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The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

ABSTRACT: The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance¹. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity², whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity^3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control⁵. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.

SUBMITTER: El K

PROVIDER: S-EPMC10290954 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

El Kimberley K Douros Jonathan D JD Willard Francis S FS Novikoff Aaron A Sargsyan Ashot A Perez-Tilve Diego D Wainscott David B DB Yang Bin B Chen Alex A Wothe Donald D Coupland Callum C Tschöp Mattias H MH Finan Brian B D'Alessio David A DA Sloop Kyle W KW Müller Timo D TD Campbell Jonathan E JE

Nature metabolism 20230605 6

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance<sup>1</sup>. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity<sup>2</sup>, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatmen ...[more]

PMID: 37277609

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Project description:Aims/hypothesisLipids are a potent stimulus for the secretion of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Traditionally, this effect was thought to involve the sensing of lipid digestion products by free fatty acid receptor 1 (FFA1) and G-protein coupled receptor 119 (GPR119) on the apical surface of enteroendocrine cells. However, recent evidence suggests that lipids may in fact be sensed basolaterally, and that fatty acid absorption and chylomicron synthesis may be a prerequisite for their stimulatory effect on gut peptide release. Therefore, we investigated the effect of chylomicrons on GLP-1 and GIP secretion in vitro.MethodsThe effect of chylomicrons on incretin secretion was investigated using GLUTag cells and duodenal cultures of both murine and human origin. The role of lipoprotein lipase (LPL) and FFA1 in GLUTag cells was assessed by pharmacological inhibition and small (short) interfering RNA (siRNA)-mediated knockdown. The effect of chylomicrons on intracellular calcium concentration ([Ca2+]i) was determined by imaging GLUTag cells loaded with Fura-2. In the primary setting, the contributions of FFA1 and GPR119 were investigated using L cell-specific Gpr119 knockout cultures treated with the FFA1 antagonist GW1100.ResultsChylomicrons stimulated GLP-1 release from GLUTag cells, and both GLP-1 and GIP secretion from human and murine duodenal cultures. Chylomicron-triggered GLP-1 secretion from GLUTag cells was largely abolished following lipase inhibition with orlistat or siRNA-mediated knockdown of Lpl. In GLUTag cells, both GW1100 and siRNA-mediated Ffar1 knockdown reduced GLP-1 secretion in response to chylomicrons, and, consistent with FFA1 Gq-coupling, chylomicrons triggered an increase in [Ca2+]i. However, LPL and FFA1 inhibition had no significant effect on chylomicron-mediated incretin secretion in murine cultures. Furthermore, the loss of GPR119 had no impact on GLP-1 secretion in response to chylomicrons, even in the presence of GW1100.Conclusions/interpretationChylomicrons stimulate incretin hormone secretion from GLUTag cells as well as from human and murine duodenal cultures. In GLUTag cells, the molecular pathway was found to involve LPL-mediated lipolysis, leading to the release of lipid species that activated FFA1 and elevated intracellular calcium.

Project description:RATIONALE:Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES:To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS:Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. MEASUREMENTS AND MAIN RESULTS:Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on β-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). CONCLUSIONS:Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.

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The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

Publications

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

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