Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical-Academic Center of Coimbra, Coimbra, Portugal; CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Portugal.
Mol Metab. 2021 Sep;51:101241. doi: 10.1016/j.molmet.2021.101241. Epub 2021 Apr 29.
The therapeutic effects of the dopamine D2 receptor (D2R) agonist, bromocriptine, in type 2 diabetes (T2D) have been attributed to central nervous system actions. However, peripheral dopamine directly modulates glucose uptake in insulin-sensitive tissues and lipid metabolism in adipose tissue (AT). We hypothesized that the dopaminergic system may be impaired in the adipose tissue of patients with T2D and that the therapeutic actions of bromocriptine could involve the modulation of metabolism in this tissue.
The expression of dopamine receptors was evaluated in visceral AT samples from patients with obesity and stratified in several groups: insulin sensitive (IS); insulin resistance (IR) normoglycaemic; insulin resistant prediabetic; insulin resistant diabetic, according to Ox-HOMA2IR, fasting glycaemia and HbA1c levels. T2D Goto-Kakizaki rats (GK) were fed a high-caloric diet (HCD) for five months and treated with bromocriptine (10 mg/kg/day, i.p.) in the last month. The levels of dopaminergic system mediators and markers of insulin sensitivity and glucose and lipid metabolism were assessed in the peri-epididymal adipose tissue (pEWAT) and brown (BAT) adipose tissues, liver, and skeletal muscle.
Patients with IR presented a decreasing trend of DRD1 expression in the visceral adipose tissue, being correlated with the expression of UCP1, PPARA, and insulin receptor (INSR) independently of insulin resistance and body mass index. Although no differences were observed in DRD2, DRD4 expression was significantly decreased in patients with prediabetes and T2D. In HCD-fed diabetic rats, bromocriptine increased D1R and tyrosine hydroxylase (TH) levels in pEWAT and the liver. Besides reducing adiposity, bromocriptine restored GLUT4 and PPARγ levels in pEWAT, as well as postprandial InsR activation and postabsorptive activation of lipid oxidation pathways. A reduction of liver fat, GLUT2 levels and postprandial InsR and AMPK activation in the liver was observed. Increased insulin sensitivity and GLUT4 levels in BAT and an improvement of the overall metabolic status were observed.
Bromocriptine treatment remodels adipose tissue and the liver dopaminergic system, with increased D1R and TH levels, resulting in higher insulin sensitivity and catabolic function. Such effects may be involved in bromocriptine therapeutic effects, given the impaired expression of dopamine receptors in the visceral adipose tissue of IR patients, as well as the correlation of D1R expression with InsR and metabolic mediators.
多巴胺 D2 受体（D2R）激动剂溴隐亭在 2 型糖尿病（T2D）中的治疗效果归因于中枢神经系统的作用。然而，外周多巴胺直接调节胰岛素敏感组织中的葡萄糖摄取和脂肪组织（AT）中的脂质代谢。我们假设 T2D 患者的脂肪组织中多巴胺能系统可能受损，溴隐亭的治疗作用可能涉及对该组织代谢的调节。
评估了肥胖患者内脏 AT 样本中多巴胺受体的表达，并根据 Ox-HOMA2IR、空腹血糖和 HbA1c 水平，将其分层为胰岛素敏感（IS）；胰岛素抵抗（IR）血糖正常；胰岛素抵抗糖尿病前期；胰岛素抵抗糖尿病。将 Goto-Kakizaki 大鼠（GK）喂饲高热量饮食（HCD）五个月，并在最后一个月用溴隐亭（10mg/kg/天，腹腔注射）治疗。评估了附睾周脂肪组织（pEWAT）和棕色脂肪组织（BAT）、肝脏和骨骼肌中多巴胺能系统介质以及胰岛素敏感性和葡萄糖及脂质代谢标志物的水平。
IR 患者内脏脂肪组织中 DRD1 的表达呈下降趋势，与 UCP1、PPARA 和胰岛素受体（INSR）的表达独立于胰岛素抵抗和体重指数相关。虽然 DRD2 没有差异，但糖尿病前期和 T2D 患者的 DRD4 表达明显降低。在 HCD 喂养的糖尿病大鼠中，溴隐亭增加了 pEWAT 和肝脏中的 D1R 和酪氨酸羟化酶（TH）水平。除了减少脂肪量外，溴隐亭还恢复了 pEWAT 中的 GLUT4 和 PPARγ 水平，以及餐后 InsR 激活和吸收后脂质氧化途径的激活。观察到肝脏脂肪、GLUT2 水平以及餐后 InsR 和 AMPK 激活的减少。BAT 中的胰岛素敏感性和 GLUT4 水平增加，整体代谢状态得到改善。
溴隐亭治疗重塑了脂肪组织和肝脏多巴胺能系统，增加了 D1R 和 TH 水平，从而提高了胰岛素敏感性和分解代谢功能。鉴于 IR 患者内脏脂肪组织中多巴胺受体表达受损，以及 D1R 表达与 InsR 和代谢介质的相关性，这种作用可能与溴隐亭的治疗效果有关。
