Given that the islets comprise an endocrine organ and are therefore dependent on close coupling with the whole-body blood circulation, it is not surprising that vascular cells such as pericytes and endothelial cells are important for islet development.

The uncovering of the roles and mechanisms of these vascular cells is interesting and potentially important for cell-based treatments for diabetes.

Exactly how pericytes and endothelial cells influence β-cell function in an adult islet is a developing area of study 44 and can, in principle, occur through a variety of effects including; capillary behaviour, secreted factors, direct contact, or ECM-driven interactions. Islet blood flow is obviously important for endocrine function and allows the rapid sensing of fluctuations in blood glucose and outflow of secreted hormones.

It is controlled by various nutrients and growth factors 1 and, in turn, impacts on β-cell insulin secretory activity 4 , Research in this area has identified several molecules responsible for the regulation of pericyte contractile tone.

For example, pericytes in the brain have been shown to express receptors for vasoactive molecules Endothelial cells are known to secrete vasoactive factors, including vasodilators nitric oxide and prostacyclin as well as vasoconstrictors thromboxane and endothelin-1 In the pancreas, adenosine released during ATP breakdown increases islet blood flow 49 and relaxes pericytes to dilate islet capillaries In contrast, the sympathetic neurotransmitter noradrenaline induces contraction of islet capillaries and reduces blood flow The cellular contacts and paracrine signalling between endothelial cells and pericytes that regulate vascular tone likely influence blood flow effects on β-cell endocrine function.

There is now extensive evidence that pericytes directly support β-cell function and glucose homeostasis independent of blood flow 6 , 22 , 23 , 26 , In vivo depletion of pericytes in the pancreas using the Diphtheria Toxin Receptor system allows study of the role in β-cell function and proliferation 22 , This depletion of pancreatic pericytes leads to glucose intolerance due to reduced islet insulin content and secretion, as well as diminished expression of cellular components required for β-cell functionality.

Importantly, reduced levels of MafA and Pdx1 , transcription factors essential for β-cell maturity, indicate β-cell de-differentiation occurs in the absence of pericytes Pancreatic pericytes are further shown to secrete factors that regulate glucose-stimulated insulin secretion GSIS.

Pancreatic mural cells, i. β-Cells express the NGF receptor tropomyosin receptor kinase A TrkA , and the activation of this receptor promotes insulin exocytosis via glucose-induced β-cell actin remodelling In humans, altered circulating NGF levels have been noted in type 2 diabetes and mutations in the TrkA gene cause decreased GSIS 50 , Pericytes further produce Bone morphogenetic protein 4 BMP4 , through which they potentially directly regulate β-cell function While the activity of the BMP4 receptor BMPR1A is essential for proper β-cell gene expression and function 52 , the involvement of pericytic BMP4 in this process was yet to be reported.

The evidence of glucose-stimulated paracrine signaling between pericytes and β-cells highlights the importance of pericytes in glucose homeostasis and GSIS under physiological conditions.

Among the many factors secreted by intra-islet endothelial cells, connective tissue growth factor CTGF and thrombospondin TSP -1 have known effects on β-cells CTGF, a matricellular protein active throughout the body 54 , drives β-cell expansion during embryogenesis in an autocrine manner 55 , thought to occur due to multiple development-related transcription factor binding sites located on the CTGF gene although a mechanism has not yet been clearly defined In the adult pancreas, CTGF is expressed mostly by islet endothelial cells Production of TSP-1, an anti-angiogenic protein secreted by intra-islet endothelial cells, is upregulated by elevated blood glucose levels in humans TSPdeficiency, however, leads to pancreatic hyperplasia, glucose intolerance, and impaired GSIS 60 despite knockdown-related improvements in transplanted islet revascularization Rescue of TSPdeficient murine islets through treatment with transforming growth factor TGF β-1 activation inhibits the decreased glucose tolerance 60 , providing insight into potential mechanisms.

However, long-term deficiency of TSP-1 results in persistent dysfunction of glucose tolerance, even in the face of compensatory normalisation of β-cell mass Additional molecules produced in non-pancreatic endothelial cells, such as hepatocyte growth factor HGF , influence β-cell function as well via exocrine signaling Due to the structure of the double-layered basement membrane 28 , 64 , β-cells are unlikely to make direct contact with intra-islet vascular endothelial cells or pericytes.

However, there are candidate proteins that might indicate direct links are possible. For example, the pre- and post-synaptic proteins neurexin and neuroligin are expressed by vascular mural and endothelial cells 65 , and have additionally been identified in β-cells In neurons, these binding partners directly contact each other and mediate a plethora of biological functions 67 including synaptic organisation.

Over-expression of post-synaptic receptor neuroligin-2 expression in β-cells increases GSIS 68 and promotes insulin granule docking The neurexin-neuroligin interactions therefore appear to be involved in regulating β-cell function.

