Role of Serotonin (5-HT) in GDM Prediction Considering Islet and Liver Interplay in Prediabetic Mice During Gestation

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Jun 24

PMID 35742878

Authors

Melissa Asuaje Pfeifer

Moritz Liebmann

Till Beuerle

Katharina Grupe

Stephan Scherneck

Affiliations

Soon will be listed here.

Abstract

Gestational diabetes (GDM) is characterized by a glucose tolerance disorder. This may first appear during pregnancy or pre-exist before conception as a form of prediabetes, but there are few data on the pathogenesis of the latter subtype. Female New Zealand obese (NZO) mice serve as a model for this subpopulation of GDM. It was recently shown that GDM is associated with elevated urinary serotonin (5-hydroxytryptamine, 5-HT) levels, but the role of the biogenic amine in subpopulations with prediabetes remains unclear. 5-HT is synthesized in different tissues, including the islets of Langerhans during pregnancy. Furthermore, 5-HT receptors (HTRs) are expressed in tissues important for the regulation of glucose homeostasis, such as liver and pancreas. Interestingly, NZO mice showed elevated plasma and islet 5-HT concentrations as well as impaired glucose-stimulated 5-HT secretion. Incubation of isolated primary NZO islets with 5-HT revealed an inhibitory effect on insulin and glucagon secretion. In primary NZO hepatocytes, 5-HT aggravated hepatic glucose production (HGP), decreased glucose uptake (HGU), glycogen content, and modulated AKT activation as well as cyclic adenosine monophosphate (cAMP) increase, indicating 5-HT downstream modulation. Treatment with an HTR2B antagonist reduced this 5-HT-mediated deterioration of the metabolic state. With its strong effect on glucose metabolism, these data indicate that 5-HT is already a potential indicator of GDM before conception in mice.

Citing Articles

PyCreas: a tool for quantification of localization and distribution of endocrine cell types in the islets of Langerhans.

Asuaje Pfeifer M, Langehein H, Grupe K, Muller S, Seyda J, Liebmann M Front Endocrinol (Lausanne). 2023; 14:1250023.

PMID: 37772078 PMC: 10523144. DOI: 10.3389/fendo.2023.1250023.

Mouse Models of Gestational Diabetes Mellitus and Its Subtypes: Recent Insights and Pitfalls.

Grupe K, Scherneck S Int J Mol Sci. 2023; 24(6).

PMID: 36983056 PMC: 10058162. DOI: 10.3390/ijms24065982.

Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate.

Liebmann M, Grupe K, Asuaje Pfeifer M, Rustenbeck I, Scherneck S Lipids Health Dis. 2022; 21(1):99.

PMID: 36209101 PMC: 9547403. DOI: 10.1186/s12944-022-01706-x.

References

Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D . Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2011; 61(1):187-96. PMC: 3237647. DOI: 10.2337/db11-1029. View

Cho H, Mu J, Kim J, Thorvaldsen J, Chu Q, Crenshaw 3rd E . Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001; 292(5522):1728-31. DOI: 10.1126/science.292.5522.1728. View

Prescott M, Lidster K . Improving quality of science through better animal welfare: the NC3Rs strategy. Lab Anim (NY). 2017; 46(4):152-156. DOI: 10.1038/laban.1217. View

Ko M, Kamimura K, Owaki T, Nagoya T, Sakai N, Nagayama I . Modulation of serotonin in the gut-liver neural axis ameliorates the fatty and fibrotic changes in non-alcoholic fatty liver. Dis Model Mech. 2021; 14(3). PMC: 8084356. DOI: 10.1242/dmm.048922. View

Ming X, Chung A, Mao D, Cao H, Fan B, Wong W . Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity. Diabetes. 2020; 70(1):119-131. DOI: 10.2337/db20-0339. View

Dyer J, Hosie K, Shirazi-Beechey S . Nutrient regulation of human intestinal sugar transporter (SGLT1) expression. Gut. 1997; 41(1):56-9. PMC: 1027228. DOI: 10.1136/gut.41.1.56. View

Ruddell R, Mann D, Ramm G . The function of serotonin within the liver. J Hepatol. 2008; 48(4):666-75. DOI: 10.1016/j.jhep.2008.01.006. View

Li X, Guo K, Li T, Ma S, An S, Wang S . 5-HT 2 receptor mediates high-fat diet-induced hepatic steatosis and very low density lipoprotein overproduction in rats. Obes Res Clin Pract. 2016; 12(Suppl 2):16-28. DOI: 10.1016/j.orcp.2016.03.015. View

Sorenson R, Brelje T . Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res. 1997; 29(6):301-7. DOI: 10.1055/s-2007-979040. View

10.

Petersen M, Shulman G . Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018; 98(4):2133-2223. PMC: 6170977. DOI: 10.1152/physrev.00063.2017. View

11.

Ohara-Imaizumi M, Kim H, Yoshida M, Fujiwara T, Aoyagi K, Toyofuku Y . Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy. Proc Natl Acad Sci U S A. 2013; 110(48):19420-5. PMC: 3845121. DOI: 10.1073/pnas.1310953110. View

12.

Tannenbaum J, Bennett B . Russell and Burch's 3Rs then and now: the need for clarity in definition and purpose. J Am Assoc Lab Anim Sci. 2015; 54(2):120-32. PMC: 4382615. View

13.

El-Merahbi R, Loffler M, Mayer A, Sumara G . The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett. 2015; 589(15):1728-34. DOI: 10.1016/j.febslet.2015.05.054. View

14.

Powe C, Allard C, Battista M, Doyon M, Bouchard L, Ecker J . Heterogeneous Contribution of Insulin Sensitivity and Secretion Defects to Gestational Diabetes Mellitus. Diabetes Care. 2016; 39(6):1052-5. PMC: 4878218. DOI: 10.2337/dc15-2672. View

15.

. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract. 2014; 103(3):341-63. DOI: 10.1016/j.diabres.2013.10.012. View

16.

Isaac R, Boura-Halfon S, Gurevitch D, Shainskaya A, Levkovitz Y, Zick Y . Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells. J Biol Chem. 2013; 288(8):5682-93. PMC: 3581374. DOI: 10.1074/jbc.M112.408641. View

17.

Hampson L, Mackin P, Agius L . Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs. Diabetologia. 2007; 50(8):1743-51. DOI: 10.1007/s00125-007-0696-y. View

18.

Choi W, Namkung J, Hwang I, Kim H, Lim A, Park H . Serotonin signals through a gut-liver axis to regulate hepatic steatosis. Nat Commun. 2018; 9(1):4824. PMC: 6240035. DOI: 10.1038/s41467-018-07287-7. View

19.

Wolf M, Sandler L, Hsu K, Vossen-Smirnakis K, Ecker J, Thadhani R . First-trimester C-reactive protein and subsequent gestational diabetes. Diabetes Care. 2003; 26(3):819-24. DOI: 10.2337/diacare.26.3.819. View

20.

Barradas M, Gill D, Fonseca V, Mikhailidis D, Dandona P . Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease. Eur J Clin Invest. 1988; 18(4):399-404. DOI: 10.1111/j.1365-2362.1988.tb01030.x. View