High-resolution imaging atlas reveals the context-dependent role of pancreatic sympathetic innervation in diabetic mice

Abstract

A better understanding of how sympathetic nerves impact pancreatic function is helpful for understanding diabetes. However, there is still uncertainty and controversy surrounding the roles of sympathetic nerves within the pancreas. To address this, we utilize high-resolution imaging and advanced three-dimensional (3D) reconstruction techniques to study the patterns of sympathetic innervation and morphology in the islets of adult wild-type (WT) and diabetic mice. Our data show that more than ~30% of α/β-cells are innervated by sympathetic nerves in both WT and diabetic mice. Additionally, sympathetic innervated α/β-cells are reduced in diet-induced obese (DIO) mice, whereas sympathetic innervated β-cells are increased in db/db mice. In addition, in situ chemical pancreatic sympathetic denervation (cPSD) improves glucose tolerance in WT and db/db mice but decreases glucose tolerance in DIO mice. In situ cPSD also enhances insulin sensitivity in diabetic mice without affecting WT mice. Overall, our findings advance our understanding of diabetes by highlighting the distinctive impact of pancreatic sympathetic innervation on glucose regulation.

1. Introduction

Glucose homeostasis is a critical physiological process that maintains the essential energy supply for the human body and prevents the detrimental effects of hyperglycemia or hypoglycemia [1]. This intricate regulation primarily hinges upon the secretion of hormones from the pancreatic islets [2]. Given that islets constitute a small fraction (1%–2%) of the total pancreatic volume [3,4], islets exhibit considerable variations in size [5]. The islets contain α-cells and β-cells that secrete glucagon to increase blood glucose and insulin to lower it. These hormones work together to ensure that glucose levels remain within a narrow, healthy range, supporting the body's energy needs. Changes in the histomorphology and function of islets correlate with aberrant blood glucose levels [6]. Despite extensive research on the endocrine function of the pancreas, our understanding of the intricate network of nerves that innervate the pancreas and their roles in regulating blood glucose remains limited.

The autonomic nervous system, particularly the sympathetic nervous system, influences the pancreas via visceral nerves originating from the prevertebral abdominal and superior mesenteric ganglia. This neural input is pivotal for the development and maturation of the pancreas [7–9]. Despite the acknowledged importance of sympathetic innervation in pancreatic function, the specific roles of these nerves within the pancreas remain unclear and controversial [10]. Sympathetic innervation currently plays a predominant role in influencing the secretion of islet hormones through the neurotransmitter norepinephrine (NE). NE, released from postganglionic sympathetic fibres or the adrenal medulla, stimulates glucagon secretion by binding to β2-adrenergic receptors on α-cells and inhibits insulin secretion by binding to α2-adrenergic receptors on β-cells [11,12]. The activation of sympathetic nerves through electrical stimulation leads to the release of NE, which mimics the inhibitory effect on glucose-stimulated insulin secretion (GSIS) [13]. Similarly, the administration of exogenous NE or adrenergic receptor agonists replicates the inhibitory effects of sympathetic nerve activation on GSIS [14]. Conversely, adrenergic receptor antagonists counteract the inhibitory effect of sympathetic nerve activation on insulin secretion [15]. In addition, the activation of sympathetic nerves stimulates glucagon secretion and inhibits insulin release, leading to elevated blood glucose levels, which are essential for the fight or flight response [16,17]. However, it has been reported that the developmental loss of sympathetic nerves results in reduced insulin secretion and impaired glucose tolerance in adult mice [7]. To address the existing controversies, we need to manipulate the sympathetic nerves in the pancreas to clarify their roles in glucose metabolism. However, the detailed sympathetic innervation patterns within the pancreas also remain unclear. A previous study revealed that few sympathetic fibres contact the endocrine cells of islets in humans [18]. However, more recent 3D imaging studies suggested significant sympathetic innervation in islets, particularly in contact with α- and δ-cells [19–21]. In the mouse pancreas, a rich supply of sympathetic nerves was found to contact α-cells but appeared not to branch in space to establish contacts wi