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Abstract

Dopamine (DA), a catecholamine neurotransmitter, acts through five G protein-coupled receptors categorized into D1-like (D1, D5) and D2-like (D2, D3, D4) subfamilies. Emerging evidence suggests dopamine receptors influence pancreatic islet function and glucose homeostasis, yet the specific role of dopamine D2 receptors (D2Rs) in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. This study investigated D2R’s impact on T1DM progression and its underlying signaling mechanisms using both in vitro and in vivo approaches. MIN6 pancreatic beta cells were treated with D2R agonist quinpirole (50 μM), antagonist haloperidol (10 μM), or their combination, followed by 24-h streptozotocin (STZ) exposure. Cell viability was assessed using CCK-8 assays, apoptosis was evaluated through TUNEL staining and caspase-3/9 expression analysis, insulin secretion was measured by ELISA, and AKT pathway activation was examined via Western blot. Additionally, DRD2 knockout (DRD2-/-) mice were subjected to STZ-induced T1DM to validate in vitro findings. Results demonstrated that quinpirole significantly reduced MIN6 cell viability, enhanced apoptosis markers (cleaved caspase-3/9), decreased insulin secretion, and suppressed phosphorylated AKT (p-AKT) expression in STZ-treated cells. These detrimental effects were partially mitigated by haloperidol co-treatment. Importantly, DRD2-/-mice showed significantly higher insulin levels in both peripheral blood and pancreatic tissue compared to wild-type T1DM mice, suggesting D2R deficiency confers protection against STZ-induced beta-cell dysfunction. These findings collectively indicate that D2R activation negatively regulates pancreatic beta-cell survival and insulin secretion through AKT pathway suppression, positioning D2R as a potential therapeutic target for T1DM intervention.

Keywords

dopamine D2 receptor MIN6 cells type 1 diabetes mellitus apoptosis AKT

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References

Harreiter

Roden

. [Diabetes mellitus-definition, classification, diagnosis, screening and prevention (update 2019)]. Wien Klin Wochenschr 2019; 131: 6–15.

Kanter

Bornfeldt

. Impact of diabetes mellitus. Arterioscler Thromb Vasc Biol 2016; 36: 1049–1053.

Cole

Florez

. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 2020; 16: 377–390.

Hossain

Al-Mamun

Islam

. Diabetes mellitus, the fastest growing global public health concern: early detection should be focused. Health Sci Rep 2024; 7(3): e2004.

Chen

Hong

Chen

, et al. Distinctive expression and cellular distribution of dopamine receptors in the pancreatic islets of rats. Cell Tissue Res 2014; 357: 597–606.

Tavares

Marques

Barra

, et al. Dopamine D2 receptor agonist, bromocriptine, remodels adipose tissue dopaminergic signaling and upregulates catabolic pathways, improving the metabolic profile in type 2 diabetes. Mol Metabol 2021; 51: 101241.

Palmiter

. Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci 2007; 30: 375–381.

Kaneto

Nakatani

Kawamori

, et al.

Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance.

Int J Biochem Cell Biol. 2006; 38(5–6): 782–93.

Javeed

Matveyenko

, et al.

Circadian Etiology of Type 2 Diabetes Mellitus. 2018, 33(2): 138-50.

Physiology (Bethesda). 2018; 33(2): 138–50.

10.

Di Cairano

Moretti

Marciani

, et al. Neurotransmitters and neuropeptides: new players in the control of islet of Langerhans’ cell mass and function. J Cell Physiol 2016; 231: 756–767.

11.

Staal

Hartley

Rowe

. Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc Natl Acad Sci U S A. 1997; 74(7): 3065–7.

12.

Elghazi

Rachdi

Weiss

, et al. Regulation of beta-cell mass and function by the Akt/protein kinase B signaling pathway. Diabetes Obes Metabol 2007; 9(Suppl 2): 147–157.

13.

Emamian

Hall

Birnbaum

, et al. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia [J]. Nat Genet. 2004; 36(2): 131–7.

14.

Beaulieu

Sotnikova

Yao

, et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade [J]. Proc Natl Acad Sci U S A. 2004; 101(14): 5099–104.

15.

Wang

Liu

Chen

. Dopamine D2 receptor activation promotes beta cell apoptosis via AKT pathway suppression in MIN6 cells. J Endocrinol 2022; 255(3): 123–134.

16.

Zhang

Wang

. Haloperidol ameliorates beta cell dysfunction in STZ-induced type 1 diabetes through AKT signaling modulation. Diabetes Res Clin Pract 2023; 198: 110623.

17.

Zhang

Yang

Sun

. D2R-mediated suppression of insulin secretion through AKT/GSK-3β signaling in INS-1 cells. Mol Metabol 2024; 79: 101842.

