Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Mateus Gonçalves, Luciana; Fahd Qadir, Mirza Muhammad; Boulina, Maria; Makhmutova, Madina; Pereira, Elizabeth; Almaça, Joana

doi:10.1016/j.celrep.2023.112913

Cited by 8 publications

(3 citation statements)

References 86 publications

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“…Efficient microvascular function and tight control of blood flow are accordingly essential to pancreatic function, and impairment of pericyte and capillary signaling as well as structural microvascular abnormalities are early events in the pathogenesis of diabetes. As such, the loss of blood flow control in pancreatic islets could be a key event that impacts nutrient sensing, hormone release, and the timely control of glycemic status ( Almaça et al, 2018 ; Gonçalves et al, 2023 ). The resulting derangements in insulin signaling and blood glucose levels in turn will have a range of further effects that could compromise efficient energy matching to local metabolic demands and contribute to multiorgan functional decline.…”

Section: Ems Uncoupling As a Driver Of Organ Failure Statesmentioning

confidence: 99%

Electro-metabolic signaling

Longden,

Lederer

2024

Journal of General Physiology

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Precise matching of energy substrate delivery to local metabolic needs is essential for the health and function of all tissues. Here, we outline a mechanistic framework for understanding this critical process, which we refer to as electro-metabolic signaling (EMS). All tissues exhibit changes in metabolism over varying spatiotemporal scales and have widely varying energetic needs and reserves. We propose that across tissues, common signatures of elevated metabolism or increases in energy substrate usage that exceed key local thresholds rapidly engage mechanisms that generate hyperpolarizing electrical signals in capillaries that then relax contractile elements throughout the vasculature to quickly adjust blood flow to meet changing needs. The attendant increase in energy substrate delivery serves to meet local metabolic requirements and thus avoids a mismatch in supply and demand and prevents metabolic stress. We discuss in detail key examples of EMS that our laboratories have discovered in the brain and the heart, and we outline potential further EMS mechanisms operating in tissues such as skeletal muscle, pancreas, and kidney. We suggest that the energy imbalance evoked by EMS uncoupling may be central to cellular dysfunction from which the hallmarks of aging and metabolic diseases emerge and may lead to generalized organ failure states—such as diverse flavors of heart failure and dementia. Understanding and manipulating EMS may be key to preventing or reversing these dysfunctions.

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Section: Ems Uncoupling As a Driver Of Organ Failure Statesmentioning

confidence: 99%

Electro-metabolic signaling

Longden,

Lederer

2024

Journal of General Physiology

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“…Alternative approaches, such as the live tissue slice preparation, now enable investigation of islets within their tissue environment from T1D, AAb+, and ND donors [29][30][31][32] . Slices from pancreatic tissue retain both the endocrine and exocrine compartments, with islets surrounded by acinar cells 33 , preserved vasculature 31,34 , and extracellular matrix (ECM) components 35 . This preparation facilitates the investigation of the collective function of endocrine cells irrespective of the disease stage (i.e., immune infiltration and degree of beta-cell destruction) as well as acinar tissue from the same donor or sample.…”

Section: Introductionmentioning

confidence: 99%

Impaired islet function with normal exocrine enzyme secretion is consistent across the head, body, and tail pancreas regions in type 1 diabetes

Drotar,

Mojica-Avila,

Bloss

et al. 2024

Preprint

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Histopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigated in situ glucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in no diabetes (ND, n=15), single islet autoantibody-positive (1AAb+, n=7), and type 1 diabetes donors (T1D, <14 months duration, n=5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features were comparable across the regions in ND. In T1D, insulin secretion and beta-cell volume were significantly reduced within all regions, while glucagon and enzymes were unaltered. Beta-cell volume was lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ were consistent across PH, PB and PT. This study supports low inter-regional variation in pancreas slice function and potentially, increased metabolic demand in 1AAb+.

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“… 27 , 28 Alternative approaches, such as live tissue slice preparation, now enable investigation of islets within their tissue environment from T1D, AAb+, and ND donors. 29 – 32 Pancreas slices retain tissue architecture with islets surrounded by acinar cells, 33 preserved vasculature, 31 , 34 and extracellular matrix, 35 facilitating the investigation of the collective function of endocrine cells and acinar tissue simultaneously.…”

Section: Introductionmentioning

confidence: 99%

Impaired islet function and normal exocrine enzyme secretion occur with low inter-regional variation in type 1 diabetes

Drotar,

Mojica-Avila,

Bloss

et al. 2024

Cell Reports

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Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Cited by 8 publications

References 86 publications

Electro-metabolic signaling

Electro-metabolic signaling

Impaired islet function with normal exocrine enzyme secretion is consistent across the head, body, and tail pancreas regions in type 1 diabetes

Impaired islet function and normal exocrine enzyme secretion occur with low inter-regional variation in type 1 diabetes

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