Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas)

Rodolfo Guardado Mendoza, Carla Perego, Giovanna Finzi, Stefano La Rosa, Carlo Capella, Lilia M. Jimenez-Ceja, Licio A. Velloso, Mario J A Saad, Fausto Sessa, Federico Bertuzzi, Stefania Moretti, Edward J. Dick, Alberto M. Davalli, Franco Folli

Research output: Contribution to journalArticle

Abstract

Aims/hypothesis: The cellular composition of the islet of Langerhans is essential to ensure its physiological function. Morphophysiological islet abnormalities are present in type 2 diabetes but the relationship between fasting plasma glucose (FPG) and islet cell composition, particularly the role of delta cells, is unknown. We explored these questions in pancreases from baboons (Papio hamadryas) with FPG ranging from normal to type 2 diabetic values. Methods: We measured the volumes of alpha, beta and delta cells and amyloid in pancreatic islets of 40 baboons (Group 1 [G1]: FPG <4.44 mmol/l [n = 10]; G2: FPG = 4.44–5.26 mmol/l [n = 9]; G3: FPG = 5.27–6.94 mmol/l [n = 9]; G4: FPG > 6.94 mmol/l [n = 12]) and correlated islet composition with metabolic and hormonal variables. We also performed confocal microscopy including TUNEL, caspase-3, and anti-caspase cleavage product of cytokeratin 18 (M30) immunostaining, electron microscopy, and immuno-electron microscopy with anti-somatostatin antibodies in baboon pancreases. Results: Amyloidosis preceded the decrease in beta cell volume. Alpha cell volume increased ∼50% in G3 and G4 (p <0.05), while delta cell volume decreased in these groups by 31% and 39%, respectively (p <0.05). In G4, glucagon levels were higher, while insulin and HOMA index of beta cell function were lower than in the other groups. Immunostaining of G4 pancreatic sections with TUNEL, caspase-3 and M30 showed apoptosis of beta and delta cells, which was also confirmed by immuno-electron microscopy with anti-somatostatin antibodies. Conclusions/interpretation: In diabetic baboons, changes in islet composition correlate with amyloid deposition, with increased alpha cell and decreased beta and delta cell volume and number due to apoptosis. These data argue for an important role of delta cells in type 2 diabetes.

Original languageEnglish
Pages (from-to)1814-1826
Number of pages13
JournalDiabetologia
Volume58
Issue number8
DOIs
Publication statusPublished - Jun 7 2015

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Papio hamadryas
Somatostatin-Secreting Cells
Papio
Islets of Langerhans
Type 2 Diabetes Mellitus
Primates
Cell Death
Cell Size
Glucose
Fasting
Immunoelectron Microscopy
In Situ Nick-End Labeling
Somatostatin
Amyloid
Caspase 3
Pancreas
Anti-Idiotypic Antibodies
Apoptosis
Keratin-18
Amyloidosis

Keywords

  • Alpha cell
  • Amyloid
  • Apoptosis
  • Baboon
  • Beta cell
  • Delta cell
  • Islet of Langerhans
  • Islet remodelling
  • Non-human primates
  • Papio hamadryas
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). / Guardado Mendoza, Rodolfo; Perego, Carla; Finzi, Giovanna; La Rosa, Stefano; Capella, Carlo; Jimenez-Ceja, Lilia M.; Velloso, Licio A.; Saad, Mario J A; Sessa, Fausto; Bertuzzi, Federico; Moretti, Stefania; Dick, Edward J.; Davalli, Alberto M.; Folli, Franco.

In: Diabetologia, Vol. 58, No. 8, 07.06.2015, p. 1814-1826.

Research output: Contribution to journalArticle

Guardado Mendoza, R, Perego, C, Finzi, G, La Rosa, S, Capella, C, Jimenez-Ceja, LM, Velloso, LA, Saad, MJA, Sessa, F, Bertuzzi, F, Moretti, S, Dick, EJ, Davalli, AM & Folli, F 2015, 'Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas)', Diabetologia, vol. 58, no. 8, pp. 1814-1826. https://doi.org/10.1007/s00125-015-3625-5
Guardado Mendoza, Rodolfo ; Perego, Carla ; Finzi, Giovanna ; La Rosa, Stefano ; Capella, Carlo ; Jimenez-Ceja, Lilia M. ; Velloso, Licio A. ; Saad, Mario J A ; Sessa, Fausto ; Bertuzzi, Federico ; Moretti, Stefania ; Dick, Edward J. ; Davalli, Alberto M. ; Folli, Franco. / Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). In: Diabetologia. 2015 ; Vol. 58, No. 8. pp. 1814-1826.
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AU - Guardado Mendoza, Rodolfo

AU - Perego, Carla

AU - Finzi, Giovanna

AU - La Rosa, Stefano

AU - Capella, Carlo

AU - Jimenez-Ceja, Lilia M.

AU - Velloso, Licio A.

AU - Saad, Mario J A

AU - Sessa, Fausto

AU - Bertuzzi, Federico

AU - Moretti, Stefania

AU - Dick, Edward J.

AU - Davalli, Alberto M.

AU - Folli, Franco

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N2 - Aims/hypothesis: The cellular composition of the islet of Langerhans is essential to ensure its physiological function. Morphophysiological islet abnormalities are present in type 2 diabetes but the relationship between fasting plasma glucose (FPG) and islet cell composition, particularly the role of delta cells, is unknown. We explored these questions in pancreases from baboons (Papio hamadryas) with FPG ranging from normal to type 2 diabetic values. Methods: We measured the volumes of alpha, beta and delta cells and amyloid in pancreatic islets of 40 baboons (Group 1 [G1]: FPG <4.44 mmol/l [n = 10]; G2: FPG = 4.44–5.26 mmol/l [n = 9]; G3: FPG = 5.27–6.94 mmol/l [n = 9]; G4: FPG > 6.94 mmol/l [n = 12]) and correlated islet composition with metabolic and hormonal variables. We also performed confocal microscopy including TUNEL, caspase-3, and anti-caspase cleavage product of cytokeratin 18 (M30) immunostaining, electron microscopy, and immuno-electron microscopy with anti-somatostatin antibodies in baboon pancreases. Results: Amyloidosis preceded the decrease in beta cell volume. Alpha cell volume increased ∼50% in G3 and G4 (p <0.05), while delta cell volume decreased in these groups by 31% and 39%, respectively (p <0.05). In G4, glucagon levels were higher, while insulin and HOMA index of beta cell function were lower than in the other groups. Immunostaining of G4 pancreatic sections with TUNEL, caspase-3 and M30 showed apoptosis of beta and delta cells, which was also confirmed by immuno-electron microscopy with anti-somatostatin antibodies. Conclusions/interpretation: In diabetic baboons, changes in islet composition correlate with amyloid deposition, with increased alpha cell and decreased beta and delta cell volume and number due to apoptosis. These data argue for an important role of delta cells in type 2 diabetes.

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KW - Papio hamadryas

KW - Type 2 diabetes mellitus

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