Biology subjects

Drucker, D. J.

Publications and source records attributed to Drucker, D. J..

6 recordsLinked to original sources

bioRxiv2026

Gut-derived GLP-1 released by rare sugar D-allulose cooperates with insulin to activate left-sided vagal afferents and enhance insulin sensitivity

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear, largely because of its limited access to pancreatic {beta} cells. Here, we show that D-allulose-induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left-sided vagal afferents forming the common hepatic branch, but not right-sided afferents. AIGS-enhanced insulin action required both GLP-1 receptors and insulin receptor substrate 2 in these neurons. Remarkably, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extra-pancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies. ARTICLE HIGHLIGHTO_LICompared with GLP-1 receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. C_LIO_LIWe utilized the rare sugar D-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. C_LIO_LID-allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-sided vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. C_LIO_LIBecause this acute mechanism improved hyperglycemia in type 2 diabetes more effectively than GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for T2DM. C_LI

physiology↗

bioRxiv2025

Glucagon receptor signaling is indispensable for the healthspan effects of caloric restriction in aging male mice

Obesity and type 2 diabetes mellitus accelerate aging, shortening the duration of healthspan. Conversely, chronic calorie restriction (CR) extends healthspan. Research aimed at understanding the mechanism by which CR slows aging has focused heavily on insulin and downstream signaling cascades. Glucagon, a hormone that counter-regulates insulin, is commonly affected by these same interventions. To investigate the role of glucagon in aging we used dietary manipulation, global and liver-specific glucagon receptor knockout, and pharmacological glucagon receptor activation. We found that globally eliminating glucagon receptor signaling (Gcgr KO) decreases median lifespan by 35% in lean mice. These lifespan shortening effects are more robust in diet-induced obese mice (54%). Extending these findings to metabolic health, we found that glucagon receptor signaling is indispensable to the metabolic response to chronic CR in young and aged mice. While CR decreased liver fat, serum triglyceride, and serum cholesterol in WT mice, these metabolic benefits were absent in Gcgr KO mice. In line with these observations, we found that critical nutrient sensing pathways known to improve aging are dysregulated in mice lacking glucagon receptor signaling at the liver (Gcgrhep-/-). Liver-specific deletion of the glucagon receptor decreases hepatic AMP Kinase activation in aging mice, regardless of diet. Further, CR decreases hepatic mTOR activity in WT mice, but not in Gcgrhep-/- mice. Together, these findings propose that glucagon signaling plays a critical role in both normal aging and the lifespan and healthspan extension driven by caloric restriction.

physiology↗

bioRxiv2025

Ectopic, hepatic GLP-1R agonism enhances the weight loss efficacy of GLP-1 analogues.

ObjectiveUnimolecular triagonists drive substantial weight loss in patients with obesity (PwO) by engaging the glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) receptors to reduce food intake (FI) and the hepatic glucagon (Gcg) receptor to enhance energy expenditure (EE). However, their development has been challenged by deleterious cardiovascular (CV) effects including increased heart rate (HR), elongated QTc, and arrhythmia mediated by GcgR agonism. GLP-1R monoagonists on the other hand improve both obesity and CV outcomes with negligible effects on EE. We sought to imbue peptide GLP-1R agonists with an EE enhancing effect by combining them with ectopic GLP-1R expression and agonism in hepatocytes. MethodsWe used an attenuated adenovirus (AAV) to induce the expression of a functional, liver-specific GLP-1R combined with traditional peptide agonist treatment to drive greater body weight loss via reduced energy intake and increased energy expenditure. ResultsAgonism of the ectopic GLP-1R with either semaglutide, a low internalization GLP-1R agonist (Sema584), or a dual GLP-1R/GIPR agonist in wild-type (WT) diet induced obese (DIO) mice led to enhanced EE and improved weight loss compared to agonist treatment alone. ConclusionsThis represents a novel mechanism for achieving polypharmacy to treat obesity. HighlightsO_LIA Glp1r encoding AAV induces expression of a functional receptor mouse livers. C_LIO_LIEndogenous GLP-1R does not mediate semaglutide clearance. C_LIO_LIEctopic GLP-1R mediates semaglutide clearance. C_LIO_LIEctopic, hepatic Glp1r plus semaglutide enhances weight loss in mice. C_LIO_LIEctopic, hepatic Glp1r plus a dual incretin agonist enhances weight loss in mice. C_LI

zoology↗

bioRxiv2024

Telocytes link epithelial nutrient sensing with amplification of the ILC2-tuft cell circuit

