Inter-organ communication and regulation of beta cell function

Hussain, Mehboob A.; Akalestou, Elina; Song, Wonkyong

doi:10.1007/s00125-015-3862-7

Cited by 25 publications

(17 citation statements)

References 84 publications

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“…Thus, locally released rather than circulating GLP-1 may be important for regulating insulin secretion. Consistent with our results in humans, rodent studies have shown that beta cell GLP-1 receptors are not required to maintain normal oral glucose tolerance and GLP-1 receptor signaling is not required for the reduction of body weight after RYGB [57–59]. …”

Section: Discussionsupporting

confidence: 90%

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

et al. 2016

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Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of enteroendocrine cells located in the proximal small intestine. Many effects of Xen are mediated by neurotensin receptor-1 on neurons. In healthy humans with normal glucose tolerance (NGT), Xen administration causes diarrhea and inhibits postprandial glucagon-like peptide-1 (GLP-1) release but not insulin secretion. This study determines i) if Xen has similar effects in humans with Roux-en-Y gastric bypass (RYGB) and ii) whether neural pathways potentially mediate effects of Xen on glucose homeostasis. Eight females with RYGB and no history of type 2 diabetes received infusions with 0, 4 or 12 pmoles Xen/kg/min with liquid meals on separate occasions. Plasma glucose and gastrointestinal hormone levels were measured and insulin secretion rates calculated. Pancreatic polypeptide and neuropeptide Y levels were surrogate markers for parasympathetic input to islets and sympathetic tone, respectively. Responses were compared to those in well-matched non-surgical participants with NGT from our earlier study. Xen similarly increased pancreatic polypeptide and neuropeptide Y responses in patients with and without RYGB. In contrast, the ability of Xen to inhibit GLP-1 release and cause diarrhea was severely blunted in patients with RYGB. With RYGB, Xen had no statistically significant effect on glucose, insulin secretory, GLP-1, glucose-dependent insulinotropic peptide, and glucagon responses. However, insulin and glucose-dependent insulinotropic peptide secretion preceded GLP-1 release suggesting circulating GLP-1 does not mediate exaggerated insulin release after RYGB. Thus, Xen has unmasked neural circuits to the distal gut that inhibit GLP-1 secretion, cause diarrhea, and are altered by RYGB.

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Section: Discussionsupporting

confidence: 90%

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

et al. 2016

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“…It is possible, however, that signals from other tissues may modulate β-cell function in Irp2 −/− mice. Iron has been shown to negatively regulate adiponectin and leptin expression in adipocytes 39,40 , and these adipokines are known to facilitate β-cell proliferation and survival [41][42][43] . In addition, Cdkal1 deficiency has been shown to regulate adipocyte differentiation in murine 3T3-L1 cells 44 and mitochondrial function in adipocyte-specific Cdkal1 KO mice 45 as well as regulation of growth hormone expression in pituitary adenomas 46 , suggesting that reduced Cdkal1 function in cell types other than β cells might modulate β-cell function in Irp2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

et al. 2020

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Regulation of cellular iron homeostasis is crucial as both iron excess and deficiency cause hematological and neurodegenerative diseases. Here we show that mice lacking ironregulatory protein 2 (Irp2), a regulator of cellular iron homeostasis, develop diabetes. Irp2 post-transcriptionally regulates the iron-uptake protein transferrin receptor 1 (TfR1) and the iron-storage protein ferritin, and dysregulation of these proteins due to Irp2 loss causes functional iron deficiency in β cells. This impairs Fe-S cluster biosynthesis, reducing the function of Cdkal1, an Fe-S cluster enzyme that catalyzes methylthiolation of t 6 A37 in tRNA Lys UUU to ms 2 t 6 A37. As a consequence, lysine codons in proinsulin are misread and proinsulin processing is impaired, reducing insulin content and secretion. Iron normalizes ms 2 t 6 A37 and proinsulin lysine incorporation, restoring insulin content and secretion in Irp2 −/− β cells. These studies reveal a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans.

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“…To achieve glucose homeostasis, pancreatic beta cells integrate a multitude of metabolic, hormonal and neural cues to determine the extent of glucose-dependent insulin release. 10 It has been discovered that pancreatic beta cells also integrate microbial signals to modulate insulin output. So far, two independent examples have been discovered.…”

Section: Introductionmentioning

confidence: 99%

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

et al. 2019

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Long-range communication between intestinal symbiotic bacteria and extra-intestinal organs can occur through circulating bacterial signal molecules, through neural circuits, or through cytokines or hormones from host cells. Here we report that Nod1 ligands derived from intestinal bacteria act as signal molecules and directly modulate insulin trafficking in pancreatic beta cells. The cytosolic peptidoglycan receptor Nod1 and its downstream adapter Rip2 are required for insulin trafficking in beta cells in a cellautonomous manner. Mechanistically, upon recognizing cognate ligands, Nod1 and Rip2 localize to insulin vesicles, recruiting Rab1a to direct insulin trafficking through the cytoplasm. Importantly, intestinal lysozyme liberates Nod1 ligands into the circulation, thus enabling long-range communication between intestinal microbes and islets. The intestine-islet crosstalk bridged by Nod1 ligands modulates host glucose tolerance. Our study defines a new type of inter-organ communication based on circulating bacterial signal molecules, which has broad implications for understanding the mutualistic relationship between microbes and host.

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Inter-organ communication and regulation of beta cell function

Cited by 25 publications

References 84 publications

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

Metabolic responses to xenin-25 are altered in humans with Roux-en-Y gastric bypass surgery

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification

Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells

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