Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

Panzer, Julia K.; Hiller, Helmut; Cohrs, Christian M.; Almaça, Joana; Enos, Stephen J.; Beery, Maria; Cechin, Sirlene; Drotar, Denise M.; Weitz, John R.; Santini, Jorge; Huber, Mollie K.; Qadir, Mirza Muhammad Fahd; Pastori, Ricardo L.; Domínguez‐Bendala, Juan; Phelps, Edward A.; Atkinson, Mark A.; Pugliese, Alberto; Caicedo, Alejandro; Kusmartseva, Irina; Speier, Stephan

doi:10.1172/jci.insight.134525

Cited by 55 publications

(66 citation statements)

References 46 publications

(67 reference statements)

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“…We have previously used this platform to monitor microvascular responses in mouse islets ex vivo ( 11 , 22 ). Similar to mouse pancreas slices, living human pancreas slices can also be produced from small pancreas pieces and used in physiological experiments acutely after slicing ( 26 ) or after long-term culture [at least 10 days ( 27 )]. We have recently performed dynamic hormone secretion assays and imaged intracellular calcium levels in living human pancreas slices to characterize endocrine cell function in individuals at different stages of type 1 diabetes ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

“…Similar to mouse pancreas slices, living human pancreas slices can also be produced from small pancreas pieces and used in physiological experiments acutely after slicing ( 26 ) or after long-term culture [at least 10 days ( 27 )]. We have recently performed dynamic hormone secretion assays and imaged intracellular calcium levels in living human pancreas slices to characterize endocrine cell function in individuals at different stages of type 1 diabetes ( 26 ). Living human pancreas slices have also enabled us to study how endocrine cells communicate with other cells in the human islet microenvironment such as islet resident macrophages ( 28 ).…”

Section: Introductionmentioning

confidence: 99%

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Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices

Gonçalves

Almaça

2021

Front. Endocrinol.

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Pancreatic islets are clusters of endocrine cells that secrete different hormones to regulate blood glucose levels. Efficient hormone secretion requires a close interaction of endocrine cells with their vascular system. Islets receive blood through feeding arteriole(s) that branch into capillaries made of endothelial cells covered by pericytes. While a lot is known about rodent islet blood vessels, the structure and function of the human islet microvasculature has been less investigated. In this study, we used living pancreas slices from non-diabetic human donors to examine the function of human islet blood vessels. Living human pancreas slices were incubated with a membrane permeant calcium indicator and pericytes/smooth muscle cells were visualized with a fluorescent antibody against the mural cell marker NG2 proteoglycan. By confocal microscopy, we simultaneously recorded changes in the diameter of lectin-labeled blood vessels and cytosolic calcium levels in mural cells in islets. We tested several stimuli with vasoactive properties, such as norepinephrine, endothelin-1 and adenosine and compared human vascular responses with those previously published for mouse islet blood vessels. Norepinephrine and endothelin-1 significantly constricted human islet feeding arterioles, while adenosine dilated them. Islet capillaries were less responsive and only 15–20% of the mouse and human islet capillary network showed vasomotion. Nevertheless, in these responsive regions, norepinephrine and endothelin-1 decreased both mouse and human islet capillary diameter. Changes in islet blood vessel diameter were coupled to changes in cytosolic calcium levels in adjacent mouse and human islet mural cells. Our study shows that mural cells in islets are the targets of different regulatory mechanisms of islet blood perfusion. Several alterations of the human islet microvasculature occur during diabetes progression. Elucidating their functional consequences in future studies will be critical for our understanding of disease pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices

Gonçalves

Almaça

2021

Front. Endocrinol.

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“…In T2D patients, the decrease in BCM is more modest (by 22–63%) [ 21 , 22 ]. In both forms of diabetes, BCM loss is preceded by progressive loss of beta cell function, as was confirmed by studies performed on pancreas slices from T1D organ donors [ 23 ]. It is thought that many beta cells are preserved as quiescent or “stunned” cells (i.e., degranulated or not releasing insulin) in both T2D [ 24 ] and T1D [ 17 , 18 , 25 ].…”

Section: Beta Cell Mass Evolution During Type 1 and Type 2 Diabetementioning

confidence: 70%

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Demine

Schulte

Territo

et al. 2020

IJMS

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There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.

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“…The development of pancreatic tissue slices has been shown to be useful to study human islet function under nearphysiological conditions [77]. The authors showed loss of insulin secretion and β cell mass at different stages of the disease in pancreas from organ donors.…”

Section: Box 3 Preclinical Approaches For β Cell Evaluation In Diabetesmentioning

confidence: 99%

Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes

Gurzov

Ahlgren

et al. 2020

Trends in Endocrinology & Metabolism

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A common feature in the pathophysiology of different types of diabetes is the reduction of β cell mass and/or impairment of β cell function. Diagnosis and treatment of type 1 and type 2 diabetes is currently hampered by a lack of reliable techniques to restore β cell survival, to improve insulin secretion, and to quantify β cell mass in patients. Current new approaches may allow us to precisely and specifically visualize β cells in vivo and provide viable therapeutic strategies to preserve, recover, and regenerate β cells. In this review, we discuss recent protective approaches for β cells and the advantages and limitations of current imaging probes in the field. Type 1 and Type 2 Diabetes (T1D and T2D) as a β Cell Pathology T1D and T2D, although arising from different etiologies, are each associated with physical and/or functional loss of insulin-secreting β cells [1-3]. T1D is described as a heterogeneous inflammatory disease characterized by infiltration of the pancreatic islets with a number of autoimmune cells (CD4+ and CD8+ T cells, macrophages, dendritic cells, and B cells) [4]. Recent evidence suggests that progression of islet infiltrates promotes β cell dysfunction (reduced first-phase insulin response) and later β cell elimination, which ultimately results in the onset of diabetes. Interestingly, it is now clear that residual β cell mass can be found several years after diagnosis. Thus, a desired strategy for T1D treatment should suppress β cell autoimmunity, along with protection and restoration of the remaining β cell mass. Currently, there are no clinically approved interventional therapies for treating the underlying autoimmunity and boosting β cell survival in T1D. T2D, however, is characterized by insulin resistance following progressive decline in β cell function and accumulation of islet amyloid polypeptide (IAPP, or amylin) in the pancreatic islets [2,5]. The pathology is far more complex, as a recent study on newly diagnosed diabetic subjects postulates a reclassification into five distinct clusters based on the metabolic profile and risk of complications; three of the different cluster are currently considered T2D [6]. The treatment of T2D is mainly limited to metformin monotherapy as the initial strategy to improve insulin sensitivity. When the patient cannot control glycemia by lifestyle and metformin, a pharmacology approach to increase β cell resistance and function will be required, as an alternative to chronic exogenous insulin injections. Highlights Pancreatic β cell failure is characteristic to both T1D and T2D. The JAK-STAT pathway is a promising target to prevent autoimmune β cell destruction. Several strategies are currently being tested to improve insulin production in T2D: preventing β cell death/dysfunction, enhancing β cell proliferation, ameliorating β cell dedifferentiation, and inducing transdifferentiation into β like cells. Imaging and diagnostic tools are required to improve the efficacy of current therapeutic strategies aimed at restoring β cell function. Nanotechnology...

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Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesis

Cited by 55 publications

References 46 publications

Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices

Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices

Beta Cell Imaging—From Pre-Clinical Validation to First in Man Testing

Novel Strategies to Protect and Visualize Pancreatic β Cells in Diabetes

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