Background and aims: Studies in the last years indicate that the adult pancreas has an inherent regenerative capacity to produce new β-cells in response to increased metabolic demand or after injury. Different mechanisms of beta cell regeneration have been proposed to occur in the adult pancreas: i) replication from endogenous β-cell, ii) neogenesis from non-β-cells precursors and iii) β-cell formation by a transdifferentiation program. This last mechanism consists in the conversion of one endocrine cell type into another (non-beta cells into beta) by lineage reprogramming. It has been clearly identified in animal models; its existence and relevance in humans has never been demonstrated. Aim of this study was to examine the islet composition and architecture in control and diabetic subjects and to verify the existence of the transdifferentiation process in diabetic islets. Materials and methods: we collected human pancreatic sections from 12 normal (7M/5F, mean age 69±7 years) and 14 diabetic donors (8M/ 6F; mean age 66.4±10.34 years; diabetes)(paraffin embedded and cryopreserved). Sections were double/triple stained with antibodies directed against hormones (insulin, glucagon and somatostatin) and samples were analysed by confocal microscopy. The total islet area, β/α/δ-cell area, % of endocrine cells co-expressing insulin and glucagon (Indicative of cell transdifferentiation), frequency of heterologous and homologous contacts among different categories of endocrine cells were calculated by means of the image-Pro 3D analyser software. Results: In pancreatic sections derived from diabetic subjects there is a significant decrease of the total islet area (27±5% reduction compared to healthy controls; p=0.01) and cell density (15±7.9% reduction compared to healthy controls) due to b-cell death and b-amyloid accumulation. In particular, we detected a 49±7% (p<0.0001) reduction in the b-cell area of T2D subjects if compared to healthy controls (the reduction was particularly evident in the islet core). No significant modification of a-cell area was measured. The overlap coefficient between the insulin and glucagone staining (co-localization index between the two stainings in the same cell) was significantly increased in diabetic subjects compared to controls (T2D 0.36±0.03; CTR 0.20±0.04; p<0.05), thus suggesting the presence of a transdifferentiation process. No correlation was found between the overlap coefficient and subjects age, sex, diabetes duration, islet area. Interestingly, subjects with higher overlap coefficient were under insulin treatment, thus suggesting a correlation with a significant islet dysfunction. Conclusions: The validation of transdifferentiation as an alternative and important mechanism occurring in adult diabetic pancreases and the understanding of how this event can be manipulated may lead to the design of new biological and pharmacological treatments aimed at promoting the survival of residual β-cell and preventing diabetes progression and/or development.

Plasticity in islets of Langerhans in type 2 diabetes / C. Perego, S. Moretti, E. Di Cairano, C. Santi, S. La Rosa, F. Bertuzzi, F. Folli. - In: DIABETOLOGIA. - ISSN 1432-0428. - 58:Suppl. 1(2015), pp. 116-117. ((Intervento presentato al 51. convegno European Association for Studies of Diabetes. EASD tenutosi a Stockolm nel 2015.

Plasticity in islets of Langerhans in type 2 diabetes

C. Perego
Primo
;
S. Moretti
Secondo
;
E. Di Cairano;F. Folli
Ultimo
2015

Abstract

Background and aims: Studies in the last years indicate that the adult pancreas has an inherent regenerative capacity to produce new β-cells in response to increased metabolic demand or after injury. Different mechanisms of beta cell regeneration have been proposed to occur in the adult pancreas: i) replication from endogenous β-cell, ii) neogenesis from non-β-cells precursors and iii) β-cell formation by a transdifferentiation program. This last mechanism consists in the conversion of one endocrine cell type into another (non-beta cells into beta) by lineage reprogramming. It has been clearly identified in animal models; its existence and relevance in humans has never been demonstrated. Aim of this study was to examine the islet composition and architecture in control and diabetic subjects and to verify the existence of the transdifferentiation process in diabetic islets. Materials and methods: we collected human pancreatic sections from 12 normal (7M/5F, mean age 69±7 years) and 14 diabetic donors (8M/ 6F; mean age 66.4±10.34 years; diabetes)(paraffin embedded and cryopreserved). Sections were double/triple stained with antibodies directed against hormones (insulin, glucagon and somatostatin) and samples were analysed by confocal microscopy. The total islet area, β/α/δ-cell area, % of endocrine cells co-expressing insulin and glucagon (Indicative of cell transdifferentiation), frequency of heterologous and homologous contacts among different categories of endocrine cells were calculated by means of the image-Pro 3D analyser software. Results: In pancreatic sections derived from diabetic subjects there is a significant decrease of the total islet area (27±5% reduction compared to healthy controls; p=0.01) and cell density (15±7.9% reduction compared to healthy controls) due to b-cell death and b-amyloid accumulation. In particular, we detected a 49±7% (p<0.0001) reduction in the b-cell area of T2D subjects if compared to healthy controls (the reduction was particularly evident in the islet core). No significant modification of a-cell area was measured. The overlap coefficient between the insulin and glucagone staining (co-localization index between the two stainings in the same cell) was significantly increased in diabetic subjects compared to controls (T2D 0.36±0.03; CTR 0.20±0.04; p<0.05), thus suggesting the presence of a transdifferentiation process. No correlation was found between the overlap coefficient and subjects age, sex, diabetes duration, islet area. Interestingly, subjects with higher overlap coefficient were under insulin treatment, thus suggesting a correlation with a significant islet dysfunction. Conclusions: The validation of transdifferentiation as an alternative and important mechanism occurring in adult diabetic pancreases and the understanding of how this event can be manipulated may lead to the design of new biological and pharmacological treatments aimed at promoting the survival of residual β-cell and preventing diabetes progression and/or development.
Diabetes, Islet of Langerhans, transdifferentiation
Settore BIO/09 - Fisiologia
Settore MED/13 - Endocrinologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/324607
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