Increased glycolysis affects ß-cell function and identity in aging and diabetes.
Mol Metab
; 55: 101414, 2022 01.
Article
en En
| MEDLINE
| ID: mdl-34871777
ABSTRACT
OBJECTIVE:
Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether ß-cell glucose metabolism is altered with aging and contributes to T2D.METHODS:
We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob/ob mice as aging models. As a diabetes model, we used db/db mice. The glucose responsiveness of insulin secretion and the [U-13C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of ß-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of ß-cell identity. ß cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1, a component of the shuttle. We analyzed Got1 KO ß cells as a model of increased glycolysis.RESULTS:
We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse ß cells. We also observed a metabolic commonality between aged and diabetic ß cells hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 (Nmnat2), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO ß cells showed increased glycolysis, ß-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO ß cells, we show that attenuation of glycolysis or Nmnat2 activity can restore ß-cell function and identity.CONCLUSIONS:
Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic ß cells, which may underlie age-related ß-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Envejecimiento
/
Células Secretoras de Insulina
/
Glucólisis
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Mol Metab
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón