GRK2 contributes to glucose mediated calcium responses and insulin secretion in pancreatic islet cells

Autor: Tian Yuzhen, Atreju I Lackey, Priscila Y. Sato, G. Schuyler Brown, Melisa Diaz, Jonathan Snyder
Rok vydání: 2021
Předmět:
0301 basic medicine
G-Protein-Coupled Receptor Kinase 2
medicine.medical_treatment
Type 2 diabetes
Mice
0302 clinical medicine
Insulin-Secreting Cells
Insulin Secretion
Cyclic AMP
Mice
Knockout
Multidisciplinary
geography.geographical_feature_category
Chemistry
Diabetes
Islet
medicine.anatomical_structure
Medicine
Pancreas
Cell signalling
medicine.medical_specialty
Science
Down-Regulation
Heart failure
Diet
High-Fat
Glucagon
Article
Cell Line
Islets of Langerhans
03 medical and health sciences
Internal medicine
Diabetes mellitus
Glucose Intolerance
medicine
Animals
Obesity
geography
Insulin
Pancreatic islets
Glucose Tolerance Test
medicine.disease
Glucose
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Calcium
Lipid Peroxidation
Metabolic syndrome
030217 neurology & neurosurgery
Zdroj: Scientific Reports
Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
ISSN: 2045-2322
DOI: 10.1038/s41598-021-90253-z
Popis: Diabetes is a metabolic syndrome rooted in impaired insulin and/or glucagon secretory responses within the pancreatic islets of Langerhans (islets). Insulin secretion is primarily regulated by two key factors: glucose-mediated ATP production and G-protein coupled receptors (GPCRs) signaling. GPCR kinase 2 (GRK2), a key regulator of GPCRs, is reported to be downregulated in the pancreas of spontaneously obesogenic and diabetogenic mice (ob/ob). Moreover, recent studies have shown that GRK2 non-canonically localizes to the cardiac mitochondrion, where it can contribute to glucose metabolism. Thus, islet GRK2 may impact insulin secretion through either mechanism. Utilizing Min6 cells, a pancreatic ß-cell model, we knocked down GRK2 and measured glucose-mediated intracellular calcium responses and insulin secretion. Silencing of GRK2 attenuated calcium responses, which were rescued by pertussis toxin pre-treatment, suggesting a Gαi/o-dependent mechanism. Pancreatic deletion of GRK2 in mice resulted in glucose intolerance with diminished insulin secretion. These differences were due to diminished insulin release rather than decreased insulin content or gross differences in islet architecture. Furthermore, a high fat diet feeding regimen exacerbated the metabolic phenotype in this model. These results suggest a new role for pancreatic islet GRK2 in glucose-mediated insulin responses that is relevant to type 2 diabetes disease progression.
Databáze: OpenAIRE
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