Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Abstract

Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.The precise control of blood glucose is dependent on the islets of Langerhans located within the pancreas. Pancreatic islets are complex structures consisting of several types of cells, including insulin-producing β-cells, glucagon-producing α-cells, and somatostatin-producing α-cells. After feeding, nutrients stimulate insulin release by the β-cell and the circulating hormone acts on peripheral tissues lowering blood glucose. The full stimulation of insulin secretion after food intake depends on the incretin effect of gut-derived peptide hormones and paracrine signaling within the islet 1 .We and others discovered that two classic gut hormones, glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), are also produced by pancreatic islets 2-5 . GLP-1 is a peptide hormone mainly secreted by intestinal L-cells and is known to decrease blood glucose levels by enhancing β-cell insulin secretion 6 . CCK is a peptide hormone mainly secreted by intestinal I-cells and is involved in the digestion of nutrients 7 and regulation of food intake 8 . The production of both GLP-1 and CCK in the islet has been associated with β-cell expansion and survival in response to metabolic stress 5,9 . While each of these gut-derived hormones can contribute to improvements in glucose homeostasis 10,11 , it is unclear whether their local production in the islet contributes to β-cell function. Moreover, it is unknown whether CCK stimulates insulin release in human islets. Here, we describe experiments with GLP-1 and CCK receptor antagonists in isolated mouse and human islets to ass...

Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity/Type 2 Diabetes

“…In another study, SKIP-deficient mice improved glucose tolerance by increasing insulin and GLP-1 secretion [ 92 ], which suggests that SKIP deficiency in mice allow SphK1 to better regulate glucose tolerance. However, it remains to be established whether SKIP is acting only at the level of intestinal L cells or on the pancreatic β cell since it is already known that islet-derived GLP-1 is necessary for glucose-stimulated insulin secretion [ 93 ]. Not surprisingly, a consensus on the role of the SphK1/S1P axis in β-cells has not been reached.…”

Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1

“…In a study using non-diabetic C57BL/6 J mice, researchers identified a subpopulation of GLP-1 expressing alpha cells in dispersed islets. 40 As these studies used isolated primary islet samples, it has been suggested that islet-isolation and culturing may cause sufficient islet stress to induce GLP-1. This stress-induced GLP-1 production may be a potential mechanism to prevent further islet cell damage.…”

“…In a study using non-diabetic C57BL/6 J mice, researchers identified a subpopulation of GLP-1 expressing alpha cells in dispersed islets. 40 …”

“… 41 Indeed, GCGR null mice have reduced fasting blood-glucose with no increased risk of hypoglycemia, whereas GCG null mice had a comparable metabolic phenotype to GCGR/GLP-1R double KO mice, 41 , 57 where both GCG null and GCGR/GLP-1R double KO mice exhibit mild fasting hyperglycemia and increases in insulin secretion. 40 , 41 In order to assess the specific effects of GLP-1 production in alpha cells, researchers have used genetic and pharmacological approaches to target PCSK1 and the GLP-1R.…”

Cell Heterogeneity and Paracrine Interactions in Human Islet Function: A Perspective Focused in β-Cell Regeneration Strategies

“…This is classically known to be mediated by glucagon signaling ( 10 ), which activates human β-cell G protein-coupled receptors (GPCR) of class B, including glucagon receptor (GCGR), and glucagon-like peptide 1 receptor (GLP-1R), promoting insulin secretion by an increase in cyclic AMP and the recruitment of insulin granules ( 50 ). However, GLP-1 is also secreted by human α-cells ( 52 – 54 ) and necessary for insulin secretion in human islets, as GLP-1R antagonism blunted glucose stimulated insulin secretion (GSIS) in vitro ( 54 ). Moreover, GLP-1 can elicit synchronous intracellular calcium oscillations in human whole islets ( 55 ), suggesting an important role of this hormone and the location of α-cells within the islet to obtain pulsatile and synchronized insulin secretion.…”