These interactions may arise through β-cell-to-β-cell contacts, but it remains an intriguing possibility that they result from interactions between the β-cells and the vascular cells.

Connexins 36 and 43, which form gap junctions between cells, are similarly expressed by both endothelial and β-cells, however there is currently no evidence demonstrating direct contacts between the two cell types Various proteins of the vascular basement membrane are implicated in the regulation of β-cell function, proliferation, and expansion 22 , 25 , 64 , The basement membrane is comprised of glycoproteins including laminins, fibronectin, nidogens, and collagens 29 , The basement membrane surrounds the intra-islet capillaries and the islet capsule but is not present between endocrine cells 29 ; therefore, β-cells contact the basement membrane only in the regions which they contact the vasculature 25 , Evidence demonstrates that these contacts, mediated through integrin activation 31 , assist in driving β-cell polarity and the targeting of insulin secretion 12 , 31 in addition to modulating insulin gene expression 25 , β-cell proliferation and survival 72 , and GSIS functionality 73 , Both endothelial and pericytes secrete ECM components that make up the islet basement membrane.

Pancreatic pericytes also produce an array of basement membrane components, including collagen IV, laminins, proteoglycans, and nidogen In particular, pancreatic pericytes and endothelial cells both produce laminin α4, which promotes the expression levels of the β-cell genes Ins1 , MafA , and Glut2 , as well as GSIS In vitro research surrounding the function of pancreatic islets is largely performed with cells derived from isolated islets, obtained through enzymatic destruction of the ECM structure 78 , This loss of vasculature negatively impacts the endocrine function of isolated islets Various lines of evidence show that attempts to preserve, restore or replace the vascular cells is beneficial to β-cells.

Endothelial cell-conditioned medium in culture of dispersed β-cells improves GSIS with a laminin-dependent mechanism Similarly, exposure to pericyte-conditioned medium stimulates proliferation in cultured β-cells in an integrin-dependent manner 10 , In islet transplantation, supplementing islets with endothelial cells improves revascularisation and functional outcomes compared to islets alone 82 — Additionally, simple incorporation of basement membrane proteins into cell cultures has repeatedly been shown to benefit cultured β-cell function and survival and is furthermore a useful approach to gain a mechanistic understanding of the processes involved.

Introduction of laminins α4 and α5 to β-cells cultured in vitro on glass increases insulin gene expression and enhances GSIS, effects that are inhibited by the blockade of the integrin β1 receptor β1 integrin has been demonstrated to regulate GSIS 85 as well as β-cell expansion 70 , furthering the evidence that β1 integrins play a key role in ECM influences on β-cell endocrine function.

In addition to affecting β-cell function, ECM contacts between islet vasculature and β-cells contribute to β-cell polarity 12 , 30 and likely orientate the site of targeted insulin secretion to the capillaries 12 , Targeting of insulin granule fusion appears to be driven by the localisation of pre-synaptic scaffold proteins, including liprin, RIM2, piccolo, and ELKS, at the contact point of β-cells and the islet vasculature 12 , 86 and has been shown to depend on localised β1 integrin activation Contact between β-cells and ECM triggers focal adhesion formation downstream of β1 integrin activation, shown via immunostaining to occur exclusively at the interface between islet blood vessels and β-cells As insulin granule fusion is biased towards this interface 12 , 31 , current evidence indicates this targeting of secretion requires the focal adhesion activation and the specific involvement of focal adhesion kinase FAK.

Evidence suggests FAK as a vital signaling mediator for β-cell endocrine function, as pharmacological and genetic inhibition of FAK reduces insulin secretion 87 and disrupts secretion targeting in vitro 12 , 31 , while in vivo knockout of pancreas-specific FAK results in impaired GSIS and diminished glucose tolerance Although the recruitment and activation of FAK appears essential for normal GSIS, further downstream pathways are currently unclear.

Other kinase-associated pathways, such as the extracellular signal-related kinase ERK , have similarly been shown to regulate GSIS 89 , however further investigation into specific signaling cascades will be required to expand on the pathways responsible for modulating β-cell function.

Abnormalities in the islet vasculature may drive β-cell dysfunction and diabetes progression. Changes in pericyte function and mass has been implicated in obesity and diabetes 6 , 7 , 26 , Pancreatic pericytes were recently demonstrated to express the diabetes gene transcription factor 7-like 2 TCF7l2 Polymorphism in TCF7L2 TCF4 strongly correlates with an increased risk of type 2 diabetes Pericyte-specific inactivation of Tcf7l2 impairs glucose homeostasis due to aberrant insulin production and GSIS This impairment has been associated with reduced expression levels of genes associated with β-cell function and maturity, including MafA , Pdx1 and NeuroD1.

