma insulin levels were diminished and plasma glucagon and blood glucose levels were elevated. Importantly, in live human pancreas tissue slices, sympathetic innervations contacted pericytes and sympathetic agonists activated pericytes and constricted islet capillaries and feeding arterioles.
Together, these results show that islet blood flow regulation and sympathetic innervation in the islets have physiological importance. These results are particularly intriguing due to the known changes in the islet microvasculature, pericyte, and sympathetic nerve prevalence in type 1 and type 2 diabetes (7,14,15). While it is not feasible to replicate such studies in humans, the similarities between pericyte and sympathetic nerve coverage in the human islet further suggest the involvement of blood flow regulation in human diabetes.
The key strengths of this study are the innovative approaches used, which combine the intraocular graft model with optogenetic stimulation of ChR2-expressing pericytes in freely moving mice. The intraocular graft model enables the minimally invasive activation of pericytes over time and local sympathetic activation in controlling islet blood flow. The incorporation of live human pancreas tissue slices allows these findings to be translated to pericyte regulation of human islet blood flow. Validation of the findings in human is particularly important given differences in the islet vascular network and innervation patterns that have been observed in human compared with mouse (16,17).
A key issue of concern is the relevance to the endogenous physiological regulation of islet blood flow. Just because changes in islet blood flow in the intraocular graft regulate insulin levels and glucose homeostasis does not necessarily mean this occurs physiologically. There are many layers to the regulation of islet blood flow within the pancreas, with islet-resident contractile pericytes representing just one mechanism. The regulation of more upstream vessels, such as arterioles, that feed the islets and surrounding exocrine tissue will likely be important. However, it is noteworthy that sympathetic activity appears to strongly stimulate arteriole contraction in human pancreas slices, providing support for sympathetic activity regulating endogenous islet blood flow. The mechanisms by which altered islet blood flow impacts circulating insulin levels and glucose homeostasis are also not fully determined. For example, it is not clear if changes in circulating insulin levels are primarily due to the decreased glucose uptake into the islets or altered delivery of insulin into the circulation or if they are a result of direct interactions with β-cells and the regulation of insulin secretion. Each of these mechanisms is possible due to the complexity in the pericyte interaction with capillary diameter and nutrient exchange. A key goal for future work should be to clarify these potential mechanisms.
By highlighting the importance of pericyte-mediated islet blood flow, this study introduces an additional layer of regulation to glucose homeostasis: the local control of blood flow. A significant obstacle in cell replacement therapy for diabetes is overcoming the delayed revascularization of the transplanted material (cadaveric islets or stem-cell–derived cells) (18). Indeed, the inclusion of microvessels improved the survival and functionality of transplanted β-cells (19,20). Tamayo et al. (13) demonstrate that islet vascularization is crucial for the ability of these cells to sense glucose and/or secrete insulin. Further, as the islet microvasculature is affected in diabetes, the loss of pericyte-regulated capillary dilation may contribute to glycemic deterioration. The findings of this study open the door for therapies targeting pericytes and islet blood flow to improve glycemic control and halt diabetes progression.
See accompanying article, p. 1679.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.