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Metabolic and microRNA expression differences in pregnancies complicated by diabetes mellitus

Matladi Masete , Stephanie Dias , Nompumelelo Malaza 1,2 , Sumaiya Adam and Carmen Pheiffer 1,3,4
1,2
3
1
1 Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa;
2 Department of Reproductive Biology, Faculty of Health Sciences University of Pretoria, Private Bag X169, Pretoria 0001, South Africa;
3 Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Private Bag X169, Pretoria 0001, South Africa;
4 Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg, 7505, South Africa
INTRODUCTION RESULTS Gene expression
• Diabetes in pregnancy is associated with adverse health effects for both Table 1. Participant characteristics Table 2. Differentially expressed miRNAs using PCR arrays
mothers and their children, with the severity related to the degree of
hyperglycemia (1). Variable Pregestational New-T2DM GDM Control P-value
• it is thus important to understand the pathogenic mechanisms that underly T1DM T2DM
these types of diabetes, to identify potential prognostic biomarkers or n 7 14 12 17 24
therapeutic targets, Age (years) 29 (28-30) 36 (33-37) 34 (30-37) 35 (32-38) 30 (26-36) 0.005
• MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules Body mass index (kg/m 2 ) 24.4 (23.8-35.6) 29.4 (21.7-38.0) 33.1 (28.8- 38.5) 33.5 (26.5-42.2) 31.2 (25.9-38.3) 0.749
that have emerged as key players in the pathophysiology of metabolic
disease and has been shown to be associated with conditions including Gestational age (weeks) 21 (19-26) 21 (16-22) 25 (20-26) 26 (22-27) 21 (18-25) 0.008
cancer, obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease Glycated hemoglobin (%) 9.6 (9.0-9.7) 8.0 (7.3- 9.6) 6.9 (6.1-10.8) 5.4 (5.3-5.7) ND 0.015
(2,3).
Fasting glucose (mmol/L) ND ND 7.5 (6.6-10.0) 5.5 (5.0-6.0) 3.9 (3.6-4.1) 0.001
2 hr glucose (mmol/L) ND ND 12.3 (11.2-17.8) 8.7 (6.5-9.7) 5 (4.3-6.1) 0.001
AIM Data presented as the median and interquartile range (25 th and 75 th percentiles)
New-T2DM: first diagnosed in pregnancy
• Investigate whether miRNA patterns differ in pregnant women with type 1 Serum markers
diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and gestational
diabetes mellitus (GDM) 50 4
15000
40 3 Figure 7: MiRNAs selected for PCR validation. *P<0.05 vs. control
A dip on e c tin (ng /m L)
METHODS In s u lin ( µ U /m L ) 30 C - pe pt i de ( ng/ m L ) 2 10000 The expression of miR-19a-3p was lower in pregnant women GDM, miR-20a-5p was lower in T1DM
and miR-29a-3p was higher in T2DM compared to normoglycemia, p<0.05. Several other miRNAs were
• Nonfasted serum samples were collected from pregnant women with T1DM, 20 5000 differentially expressed between the diabetes groups, however, these were not statistically significant.
T2DM, GDM and normoglycaemia (control) at 16-27 weeks of gestation 10 1 MicroRNA-19a-3p enhances the proliferation and insulin secretion, while it inhibits apoptosis of
• Pregestational diabetes (T1DM or T2DM) were self-reported, while new 0 0 0 pancreatic β cells (4). MiR-20a-5p controls various metabolic pathways, including insulin signaling (5).
Overexpression of miR-29a causes a decrease in levels of glucose transporter 4 in skeletal muscle,
T2DM or GDM was diagnosed using the oral glucose tolerance test c ontrol T 1D M T 2D M n ew -T 2D M G DM control T1D M T2D M n ew -T2D M G DM c ontrol T 1D M T 2D M n ew -T 2D M G DM which causes a decrease insulin dependent glucose uptake (6).
according to the International Association of Diabetes and Pregnancy Study Figure 1. Insulin Figure 2. C-peptide Figure 3. Total adiponectin
Groups (IADPSG) criteria
15000
• Insulin, C-peptide, total and high-molecular weight adiponectin, C-reactive 30 p = 0.052
protein and Triglycerides concentrations were measured using enzyme 600 * CONCLUSION
linked immunosorbent assays (ELISAs) 10000
• MiRNAs were isolated from serum using the miRNeasy Serum/Plasma kit H M W A d ipo ne c t in ( ng/m L ) 20 400 Metabolic parameters and miRNA levels differ according to the type of diabetes in
pregnancy. These findings highlight the different pathophysiological mechanisms that
and miRNA quantity was assessed using the Agilent Bioanalyser 5000 C R ea ct iv e P r o t ein (µ g /m L ) T rig lycerid es (m g /d L ) underlie diabetes during pregnancy and may offer opportunities for risk stratification
• Differentially expressed miRNAs were identified using the Human 10 200 and intervention to mitigate adverse effects.
serum/plasma miScript miRNA PCR array, which profiles 84 different serum
miRNAs (n=4 per group) 0 0 0
c ontro T 1D M T 2D M n ew -T 2D M G DM C o n t r o l T 1 DM T 2 DM n e w - T 2 DM G DM C o n tro l T 1D M T 2D M n e w -T 2 D M G DM ACKNOWLEDGEMENTS
• 2-fold cut-off threshold Figure 4. HMW adiponectin Figure 5. C-Reactive Protein Figure 6. Triglycerides This work was funded by the National Research Foundation (NRF)
Grant No: 120832
REFERENCES
1. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, et al. (2008) Hyperglycemia and adverse pregnancy outcomes. The New England Journal of Medicine 358(19): 1991–2002.
2. Cai M, Kolluru GK and Ahmed A (2017) Small Molecule, Big Prospects: MicroRNA in Pregnancy and Its Complications. Journal of Pregnancy 2017: 6972732.
3. Méndez-Mancilla A, Lima-Rogel V, Toro-Ortíz JC, et al. (2018) Differential expression profiles of circulating microRNAs in newborns associated to maternal pregestational overweight and obesity: Newborns miRNAs alterations. Pediatric Obesity 13(3): 168–174. DOI: 10.1111/ijpo.12247.
4. Li Y, Luo T, Wang L, Wu J and Guo S: MicroRNA-19a-3p enhances the proliferation and insulin secretion, while it inhibits the apoptosis of pancreatic β cells via the inhibition of SOCS3. Int J Mol Med 38: 1515-1524, 2016
5. Pheiffer C, Dias S, Rheeder P, Adam S. Decreased Expression of Circulating miR-20a-5p in South African Women with Gestational Diabetes Mellitus. Mol Diagn Ther. 2018 Jun;22(3):345-352. doi: 10.1007/s40291-018-0325-0. PMID: 29556924.
6. Zhou Y, Gu P, Shi W, Li J, Hao Q, Cao X, Lu Q and Zeng Y: MicroRNA-29a induces insulin resistance by targeting PPARδ in skeletal muscle cells. Int J Mol Med 37: 931-938, 2016