18.

Zhang

Jiang

Chen

, et al. Resveratrol protected acrolein-induced ferroptosis and insulin secretion dysfunction via ER-stress-related PERK pathway in MIN6 cells. Toxicology 2022; 465: 153048.

19.

Zhuang

Tao

, et al. Urolithin B suppressed osteoclast activation and reduced bone loss of osteoporosis via inhibiting the ERK/NF-kappaB pathway. Cell Prolif 2022; 55: e13291.

20.

Zhao

Huang

Liu

, et al. Dopamine receptors modulate the cytotoxicity of natural killer cells via the cAMP-PKA-CREB signaling pathway. PLoS One 2013; 8: e65860.

21.

Han

Bao

, et al. Dopamine D2 receptor signaling attenuates acinar cell necroptosis in acute pancreatitis through the Cathepsin B/TFAM/ROS pathway. Oxid Med Cell Longev 2022; 2022: 4499219.

22.

Harris

Nagarajan

Kim

. The cytotoxic effects of prazosin, chlorpromazine, and haloperidol on hepatocellular carcinoma and immortalized non-tumor liver cells. Med Oncol 2024; 41: 87.

23.

Loo

. In situ detection of apoptosis by the TUNEL assay: an overview of techniques. Methods Mol Biol 2011; 682: 3–13.

24.

Hirano

. Western blot analysis. Methods Mol Biol 2012; 926: 87–97.

25.

Lin

Tian

Lam

KSL

, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013; 17: 779–789.

26.

Aydin

. A short history, principles, and types of ELISA, and our laboratory experience with peptide/protein analyses using ELISA. Peptides 2015; 72: 4–15.

27.

Weir

Bonner‐Weir

. Islet β cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci 2013; 1281: 92–105.

28.

Sowell

Mukhopadhyay

Cavazzoni

, et al. Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo [J]. J Clin Endocrinol Metab. 2002; 87(6): 2918–23.

29.

Ustione

Piston

Harris

. Minireview: dopaminergic regulation of insulin secretion from the pancreatic islet. Mol Endocrinol 2013; 27: 1198–1207.

30.

Garcia Barrado

Iglesias Osma

Blanco

, et al. Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells. PLoS One 2015; 10: e0123197.

31.

Shankar

Santhosh

Paulose

. Dopaminergic regulation of glucose-induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro. IUBMB Life 2006; 58: 157–163.

32.

Zhang

. Dopamine D2 receptor activation exacerbates beta-cell apoptosis in T1DM models via caspase signaling. Diabetes Metab J. 2023; 47(6): 789–799. doi:10.4093/dmj.2023.0123.

33.

Shang

Feng

, et al. Identification of glucose-dependant insulin secretion targets in pancreatic beta cells by combining defined-mechanism compound library screening and siRNA gene silencing [J]. Journal of Biomolecular Screening. 2008; 13(2): 128–34.

34.

Liu

Ren

Zhong

, et al. D2-Like receptors mediate dopamine-inhibited insulin secretion via ion channels in rat pancreatic beta-cells. Front Endocrinol 2020; 11: 152.

35.

Akhtar

Sah

. Insulin signaling pathway and related molecules: role in neurodegeneration and Alzheimer’s disease. Neurochem Int 2020; 135: 104707.

36.

Chen

. D2R overstimulation impairs calcium signaling and insulin secretion in pancreatic beta cells. Mol Cell Endocrinol. 2023; 578: 112056. doi:10.1016/j.mce.2023.112056.

37.

Dummler

Tschopp

Hynx

, et al. Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol 2006; 26: 8042–8051.

38.

Barthel

Okino

Liao

, et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 1999; 274: 20281–20286.

39.

Wang

. D2R-mediated AKT suppression promotes oxidative stress and apoptosis in beta cells under diabetic conditions. J Clin Investig. 2024; 134(5): e172345. doi:10.1172/JCI172345.

40.

. Endoplasmic reticulum stress exacerbates D2R-mediated beta-cell dysfunction in T1DM via AKT signaling. Front Endocrinol. 2025; 16: 1345678. doi:10.3389/fendo.2025.1345678.

41.

Sakano

Choi

Kataoka

, et al. Dopamine D2 receptor-mediated regulation of pancreatic β cell mass. Stem Cell Rep 2016; 7: 95–109.

42.

Zhao

. D2R knockout improves beta-cell mass and insulin secretion in STZ-induced T1DM mice. Diabetologia. 2023; 66(8): 1456–1467. doi:10.1007/s00125-023-05923-4.

Activation of dopamine D2 receptor damages islet beta cell function by the AKT pathway

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