TO THE EDITOR
Why should a seemingly rare hormone found in the intestines demand significant attention from diabetes researchers and clinicians worldwide? Type 1 diabetes (T1D) is a pervasive autoimmune disorder characterized by the body's failure to produce insulin, affecting millions globally[1]. A common and dangerous complication faced by these patients is hypoglycemia, a condition that can lead to severe cognitive and physical impairment if not managed correctly. The primary objective of this editorial is to delve into the recent groundbreaking findings by Jin et al[2], which reveal a novel role of intestinal glucagon-like peptide-1 (GLP-1) in altering hypoglycemic counter-regulation. This analysis aims to unravel the implications of these discoveries, potentially steering future therapies that could revolutionize hypoglycemia management in T1D.
Overview of the study
The study conducted by Jin et al[2] explores the intricate role of intestinal GLP-1 in the counter-regulation of hypoglycemia in T1D mice. Utilizing an experimental design where T1D was induced in C57BL/6J mice, the research investigates how recurrent episodes of hypoglycemia affect GLP-1 levels and its receptor expression in the intestine. Key methods such as immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA) were employed to measure hormonal changes and receptor expression. The results reveal a significant increase in intestinal GLP-1 and its receptor levels in mice experiencing recurrent hypoglycemia. This overexpression was linked to compromised adrenal response and glucagon secretion, suggesting that excessive intestinal GLP-1 disrupts normal hormonal counter-regulation during hypoglycemic events, leading to potential worsening of the hypoglycemic episodes in diabetic conditions.
Overview of GLP-1 and its functions
GLP-1, a hormone produced in both the gut endocrine cells and the brain, plays a crucial role in regulating islet function, satiety, and gut motility. It primarily stimulates insulin secretion in a glucose-dependent manner and modulates gut motility and food intake[3,4]. Beyond its metabolic functions, GLP-1 exhibits cardio- and neuroprotective properties, significantly reducing inflammation and apoptosis, and impacting cognitive and behavioral aspects like learning, memory, and reward behaviors[5]. It operates through hormonal and neural pathways, with its receptors (GLP-1R) mainly found in pancreatic β-cells enhancing insulin secretion, β-cell survival, and addressing inflammation and cardiovascular functions[6]. Clinically, GLP-1R agonists are pivotal in managing type 2 diabetes (T2D) and obesity, and they are also being explored for their potential in treating neurodegenerative disorders, supported by their ability to regulate signaling pathways crucial for β-cell function and overall metabolic health[7,8].
Biological mechanisms of GLP-1 in the intestine
Production and regulation of GLP-1 in the gut: GLP-1 produced by enteroendocrine L cells primarily in the distal intestine, is crucial for regulating insulin secretion, intestinal function, and food intake, released in response to nutrient ingestion[3,9]. The secretion of GLP-1 is stimulated by different nutrients through specific receptors and transporters: carbohydrates via the SGLT1 and K+ ATP channels, fats through the FFA1 and GPR119, and proteins by Pept1 and the CaSR[10]. Additionally, the gut microbiota significantly influences GLP-1 production by interacting with intestinal cells and modifying bile acid composition, with bile acids like ω-muricholic acid and hyocholic acid activating TGR5 to enhance GLP-1 release[11]. Changes in gut microbiota from antibiotics or dietary shifts can also affect GLP-1 levels, impacting glucose metabolism and gut health[12]. Furthermore, immune cells such as intraepithelial T cells within the gut capture GLP-1, altering its availability, while the mitochondrial protein IF1 regulates its secretion, particularly under mitochondrial stress conditions in intestinal cells[9,13].
Impact of intestinal GLP-1 on hypoglycemia: How intestinal GLP-1 influences blood glucose levels: GLP-1 secreted by L cells in the distal intestine, significantly regulates blood glucose by enhancing insulin secretion in response to nutrients, thus playing a vital role in controlling postprandial glucose levels[14]. This hormone not only slows gastric emptying but also suppresses glucagon secretion, which collectively reduces blood glucose spikes after meals[15]. GLP-1 receptor agonists (GLP-1RAs), used extensively in managing T2D, mimic this natural hormone's action, thereby lowering both fasting and postprandial glucose levels with minimal risk of hypoglycemia due to their glucose-dependent action[14]. Furthermore, these agonists improve insulin sensitivity and decrease hepatic glucose production, ensuring efficient blood glucose management without inducing hypoglycemia, particularly critical in T2D[16]. Clinically, GLP-1RAs not only reduce glucose levels but also ameliorate other metabolic parameters like body weight and lipid profiles, enhancing overall metabolic health[17]. The modulation of gut microbiota by GLP-1, promoting beneficial bacteria such as Faecalibacterium prausnitzii, also plays a role in glycemic control, while its immunomodulatory properties help stabilize blood glucose levels and mitigate inflammation-related complications[18,19] (Figure 1).
