ROCK1 regulates insulin secretion from ß-cells.
Mol Metab
; 66: 101625, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36374631
ABSTRACT
OBJECTIVE:
The endocrine pancreatic ß-cells play a pivotal role in maintaining whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate ß-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis.METHODS:
Mice lacking ROCK1 in pancreatic ß-cells (RIP-Cre; ROCK1loxP/loxP, ß-ROCK1-/-) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. An insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from ß-ROCK1-/- mice or ß-cell lines with knockdown of ROCK1 was also evaluated. A proximity ligation assay was performed to determine the physical interactions between PK and ROCK1.RESULTS:
Mice with a deficiency of ROCK1 in pancreatic ß-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, ß-ROCK1-/- mice displayed a progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium and ATP levels and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown ß-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that glucose stimulation in ß-cells greatly enhanced ROCK1 binding to PK.CONCLUSIONS:
Our findings demonstrate that ß-cell ROCK1 is essential for glucose-stimulated insulin secretion and for glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Piruvato Quinase
/
Quinases Associadas a rho
/
Secreção de Insulina
/
Insulina
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article