Tyrosine nitration of glucagon impairs its function: Extending the role of heme in T2D pathogenesis

• Published in: Journal of inorganic biochemistry 2024-06, Vol.255, p.112519, Article 112519
• Main Authors: Yin, Xiaoying, Ni, Guoqi, Zhang, Xuan, Fu, Shitao, Li, Hailing, Gao, Zhonghong
• Format: Article
• Language: English
• Subjects: cAMP; Diabetes Mellitus, Type 2 - metabolism; Glucagon; Glucagon - metabolism; Glucagon - pharmacology; Glucose - metabolism; Glucose-stimulated insulin secretion; Heme; Heme - metabolism; Humans; Insulin - metabolism; Islets of Langerhans - metabolism; Type 2 diabetes; Tyrosine - chemistry; Tyrosine nitration
• ISSN: 0162-0134; 1873-3344; 1873-3344
• DOI: 10.1016/j.jinorgbio.2024.112519

New studies raise the possibility that the higher glucagon (GCG) level present in type 2 diabetes (T2D) is a compensatory mechanism to enhance β-cell function, rather than induce dysregulated glucose homeostasis, due to an important role for GCG that acts directly within the pancreas on insulin secretion by intra-islet GCG signaling. However, in states of poorly controlled T2D, pancreatic α cell mass increases (overproduced GCG) in response to insufficient insulin secretion, indicating decreased local GCG activity. The reason for this decrease is not clear. Recent evidence has uncovered a new role of heme in cellular signal transduction, and its mechanism involves reversible binding of heme to proteins. Considering that protein tyrosine nitration in diabetic islets increases and glucose-stimulated insulin secretion (GSIS) decreases, we speculated that heme modulates GSIS by transient interaction with GCG and catalyzing its tyrosine nitration, and the tyrosine nitration may impair GCG activity, leading to loss of intra-islet GCG signaling and markedly impaired insulin secretion. Data presented here elucidate a novel role for heme in disrupting local GCG signaling in diabetes. Heme bound to GCG and induced GCG tyrosine nitration. Two tyrosine residues in GCG were both sensitive to the nitrating species. Further, GCG was also demonstrated to be a preferred target peptide for tyrosine nitration by co-incubation with BSA. Tyrosine nitration impaired GCG stimulated cAMP-dependent signaling in islet β cells and decreased insulin release. Our results provided a new role of heme for impaired GSIS in the pathological process of diabetes. The possible mechanism of intra-islet GCG activity impairment in diabetes. Since the majority of beta cells in human islets are in direct contact with alpha cells, there is a functional crosstalk between these two major islet cell types. Mechanistically, the positive effect of GCG on beta cell function is achieved by GCG binding to G protein-coupled receptors (GPCRs) (including GLP-1 receptor and GCG receptor), that are expressed in beta cells, and the activation of GPCRs signaling to stimulate the production of cAMP that acts as a necessary cofactor to support glucose-stimulated insulin secretion (GSIS) (the mechanism of GCG maintaining “β-cell tone” is shown as “Normal”). We proposed that tyrosine nitration of GCG may be one of the reason for a diminished intra-islet paracrine hormone action of GCG in diabetes. Heme bound to GCG p