Figure 1 Illustrates the mechanism of action of glucagon-like peptide-1.
When food is consumed, it stimulates L-cells in the intestine to release glucagon-like peptide-1 (GLP-1). In response, GLP-1 activates the pancreas to release insulin in a glucose-dependent manner while simultaneously inhibiting glucagon secretion, which helps to reduce blood glucose levels. Additionally, GLP-1 influences the anterior pituitary gland to secrete adrenocorticotropic hormone, which then stimulates the adrenal gland to produce hormones such as cortisol, epinephrine, and norepinephrine. During hypoglycemic conditions, the release of GLP-1 is inhibited, leading to decreased insulin production and reduced secretion of adrenal hormones, thereby contributing to the stabilization of blood glucose levels (Created in BioRender, Supplementary material). GLP-1: Glucagon-like peptide-1.
GLP-1 and hypoglycemic counterregulatory responses: Interaction between GLP-1 and counterregulatory hormones: GLP-1 significantly impacts glucose regulation, not just by enhancing insulin secretion but also by influencing counterregulatory responses during hypoglycemic episodes. Secreted by enteroendocrine cells in response to nutrients, GLP-1 helps maintain glucose homeostasis, yet its activation can inhibit glucagon secretion. This inhibition may impair the body's natural ability to counter low blood glucose, potentially heightening the risk of severe hypoglycemia under certain conditions, such as in non-diabetic individuals post-gastric bypass surgery, where altered endogenous GLP-1 levels lead to impaired glucose counterregulatory responses[15,20,21]. Additionally, despite the absence of significant effects on acute counterregulatory responses in post-bariatric patients, exogenous GLP-1 receptor agonists can modulate autonomic functions like sympathetic nerve activity, potentially affecting heart rate variability and other autonomic responses[22].
Further research explores the interaction between GLP-1, and other hormones involved in hypoglycemia management. Studies indicate that SGLT2 inhibitors, although they increase basal glucagon levels, do not correct the impaired glucagon response during hypoglycemic episodes, suggesting that a simple increase in basal glucagon is not enough for effective counter-regulation[23]. Additionally, GDF15, a novel hormone, supports hepatic gluconeogenesis and lipolysis, helping manage hypoglycemia; however, its production is reduced in individuals with frequent hypoglycemic events, such as those with T1D, presenting a potential area for therapeutic intervention[24]. Moreover, GLP-1 interacts with cortisol, catecholamines, and growth hormone, adding complexity to its role in modulating the hormonal and autonomic responses to hypoglycemia, with the impact of GLP-1RAs varying by clinical and physiological contexts[25].
Effect on adrenal secretion
GLP-1 is well-recognized for its role in glucose metabolism and insulin secretion, but recent findings have also illuminated its impact on adrenal secretion, influencing the production of crucial hormones such as cortisol, adrenaline, and noradrenaline. GLP-1RAs, like exendin-4, enhance catecholamine synthesis and release in the adrenal medulla by boosting cyclic adenosine monophosphate (cAMP) production and activating tyrosine hydroxylase, key for catecholamine biosynthesis[26]. This interaction notably affects metabolic and cardiovascular health by potentially modulating the fight-or-flight response, which could be beneficial in managing conditions like hypertension and heart failure. Additionally, GLP-1's influence extends to cortisol secretion by potentially reducing inflammation and stress responses, thereby indirectly affecting cortisol levels[18].
