Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes

Wigger, Leonore; Barovic, Marko; Brunner, Andreas-David; Marzetta, Flavia; Schöniger, Eyke; Mehl, Florence; Kipke, Nicole; Friedland, Daniela; Burdet, Frédéric; Kessler, Camille; Lesche, Mathias; Thorens, Bernard; Bonifacio, Ezio; Legido‐Quigley, Cristina; Hilaire, Pierre Barbier Saint; Delerive, Philippe; Dahl, Andreas; Klose, Christian; Gerl, Mathias J.; Simons, Kai; Aust, Daniela E.; Weitz, Jürgen; Distler, Marius; Schulte, Anke M.; Mann, Matthias; Ibberson, Mark; Solimena, Michele

doi:10.1038/s42255-021-00420-9

Cited by 98 publications

(95 citation statements)

References 69 publications

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“…Given the available data from individuals with T2D, it is now widely believed that a relative deficit of β-cells exists in this disease. The recently appreciated heterogeneity of T2D phenotypes and human β-cell mass [39][40][41][42] may help explain the ongoing debate as to the role of β-cell loss in T2D pathogenesis.…”

Section: β-Cell Loss In T2dmentioning

confidence: 99%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.

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Section: β-Cell Loss In T2dmentioning

confidence: 99%

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

et al. 2021

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“…Mitochondria provide the energy necessary for β-cell insulin release 4, 5 , and abnormalities in mitochondrial structure and bioenergetics have been observed in the β-cells of humans with type 2 diabetes (T2D; 6, 7 ). Further, mitochondrial defects have been recently found to precede the development of T2D in human β-cells 8 . Thus, strategies to understand and overcome mitochondrial dysfunction in β-cells are of great appeal for the treatment of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis

Sidarala

Zhu

Pearson

et al. 2021

Preprint

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Mitochondria are vital for β-cell function, yet the importance of mitochondrial fusion for glucose homeostasis is uncertain. Here, we report that the dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are critical for glucose-stimulated insulin secretion (GSIS). Whereas Mfn1 and Mfn2 individually were dispensable for glucose control, combined Mfn1/2 deletion in β-cells induced mitochondrial fragmentation, reduced mtDNA content, and impaired respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies revealed that Mfn1/2 control of glucose homeostasis is dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Further, mitofusin agonists rescued mtDNA content and GSIS in islets from db/db mice, a model of type 2 diabetes. Thus, Mfn1 and 2 act collectively to promote both optimal mitochondrial dynamics and mtDNA copy number in β-cells, and may be promising therapeutic targets to improve insulin release in diabetes.

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“…In response to this issue, high-quality human pancreata, obtained from deceased organ donors, are increasingly being procured in limited numbers through organizations such as the Network for Pancreatic Organ donors with Diabetes (nPOD) ( Campbell-Thompson et al, 2012 ) and, more recently, the NIH-supported Human Pancreas Analysis Program (HPAP; ( Kaestner et al, 2019 ). Additionally, important data are being collected from metabolically phenotyped pancreatectomized patients as living donors ( Wigger et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes

Cited by 98 publications

References 69 publications

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances

Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis

Single-cell analysis of the human pancreas in type 2 diabetes using multi-spectral imaging mass cytometry

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