Cholecystokinin expression in the developing and regenerating pancreas and intestine

Liu, G; Pakala, SV; Gu, Danling; Krahl, Troy; Mocnik, Lorraine; Sarvetnick, Nora

doi:10.1677/joe.0.1690233

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…Furthermore, we demonstrate that intra-islet GLP-1 signaling between α to β-cell is necessary for normal insulin secretion.CCK signaling in mouse and human islets. CCK is another peptide hormone commonly expressed in neuroendocrine cells in the gut, yet rodent pancreatic islets also express and secrete CCK under conditions of metabolic stress such as obesity and insulin resistance 5,18,19 . Here, we confirmed our previous findings 5 that Cck is up-regulated in leptin-deficient obese mouse islets (ob/ob) (Fig.…”

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confidence: 99%

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

Souza

Tang

Yadev

et al. 2020

Sci Rep

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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...

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confidence: 99%

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

Souza

Tang

Yadev

et al. 2020

Sci Rep

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“…It is best known for the stimulation of exocrine pancreas enzyme secretion but has also been shown to stimulate adaptive pancreatic growth in neonatal and adult rodent models [22]. Little research exists on the role of CCK during pancreatic development, especially in sheep; however, studies in mice have shown the expression of CCK as a marker of endocrine cell lineage early on, as well as expression in acinar and α-cells in later stages [23]. A study utilizing human pancreatic tissues reported that CCK-B/Gastrin receptors mediate the autocrine effects of gastrin on developing islets in the fetal pancreas, implicating an important role for CCK in the regulation of glucose homeostasis [24].…”

Section: Discussionmentioning

confidence: 99%

Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation

Kennedy,

Lynch,

Tanner

et al. 2024

IJMS

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Glucose, the primary energy substrate for fetal oxidative processes and growth, is transferred from maternal to fetal circulation down a concentration gradient by placental facilitative glucose transporters. In sheep, SLC2A1 and SLC2A3 are the primary transporters available in the placental epithelium, with SLC2A3 located on the maternal-facing apical trophoblast membrane and SLC2A1 located on the fetal-facing basolateral trophoblast membrane. We have previously reported that impaired placental SLC2A3 glucose transport resulted in smaller, hypoglycemic fetuses with reduced umbilical artery insulin and glucagon concentrations, in addition to diminished pancreas weights. These findings led us to subject RNA derived from SLC2A3-RNAi (RNA interference) and NTS-RNAi (non-targeting sequence) fetal pancreases to qPCR followed by transcriptomic analysis. We identified a total of 771 differentially expressed genes (DEGs). Upregulated pathways were associated with fat digestion and absorption, particularly fatty acid transport, lipid metabolism, and cholesterol biosynthesis, suggesting a potential switch in energetic substrates due to hypoglycemia. Pathways related to molecular transport and cell signaling in addition to pathways influencing growth and metabolism of the developing pancreas were also impacted. A few genes directly related to gluconeogenesis were also differentially expressed. Our results suggest that fetal hypoglycemia during the first half of gestation impacts fetal pancreas development and function that is not limited to β cell activity.

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“…The effect of CCK during embryonic development has mainly focused on mammals. Previous studies in mice reported that CCK might promote the development of pancreas and intestine (Liu et al., ; Zhai et al., ; Guo et al., ) and may play an important regulatory function in brain embryogenesis and the fertilization process (Persson et al., ; Giacobini and Wray, ). Cholecystokinin mRNA expression in fish embryos has only been studied in grass carp, in which it could be detected in fertilized eggs and then decreased significantly after later cleavage stage during the embryonic development, but the expression levels in embryonic stages were significantly higher than those in larval stages (Feng et al., ).…”

Section: Discussionmentioning

confidence: 99%

Ontogeny expression of ghrelin, neuropeptide Y and cholecystokinin in blunt snout bream, Megalobrama amblycephala

Ping

Feng

Zhang

et al. 2013

Animal Physiology Nutrition

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Ghrelin, neuropeptide Y (NPY) and cholecystokinin (CCK) all have important roles in the regulation of feeding in fish and mammals. To better understand the role of the three peptides in appetite regulation in the early developmental stages of blunt snout bream (Megalobrama amblycephala), partial cDNA sequences of ghrelin, NPY and CCK genes were cloned. And then, real-time quantitative PCR and RT-PCR were used to detect and quantify the mRNA expressions of these genes from zygotes to larvae of 50 days after hatching (DAH). Ghrelin, NPY and CCK were all expressed throughout the embryonic and larval development stages, and the expression levels were higher in larval stages than in embryonic stages. Ghrelin and NPY mRNA expressions were upregulated at 1, 3, 5 DAH, while CCK mRNA expression was reduced significantly at 3 DAH. The mRNA expression levels of three genes in larvae varied significantly until 30 DAH. In adult fish, all three peptides were detected to be expressed in brain and several peripheral tissues. Ghrelin mRNA was mainly expressed in the intestine, whereas NPY and CCK mRNAs were mainly expressed in the brain. Taken together, these results indicate that ghrelin, NPY and CCK may have roles in early development and participate in the regulation of feeding of larvae in blunt snout bream and will be helpful for further investigation into feed intake regulation in adults of this species.

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Cholecystokinin expression in the developing and regenerating pancreas and intestine

Cited by 10 publications

References 23 publications

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

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

Fetal Hypoglycemia Induced by Placental SLC2A3-RNA Interference Alters Fetal Pancreas Development and Transcriptome at Mid-Gestation

Ontogeny expression of ghrelin, neuropeptide Y and cholecystokinin in blunt snout bream, Megalobrama amblycephala

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