The Sensory Neuron–Mast Cell Axis Regulation of Skin Microcirculation in Diabetes: Implication for Diabetes-Related Cutaneous Complications

Type 2 diabetes (T2D) is in essence a vascular disease, as the majority of patients eventually succumb to either macrovascular or microvascular complications. One of the often overlooked, yet critically important, complications of T2D is microvascular abnormalities. The microcirculation comprises the smallest blood vessels, including capillaries, arterioles, and venules, and is essential for the delivery of oxygen, nutrients, and hormones to tissues, as well as the removal of metabolic wastes from the tissues, by providing an endothelial exchange surface area. Evidence has confirmed the presence of both functional and structural microvascular abnormalities in T2D, which can lead to a cascade of pathophysiological changes and contribute to the development and progression of diabetes-related microvascular and macrovascular complications. In this issue of Diabetes, Li et al. (1) reveal a novel mechanism by which T2D engenders skin microvascular abnormalities via an intricate interplay between the nervous and immune systems. The authors demonstrated an essential role of mast cells in the development of reduced cutaneous blood flow and capillary density, and that enhanced sensory neuron transient receptor potential vanilloid 1 (TRPV1) activities trigger mast cells to degranulate and compromise skin microcirculation—a process probably mediated by elevated levels of substance P.

Microcirculatory dysfunction, both structural and functional, is a well-recognized phenomenon in T2D (2) and contributes to tissue hypoxia and dysfunction, poor wound healing, and increased risk of infection. However, the underlying mechanisms remain poorly defined. The skin is the largest and most accessible organ and offers a valuable window into studying microcirculatory function in health and disease. Over the past several decades, multiple methods have been developed to noninvasively explore cutaneous microcirculatory function, including optical microscopy, such as nailfold videocapillaroscopy, laser Doppler coupled with reactivity testing, and laser speckle contrast imaging (LSCI); each has advantages and limitations (3). Using these techniques, investigators have shown that the skin is an insulin-sensitive organ and that insulin at physiologically relevant concentrations increases cutaneous microvascular perfusion in healthy humans (4,5) but not in those who are insulin resistant (6,7). Importantly, this insulin response pattern in the skin microcirculation mirrors that occurring in the skeletal and cardiac muscle, which reflects systemic microvascular dysfunction. Indeed, using contrast-enhanced ultrasound, investigators have repeatedly shown that in both skeletal and cardiac muscle, physiological hyperinsulinemia increases microvascular perfusion in health but not in the insulin-resistant state, in both rodents (8,9) and humans (10–13). The cutaneous and skeletal muscle microvascular effects of insulin were directly compared and assessed by capillary videomicroscopy and contrast-enhanced ultrasound, respectively, in a group of normotensive and glucose-tolerant human adults with a wide range of insulin sensitivity (5). Insulin-augmented microvascular perfusion in the skin paralleled insulin-mediated microvascular perfusion in muscle, and both showed comparably strong correlations with insulin-mediated glucose uptake (5). Thus, studying skin microcirculation as a proxy for internal organ microcirculation appears to be a reasonable approach given the fundamental similarities in the underlying vascular dynamics.

Mast cells play a crucial role in regulating inflammatory responses and allergic reactions and are typically present in tissues throughout the body in close proximity to blood vessels and nerves. This strategic topographic juxtaposition allows a rapid and coordinated response to tissue injury. When activated, mast cells release a variety of mediators through degranulation, including histamine, cytokines, and proteases, which can induce vasodilation and increase the permeability of blood vessels to facilitate the movement of immune cells and proteins to sites of inflammation (Fig. 1). This process helps contain and eliminate pathogens but can also lead to symptoms such as swelling, redness, and heat during an inflammatory response. The findings by Li et al., which showed that T2D hypersensitizes TRPV1⁺ nociceptors, leading to the increased release of substance P, an undecapeptide that plays a pivotal role in modulating inflammation, vasomotion, and vascular permeability (14), and resulting in reduced cutaneous blood flow and capillary density, highlight the importance of neuroimmune interactions in regulating cutaneous microcirculation. This perspective is crucial, as traditional views often separate the nervous and immune systems in the regulation of vascular function.

Insulin resistance is the hallmark underlying pathophysiology of T2D, and previous studies have suggested that mast cells contribute directly to insulin resistance and T2D. Mast cell–deficient Kit^W-sh/W-sh mice exhibited higher insulin sensitivity and better glucose tolerance than wild-type mice on high-fat diet (HFD), while treatment of mice with mast cell stabilizer disodium cromoglycate (DSCG) attenuated HFD-induced weight gain in wild-type but not Kit^W-sh/W-sh mice, suggesting an essential role of mast cells in this process (15). Importantly, mast cell stabilization with either DSCG or ketotifen was able to reverse pre-established, HFD-induced obesity and diabetes in mice (15). The effect of mast cells on angiogenesis is more complex. T2D is associated with a reduction of capillarity in muscle (16,17), which correlates with the severity of insulin resistance (17,18), possibly through the action of the vascular endothelial growth factor (VEGF) family of proteins (19). VEGF recruits and differentiates endothelial progenitor cells and induces endothelial cell proliferation and migration, leading to new vessel formation (19). In the insulin-resistant state, VEGF action on vasculature is impaired, which triggers capillary regression (16,20). On the other hand, mast cells are both a source and target of angiogenesis, as they express abundant VEGF receptors and can synthesize a variety of VEGFs in response to prostaglandin E2 (21). Interestingly, mast cell deficiency and pharmacological stabilization have each been shown to suppress the number of CD31⁺ cells in fat and skeletal muscle in the setting of HFD feeding (15). Further studies are clearly needed to confirm the current findings in other tissues, and in other animal models or humans with T2D.

While Li et al. demonstrated compelling evidence for a critical role of the sensory neuron–mast cell axis in the development of skin microvascular dysfunction in T2D (Fig. 1), it is important to first consider the extrapolability of the study findings to humans. Although the study revealed decreased perfusion, reduced capillary density, and increased mast cell degranulation in the skin of humans with T2D, all evidence underpinning an enhanced sensory neuron–mast cell circuit was derived from rodents fed a 7-week HFD with a diabetes duration of 4 weeks. Conversely, human participants included in the study had a diabetes duration of 8–13 years. It would be important to expand the human study sample size to include those with or without diabetes-related cutaneous complications. Given the topographic proximity among mast cells, nerve fibers, and blood vessels in other organs and tissues, it would be important to examine whether the sensory neuron–mast cell axis also regulates blood flow and tissue capillarity in other organs and tissues such as muscle and fat. It would certainly be prudent to corroborate the blood flow findings using other technologies, as LSCI has a limited depth resolution of <900 µm, is unable to quantify absolute blood flow, and can be influenced by the scattering and absorption effects of red blood cells. These issues should be addressed before exploring the possibilities of preventive or therapeutic interventions for diabetes-related cutaneous complications. Nonetheless, the study findings provide an entirely new perspective on the complex interplay between the nervous and immune systems in regulating cutaneous microvascular function in diabetes and open up new avenues for therapeutic intervention that aim to restore cutaneous blood flow and health in T2D by targeting neuropeptide signaling pathways or modulating mast cell activity.