Homocysteine (Hcy) is a sulfur-containing nonprotein amino acid derived from the metabolism of methionine. Elevated levels of Hcy are observed in various disorders, such as vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes mellitus, renal disease, osteoporosis, neuropsychiatric disorders, and cancer (Brustolin et al., 2010; Zaric et al., 2019). Hyperhomocysteinemia (HHcy) is characterized by plasma Hcy levels exceeding 15 μmol/L (Maron and Loscalzo, 2006). Type 2 diabetes mellitus (T2DM), however, is a chronic progressive metabolic disease in which the body undergoes successive irreversible pathophysiological changes associated with the onset of hyperglycemia, such as insulin resistance and impaired insulin secretion (Galicia-Garcia et al., 2020). Patients with T2DM have been found to have high plasma Hcy levels (Joshi et al., 2016; Ala et al., 2017). In patients with T2DM, those with HHcy are at a greater risk of developing diabetic complications, for example, the endothelial function is poor, diabetic retinopathy (Luo et al., 2022)and macular edema. Hcy level has been independently associated with the severity of peripheral polyneuropathy in patients with T2DM and the development of early diabetic nephropathy (González et al., 2012; Wang et al., 2013).

It is noteworthy that diabetes increases Hcy levels, and in turn, elevated Hcy levels contribute to the development of diabetes. Elevated Hcy level is also an important independent risk factor for T2DM (Jan et al., 2021). Insulin resistance, a key pathogenic component of T2DM, is defined as a state of reduced responsiveness of insulin-targeted tissues to physiological levels of insulin (Lee et al., 2022). Several relevant studies have demonstrated that elevated Hcy levels may increase the risk of developing diabetes through insulin resistance; for example, elevated Hcy levels reduce the abundance of insulin proreceptors (IR-α and IR-β) and react with proinsulin receptor (Pro-IR), which cleaves the proinsulin receptor, thereby inducing insulin resistance (Zhang et al., 2021). Yang et al. reported that HHcy promotes proinflammatory cytokine production and macrophage infiltration by activating the endoplasmic reticulum stress of c-Jun N-terminal kinase, which inhibits insulin sensitivity in the adipose tissue, ultimately leading to insulin resistance (Li et al., 2013).

Impaired insulin secretion in pancreatic cells is also a major factor in the pathogenesis of T2DM (Rachdaoui, 2020). To investigate the functionally damaging effect of Hcy on pancreatic β-cells, we constructed an HHcy mouse model. After the mice developed impaired glucose tolerance, glucose-stimulated insulin secretion was reduced. We hypothesized that the diabetes mellitus in the HHcy mice may have been caused by insufficient insulin levels due to impaired pancreatic β-cell insulin secretion. Based on this finding, we further investigated the mechanism of the effect of Hcy on pancreatic β-cell function and screened new targets by transcriptomics, which provides a new theoretical basis for the prevention and treatment of diabetes mellitus.