{"doi":"10.3389/fendo.2025.1532414","title":"Biological mechanisms of dopamine D2-like receptor agonist therapy in diabetes","abstract":"A recent case report by Sahota and colleagues has provided new insights into treatment of dysglycemia via dopamine (DA) receptor stimulation in the setting of autoimmune diabetes [1].Briefly, a patient with autoimmune diabetes was diagnosed with a pituitary prolactinoma, resulting in treatment with cabergoline, an agonist of DA D2-like receptors, alongside preexisting diabetes medications. Over time, the patient was switched to cabergoline monotherapy which reversed his insulin requirement. This led to significantly improved glycemic control and a revised diagnosis of latent autoimmune diabetes of adults (LADA). Ultimately, however, the patient was restarted on insulin therapy in the setting of progressively increased blood glucose.Patients with LADA often achieve adequate glycemic control soon after the initiation of antihyperglycemic treatment, including non-insulin agents [2]. Consistent with this, recent studies in LADA patients with non-insulin agents like dipeptidyl peptidase 4 inhibitors (e.g., saxagliptin), or glucagon-like peptide 1 receptor agonists (e.g., dulaglutide) showed improved glycemic control for months and delayed progression to insulin requirement [2; 3; 4; 5]. Importantly, in contrast to the more commonly used drug classes above, this case represents the first description of DA receptor agonist monotherapy for autoimmune diabetes [1]. These findings have raised important questions concerning the biological mechanisms by which D2-like receptor agonists can effectively treat dysglycemia, particularly in the setting of diabetes.D2-like receptor agonists such as cabergoline and bromocriptine have been used for decades to control CNS prolactinoma size and secretion given their expression of the DA D2 receptor (D2R) [6]. There is much evidence that these agonists are associated with improved glycemic control [7]. Moreover, bromocriptine was approved by the United States Food & Drug Administration as a novel treatment for dysglycemia in type 2 diabetes mellitus (T2DM) [8; 9].While mechanisms by which D2-like receptor agonists improve glycemic control have remained unclear, most attention has been devoted to these drugs' actions on neuroendocrine targets within the central nervous system (CNS) [8].Sahota et al. suggested that drug-induced reduction of pathological prolactin levels led to the patient's metabolic improvements [1]. CNS D2R agonism via cabergoline therapy could therefore modify prolactin-induced disruptions in lipid and glucose metabolism in insulinresponsive tissues including adipose tissue and skeletal muscle [1; 10; 11]. These prolactin reductions also likely contributed to improved testosterone levels, which in turn reversed the patient's hypogonadism. This is consistent with evidence showing that testosterone restoration contributes to significant weight loss as well as improved insulin resistance and overall glycemic control [12; 13]. Cabergoline-induced normalization of prolactin may therefore lead to restored total and free testosterone levels to improve glycemic control via a wide range of mechanisms including via reductions in inflammation and weight gain -factors that further drive insulin resistance [11; 14]. Moreover, D2R is also expressed in the hypothalamus and is implicated in centrally-mediated metabolic regulation, including through control over satiety [15; 16].Therefore, it is possible that D2R agonists may improve glycemic control via these CNS pathways, in addition to its actions in the pituitary (Figure 1A).Though CNS DA receptor agonism was proposed by Sahota et al. as a primary driver of improved glycemic control [1], additional factors likely play key roles. A leading determinant of improved glucose control is the "honeymoon" effect where patients present with temporary remission after symptomatic onset. The honeymoon period in LADA typically lasts weeks to months and may reflect reduced stress on remaining islet beta-cells [17; 18; 19]. 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Codario","orcid":"0000-0002-2193-1539","position":1,"is_corresponding":false},{"id":307539,"name":"Zachary Freyberg","orcid":"0000-0001-6460-0118","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:54:12.321988Z","pmid":"39906261","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}