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

Abstract

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.

G protein–coupled receptor kinase 6 (GRK6) regulates insulin processing and secretion via effects on proinsulin conversion to insulin

“…Moreover, MIN6 cells with β-arrestin2 knockdown and mice with β-arrestin2 KO in β-cells have impaired glucose-stimulated insulin secretion (GSIS) from inactivation of calmodulin kinase II (CAMKII) ( 27 ). This is similar to that seen in mice with pancreatic deletion of GRK2, where glucose intolerance and diminished insulin secretion is observed ( 28 ). Since β-arrestin function is often preceded by GPCR phosphorylation by GRKs, these non-GPCR pathways suggest alternative modes to β-arrestin activation.…”

The Role of G Protein–Coupled Receptors and Receptor Kinases in Pancreaticβ-Cell Function and Diabetes

“…Interestingly, a subsequent study reported that silencing GRK2 in MIN6 cells led to diminution of GSIS that was recovered by PTX treatment ( Snyder et al, 2021 ). This suggested that loss of GRK2-mediated regulation/phosphorylation of G i -coupled receptors allowed these receptors to influence β -cell secretory tone by maintaining G i signaling and inhibiting GSIS.…”

“…Furthermore, in mice with pancreatic-specific GRK2 knockout, a similar effect was seen, where insulin secretion was reduced and cardiac function attenuated, with both exacerbated by a high-fat diet. Essentially, GRK2 had a positive effect on insulin secretion by keeping G i signaling in check ( Snyder et al, 2021 ). This contrasts with previous reports that show GRK2 inhibition as having beneficial outcomes in metabolic parameters, such as glucose tolerance ( Usui et al, 2004 ; Vila-Bedmar et al, 2015 ; Taguchi et al, 2017 ; Cipolletta et al, 2019 ).…”

Double life: How GRK2 and β-arrestin signaling participate in diseases

“…Nonetheless, β-adrenergic stimulation revealed increased sensitivity of inotropic and lusitropic tachyphylaxis in the adult heart, suggesting the importance of cardiac GRK2 in protective effects in cardiomyopathy induced by catecholamine toxicity [ 115 ]. Further studies, using pancreatic-specific GRK2 knockout mice revealed a decrease in glucose-mediated insulin secretion linked to decreased calcium influx in pancreatic islets [ 123 ]. Whether this is developmentally linked remains to be further investigated but may be an important contributor to diabetes disease progression.…”

“…Overall preventing GRK2 upregulation in the heart appears to be a viable strategy to treat HF. Notably, recent studies have shown that whole pancreas GRK2 knockdown leads to decreased glucose-mediated insulin secretion, increased weight gain when in a high fat regimen, and decreased cardiac function [ 123 ]. Kidney inhibition of GRK2 has also been reported to negatively impact kidney function and blood pressure [ 136 ].…”