Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis

Abstract

Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels

“…; Traub et al. ). ω ‐Agatoxin was purchased from the Peptide Institute (Minoh‐shi Osaka, Japan), 8‐Br‐Rp‐cAMPS (Rp‐cAMPS) from BioLog Life Science Institute (Bremen, Germany) and CYN154806 from Tocris Bioscience (Bristol, UK).…”

“…GLP-1 (7-36) amide was from Bachem (Weil am Rhein, Germany). We used GLP-1 at a concentration of 10 nM, in keeping with other islet cell studies (Bode et al 1999;Tsuboi et al 2003;de Heer et al 2008;De Marinis et al 2010;Shigeto et al 2015;Traub et al 2017). x-Agatoxin was purchased from the Peptide Institute (Minoh-shi Osaka, Japan), 8-Br-Rp-cAMPS (Rp-cAMPS) from Bio-Log Life Science Institute (Bremen, Germany) and CYN154806 from Tocris Bioscience (Bristol, UK).…”

Islet prohormone processing in health and disease

“…In humans, islet GLP‐1 secretion, and effects of GLP‐1 on potentiation of glucose‐stimulated insulin secretion remain intact in T2D, suggesting α‐cell upregulation of PC1/3 is an endogenous adaptive mechanism to protect and enhance β‐cells during stress . IL‐6 and Sdf1 have both been proposed to induce α‐cell Pc1/3 expression and GLP‐1 release in states of islet stress . The importance of stress‐induced α‐cell Pc1/3 expression was recently shown in a cell‐specific Pcsk1 knockout mouse, where α‐cell Pc1/3 was relatively dispensable in healthy islets, but in mice challenged with high‐fat diet and low dose STZ (a model of islet inflammation and partial β‐cell loss), the lack of α‐cell Pc1/3 and its accompanying altered proglucagon processing resulted in worsened glucose tolerance and reduced insulin secretion .…”

Time zones of pancreatic islet metabolism

“…81 Therefore, studies of α-cell physiology, regulation of glucagon secretion and most importantly molecular and functional interactions between αand β-cells have increasingly caught attention, in particular with respect to the development and management of diabetes mellitus. [82][83][84][85][86][87][88] Although fundamental aspects concerning the circadian control of transcription and functional regulation in the context of the intact pancreatic islet have been largely explored (as highlighted in the previous chapter), studies aiming to zoom into pancreatic islet cells in order to decipher circadian clock function in different islet cell types have only recently emerged. Our own recent study focuses on the molecular characterization of the αand β-cellular clocks, their interactions, impact on gene transcription and islet hormone secretion.…”