Furthermore, pancreatic pericytes are shown to produce secreted factors in a Tcf7l2-dependent manner that potentially support β-cell function and glucose response Diabetic retinopathy is characterized by an early loss of retinal pericytes under hyperglycemic conditions 92 , Loss of pericytes in the liver and brain leads to endothelial hyperplasia and abnormal vascular 94 , In the islets, progression of type 2 diabetes is associated with and may be contributed to by a gradual loss of pericytic coverage of islet capillaries As β-cell function declines and diabetes progresses, poorly controlled blood glucose levels in the form of chronic hyperglycaemia contributes significantly to abnormal protein glycation throughout the islets and other non-pancreatic tissues 97 , The advanced glycation end-products AGEs formed by this process are implicated in both worsening β-cell function as well as in development of long-term diabetic complications including diabetic retinopathy 99 , , nephropathy , , and decreased insulin sensitivity in adipose tissues Although not currently clear, effects on β-cell endocrine function may, in part, be mediated by effects on the ECM proteins of the basement membrane, which are generally long-lived proteins and therefore more susceptible to accumulating effects of glycation.

Both type 1 and type 2 diabetes have been associated ECM abnormalities: progression of type 1 diabetes-related β-cell destruction is correlated with the amount of leukocyte-induced damage to the peri-islet basement membrane , while type 2 diabetes islets exhibit thicker, less branched intra-islet capillaries with increased fibrosis surrounding the vasculature Furthermore, pancreatic pericytes can convert to myofibroblasts 96 which leads to aberrant ECM production and tissue fibrosis and would further contribute to impaired β-cell function.

Specifically for AGE-related changes to ECM structure, AGE increases crosslinking of the ECM to increase stiffness which may impact on the local islet environment and may inhibit cellular signaling and behaviour.

Alteration in ECM stiffness is associated with dysfunction in numerous well-studied disease states, including cancer — , cardiovascular disease , and other fibrotic diseases , Additionally, the receptor for AGEs RAGE is expressed by both endothelial cells and pericytes Along with AGE-triggered basement membrane modification , AGE receptors are thought to be involved in the triggering of retinal pericyte apoptosis that occurs in diabetic retinopathy - it may be that islet pericytes undergo similar apoptotic signaling, further impacting pancreatic endocrine function.

The islet vasculature affects various aspects of pancreatic function and GSIS through both blood flow-dependent and -independent pathways as summarized in Table 1. While each of the vascular components, namely endothelial cell and pericytes, are known to individually support β-cell function, whether these cells have a synergistic effect are yet to be directly studied.

For example, heterotypic interactions of pericytes and endothelial cells are required for vascular basement membrane assembly in many tissues but this has not yet been shown in the pancreas.

GB, CB, PT, and LL wrote and edited the manuscript. All authors contributed to the article and approved the submitted version. Project funding was obtained from the National Health and Medical Research Council APP and APP; to PT , the Israel Science Foundation ISF; Grant agreement no.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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This work has been supported by grants from NIH DK, DK, DK, DK, HL, F32DK, K01DK , Astra-Zeneca, Merck, Takeda, Servier, and the JPB Foundation. Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, , USA.

You can also search for this author in PubMed Google Scholar. Correspondence to Jinsook Son. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med 55 , — Download citation.

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Abstract The maintenance of glucose homeostasis is fundamental for survival and health. Introduction Diabetes is a chronic metabolic disease that poses a significant threat to public health, shortening life expectancy due to secondary complications such as cardiovascular disease, nephropathy, retinopathy, and neuropathy 1.

Insulin resistance in the development of T2D When blood glucose concentrations rise after a meal, pancreatic islet β-cells secrete insulin, which activates peripheral glucose disposal and maintains glucose homeostasis Full size image.

Causes of β-cell failure in T2D Numerous hypotheses have been proposed to explain β-cell failure. Oxidative stress In β-cells, unlike other mammalian cells, glycolytic flow is tightly linked to elevated mitochondrial oxidative phosphorylation activity, where almost all glucose carbons are oxidized to CO 2 Mitochondrial dysfunction β-cells take up glucose through the glucose transporter GLUT2 and carry out glycolysis via glucokinase to generate pyruvate.

Cellular consequences of stressed and dysfunctional β-cells Chronic metabolic stress leads to dysfunction of β-cells and consequent loss of β-cell mass Fig. Heterogeneity of islet cells in the wake of single-cell RNA sequencing studies The occurrence of dedifferentiation and transdifferentiation in β-cells in response to chronic hyperglycemia suggests that islet cells have a high degree of plasticity.

Therapeutic strategies to treat T2D-associated β-cell failure Treatment strategies for β-cell failure can be categorized into two groups: increasing cell number or enhancing insulin secretion.

Conclusions and perspectives Multiple factors, including oxidative and ER stress and mitochondrial dysfunction, contribute to the development of β-cell failure and altered β-cell identity.

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