GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

Saikia, Mridusmita; Holter, Marlena M.; Donahue, Leanne R.; Lee, Isaac S.; Zheng, Qiaonan C.; Wise, Journey L.; Todero, Jenna E; Phuong, Daryl J.; Garibay, Darline; Coch, Reilly W.; Sloop, Kyle W.; Garcı́a-Ocaña, Adolfo; Danko, Charles G.; Cummings, Bethany P.

doi:10.1172/jci.insight.141851

Cited by 36 publications

(49 citation statements)

References 114 publications

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“…6 ). We speculate that the harmine and harmine-exendin-4 combination may encourage alpha-to-beta cell transdifferentiation as has been reported in rodent islets (43,47–50). Documenting this possibility will require lineage tracing genetic studies which have been performed in rodent models using rodent alpha cell-specific gene promoters.…”

Section: Discussionsupporting

confidence: 55%

Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Rosselot

Alvarsson

Wang

et al. 2020

Preprint

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Since all diabetes results from reductions in numbers of functional pancreatic beta cells, beta cell regenerative drugs are required for optimal and scalable future diabetes treatment. While many diabetes drugs are in clinical use, none increases human beta cell numbers. We have shown that a combination of the DYRK1A inhibitor, harmine, with the GLP1 receptor agonist, exendin-4, markedly increases human beta cell proliferation in vitro. However, technological limitations have prevented assessment of human beta cell mass in vivo. Here, we describe a novel method that combines iDISCO+ tissue clearing, insulin immunolabeling, light sheet microscopy, and volumetric quantification of human beta cells transplanted into immunodeficient mice. We demonstrate a striking seven-fold in vivo increase in human beta cell mass in response to three months of combined harmine-exendin-4 combination infusion, accompanied by lower blood glucose levels, increased plasma human insulin concentrations and enhanced beta cell proliferation. These studies unequivocally demonstrate for the first time that pharmacologic human beta cell expansion is a realistic and achievable path to diabetes therapy, and provide a rigorous, entirely novel and reproducible tool for quantifying human beta cell mass in vivo.

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Section: Discussionsupporting

confidence: 55%

Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Rosselot

Alvarsson

Wang

et al. 2020

Preprint

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show abstract

“…The copyright holder for this preprint this version posted October 18, 2021. ; https://doi.org/10.1101/2021.10.17.464749 doi: bioRxiv preprint be clarified [29][30][31][32][33][34] , our observations may provide useful information to improve clinical human islet transplantation outcomes. GLP-1 is known to promote the survival of beta cells 35 and stimulate insulin secretion 35 .…”

Section: Discussionmentioning

confidence: 90%

“…The overall percentage GLP-1-positive cell population in human islet grafts is within the range of previously published human islet studies 27,28 , highlighting the potential roles of islet-derived incretins as autocrine or paracrine in islet transplantation. While the precise mechanism leading to GLP-1 production in alpha cells remains to be clarified [29][30][31][32][33][34] , our observations may provide useful information to improve clinical human islet transplantation outcomes. GLP-1 is known to promote the survival of beta cells 35 and stimulate insulin secretion 35 .…”

Section: Discussionmentioning

confidence: 92%

Elevated islet prohormone ratios as indicators of insulin dependency in islet transplant recipients

Chen¹,

Klimek‐Abercrombie²,

Potter³

et al. 2021

Preprint

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Autologous pancreatic islet transplantation is an established therapy for patients with chronic pancreatitis. However, the long-term transplant outcomes are modest. Identifying indicators of graft function will aid the preservation of transplanted islets and glycemic control. To this end, we analyzed beta cell prohormone peptide levels in a retrospective cohort of total pancreatectomy autologous islet transplant patients (n=28). Proinsulin-to-C-peptide (PI/C) and proIAPP-to-total IAPP (proIAPP/IAPP) ratios measured at 3 months post-transplant were significantly higher in patients who remained insulin dependent at 1 year follow-up. In a mouse model of human islet transplantation, recipient mice that later became hyperglycemic displayed significantly higher PI/C ratios than mice that remained normoglycemic. Histological analysis of islet grafts showed reduced insulin- and proinsulin-positive area, but elevated glucagon-positive area in grafts that experienced greater secretory demand. Increased prohormone convertase 1/3 was detected in glucagon-positive cells, and glucagon-like peptide 1 (GLP-1) area was elevated in grafts from mice that displayed hyperglycemia or elevated plasma PI/C ratio, demonstrating intra-islet incretin production in metabolically challenged human islet grafts. These data indicate that in failing grafts, alpha cell prohormone processing is likely altered, and incomplete beta cell prohormone processing may be an early indicator of insulin dependency.

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“… 6 Subsequently, scientists extended this concept to humans by using histological and single‐cell transcriptomic analyses. 7 , 8 Treatments of diabetes with diet control, 9 gastric bypass surgery, 10 and several antidiabetic therapies including intensive insulin therapy, 11 sodium‐glucose co‐transporter type 2 (SGLT2) inhibitor, 12 and glucagon‐like peptide‐1 (GLP‐1)‐based therapies 13 have been reported to promote β cell re‐differentiation in type 2 diabetic rodents and in cultured primary islets. Apart from the anti‐hyperglycemic strategies, anti‐inflammatory agents and inhibition of oxidative stress can also induce β cell identity restoration.…”

Section: Re‐differentiation Of the Dedifferentiated Pancreatic β Cellsmentioning

confidence: 99%

Regeneration of β cells from cell phenotype conversion among the pancreatic endocrine cells

Wei

Hong

2022

Chronic Diseases and Translational Medicine

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GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells

Cited by 36 publications

References 114 publications

Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging

Elevated islet prohormone ratios as indicators of insulin dependency in islet transplant recipients

Regeneration of β cells from cell phenotype conversion among the pancreatic endocrine cells

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