Group 2 innate lymphocytes (ILC2s) are prevalent in small intestine but engagement of type 2 immunity during basal processes are incompletely described. Thymic stromal lymphopoietin (TSLP), a cytokine implicated in ILC2 activation, was constitutively expressed in villus telocytes and crypt-associated trophocytes, specialized fibroblasts that sustain epithelial identity. Feeding increased TSLP and induced ILC2 type 2 cytokines that were attenuated by deletion of TSLP in PDGFR+ stromal cells or TSLP receptor on ILC2s. Mouse and human telocytes expressed receptors for glucagon-like peptide-2 (GLP-2), which is released by enteroendocrine cells (EECs) after eating. GLP-2 induced intestinal TSLP, TSLP-dependent ILC2 cytokine production, and tuft cell hyperplasia. The telocyte-alarmin relay couples EEC nutrient detection with amplification of a tuft cell chemosensory circuit that diversifies surveillance of ingested cargo. One-Sentence SummaryIntestinal telocyte TSLP relays signals from enteroendocrine cells to ILC2s to amplify the tuft cell circuit in response to feeding.

immunology↗

bioRxiv2023

Liver Fibroblast Growth Factor 21 (FGF21) is Required for the Full Anorectic Effect of the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide in Male Mice fed High Carbohydrate Diets

Glucagon-like peptide-1 receptor (GLP-1R) agonists and fibroblast growth factor 21 (FGF21) confer similar metabolic benefits. Studies report that GLP-1RA induce FGF21. Here, we investigated the mechanisms engaged by the GLP-1R agonist liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. We show that liraglutide increases FGF21 levels via neuronal GLP-1R activation. We also demonstrate that lack of liver Fgf21 expression confers partial resistance to liraglutide-induced weight loss. Since FGF21 reduces carbohydrate intake, we tested whether the contribution of FGF21 to liraglutide-induced weight loss is dependent on dietary carbohydrate content. In control and liver Fgf21 knockout (LivFgf21-/-) mice fed calorically matched diets with low- (LC) or high-carbohydrate (HC) content, we found that only HC-fed LivFgf21-/- mice were resistant to liraglutide-induced weight loss. Similarly, liraglutide-induced weight loss was partially impaired in LivFgf21-/- mice fed a high-fat, high-sugar (HFHS) diet. Lastly, we show that loss of neuronal {beta}-klotho expression also diminishes liraglutide-induced weight loss in mice fed a HC or HFHS diet, indicating that FGF21 mediates liraglutide-induced weight loss via neuronal FGF21 action. Our findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in the presence of high dietary carbohydrate content.

physiology↗

bioRxiv2022

Intra-islet glucagon signalling regulates pulsatile insulin secretion and glucose homeostasis

BackgroundType 2 diabetes (T2D) is characterised by the loss of pulsatile insulin secretion. We studied mice with {beta}-cell specific loss of the glucagon receptor (Gcgr fl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor signalling on pan-islet calcium oscillations and insulin pulsatility. MethodsFrequently sampled intravenous glucose tolerance tests were conducted on Gcgr {beta}-cell-/- and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for {beta}-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in {beta}-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. ResultsGcgr {beta}-cell-/- mice exhibited impaired glucose tolerance following intraperitoneal glucose challenge (control 12.7mmol/L {+/-}0.6 vs. Gcgr {beta}-cell-/- 15.4mmol/L {+/-}0.0 at 15 min, p=0.002); fasting glycaemia was not different to controls. In vitro, Gcgr {beta}-cell-/- islets showed profound loss of synchronised calcium waves in response to glucose which was only partially rescued in vivo. First-phase insulin pulsatility on peripheral blood sampling (n=5) was significantly disordered in Gcgr {beta}-cell-/- mice (burst mass Gcgr {beta}-cell-/- 0.30 {+/-}0.03 versus 0.84 {+/-}0.23 for controls p=0.04). Diet induced obesity and hyperglycaemia resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n=8). ConclusionThese data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised calcium oscillations and support a possible therapeutic role for glucagonergic agents to restore the insulin pulsatility lost in T2D.

physiology↗