Impact on glucagon secretion: GLP-1 significantly influences glucose homeostasis, notably by inhibiting glucagon secretion from pancreatic alpha cells and enhancing insulin secretion, key actions for managing blood glucose levels effectively. Although alpha cells exhibit low levels of GLP-1 receptor, GLP-1's inhibition of glucagon secretion is potent, partly due to the direct effects on these cells and also through its degradation product, GLP-1(9-36), which interacts with the glucagon receptor (GCGR)[27]. Mechanistically, GLP-1 receptor activation raises cAMP levels, initiating a cascade that suppresses glucagon release and increases insulin and somatostatin production through paracrine signaling within the pancreatic islets[5,28]. These dynamics are crucial for the incretin effect of GLP-1 and underline the clinical utility of GLP-1RAs in treating T2D, as they not only boost insulin but also curb glucagon production, thereby regulating hyperglycemia effectively without significant risk of hypoglycemia[29].
Mechanism of action of GLP-1: GLP-1, an incretin hormone produced in the gut and brain, is central to regulating glucose homeostasis, insulin secretion, and appetite, with broad implications for diabetes and obesity management. GLP-1 is released from intestinal enteroendocrine L cells in response to nutrient ingestion, with its secretion facilitated by interactions with various receptors and transporters sensitive to carbohydrates, proteins, and lipids[30]. Upon binding to the GLP-1R on pancreatic beta cells and other tissues, GLP-1 triggers a cascade involving cAMP and PKA, enhancing glucose-dependent insulin secretion and inhibiting glucagon release, thereby aiding in glucose regulation[5,31]. Additionally, GLP-1 influences gastric emptying and appetite through its receptors in the gastrointestinal tract and central nervous system, supporting weight management by promoting satiety and reducing food intake[32].
Beyond metabolic regulation, GLP-1 exhibits cardioprotective actions, improving endothelial function and reducing blood pressure, mediated through its cardiovascular receptors and effects like enhanced nitric oxide production[33]. It also offers neuroprotective benefits, relevant for conditions such as Alzheimer’s disease, by mitigating neuronal damage through anti-apoptotic, anti-inflammatory, and antioxidative pathways[14]. Emerging research further reveals that GLP-1(28-36), a metabolite of GLP-1, provides cardioprotection by altering metabolic pathways to favor glycolysis and reduce mitochondrial oxidative stress, showcasing novel cellular targets and mechanisms of GLP-1 action[33].
Strengths: The study by Jin et al[2] on the role of intestinal GLP-1 in hypoglycemic counter-regulation in T1D mice highlights notable methodological rigor and the relevance of its animal model, enhancing its scientific merit. Methodologically, the study employs comprehensive biochemical and histological techniques such as immunofluorescence, Western blot, and ELISA, enabling precise measurement of GLP-1 and its impacts. The controlled design, which involves the induction of diabetes in mice followed by systematic hypoglycemic challenges, ensures the reliability of results attributing changes directly to GLP-1’s influence. Furthermore, the use of GLP-1RAs and antagonists adds depth to understanding the therapeutic potential of GLP-1 modulation. This study not only deepens our understanding of GLP-1’s physiological roles but also underpins potential new treatments for managing diabetes-related hypoglycemia.
Weaknesses and limitations
The study by Jin et al[2] on the role of intestinal GLP-1 in T1D mice, despite offering valuable insights, confronts significant limitations concerning the extrapolation of findings to humans and the choice of an animal model. A primary challenge lies in the species-specific differences between mice and humans, particularly in disease pathology and physiological responses, which may not accurately mirror human GLP-1 dynamics or hypoglycemic counter regulation. The streptozotocin-induced diabetes model in mice oversimplifies the complex, multifactorial nature of human T1D, potentially missing critical autoimmune and genetic dimensions. Moreover, while the application of GLP-1RA and antagonists explores potential therapeutic avenues, the dosages and administration methods employed may not directly translate to human clinical use, necessitating a thorough evaluation of therapeutic windows and potential side effects.
Conclusion
The study by Jin et al[2] offers compelling evidence on the critical role of intestinal GLP-1 in disrupting hypoglycemic counter-regulation in T1D mellitus mice. By highlighting the increased expression of GLP-1 and its receptors, the research provides insights into how recurrent hypoglycemia alters crucial hormonal responses, potentially exacerbating the challenge of managing stable glucose levels in patients with T1D. These findings could pave the way for revising therapeutic approaches to hypoglycemia management in diabetes, emphasizing the need for treatments that address the underlying hormonal interactions without compromising the body's natural counterregulatory mechanisms. This study not only broadens our understanding of the physiological underpinnings of T1D but also suggests a targeted focus on intestinal hormones as a strategic component in optimizing diabetes treatment.
