Advancements and challenges in generating accurate animal models of gestational diabetes mellitus

The maintenance of glucose homeostasis during pregnancy is critical to the health and well-being of both the mother and the developing fetus. Strikingly, approximately 7% of human pregnancies are characterized by insufficient insulin production or signaling, resulting in gestational diabetes mellitus (GDM). In addition to the acute health concerns of hyperglycemia, women diagnosed with GDM during pregnancy have an increased incidence of complications during pregnancy as well as an increased risk of developing type 2 diabetes (T2D) later in life. Furthermore, children born to mothers diagnosed with GDM have increased incidence of perinatal complications, including hypoglycemia, respiratory distress syndrome, and macrosomia, as well as an increased risk of being obese or developing T2D as adults. No single environmental or genetic factor is solely responsible for the disease; instead, a variety of risk factors, including weight, ethnicity, genetics, and family history, contribute to the likelihood of developing GDM, making the generation of animal models that fully recapitulate the disease difficult. Here, we discuss and critique the various animal models that have been generated to better understand the etiology of diabetes during pregnancy and its physiological impacts on both the mother and the fetus. Strategies utilized are diverse in nature and include the use of surgical manipulation, pharmacological treatment, nutritional manipulation, and genetic approaches in a variety of animal models. Continued development of animal models of GDM is essential for understanding the consequences of this disease as well as providing insights into potential treatments and preventative measures.

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The Pathophysiology of Gestational Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms19113342 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3342 ◽

Cited By ~ 112

Author(s):

Jasmine Plows ◽

Joanna Stanley ◽

Philip Baker ◽

Clare Reynolds ◽

Mark Vickers

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Molecular Mechanisms ◽

Overweight And Obesity ◽

Chronic Hyperglycemia ◽

Increased Risk

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic β-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist—including insulin and lifestyle interventions—there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.

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Type 2 Diabetes mellitus genetic risk variant T in TCF7L2 rs 7903146 in women is associated with an increased risk for the development of gestational diabetes mellitus (GDM) with necessity of insulin therapy

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1375153 ◽

2014 ◽

Vol 9 (S 01) ◽

Author(s):

L Potasso ◽

N Perakakis ◽

A Lamprinou ◽

E Polyzou ◽

D Kassanos ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Genetic Risk ◽

Risk Variant ◽

Increased Risk ◽

Genetic Risk Variant

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Air pollution and gestational diabetes mellitus: evidence from cohort studies

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000937 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000937 ◽

Cited By ~ 2

Author(s):

Xingyao Tang ◽

Jian-Bo Zhou ◽

Fuqiang Luo ◽

Yipeng Han ◽

Yoriko Heianza ◽

...

Keyword(s):

Diabetes Mellitus ◽

Particulate Matter ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Air Pollutants ◽

Evidence Base ◽

Second Trimester ◽

Increased Risk ◽

Particulate Matter 2.5

Exposure to different air pollutants has been linked to type 2 diabetes mellitus, but the evidence for the association between air pollutants and gestational diabetes mellitus (GDM) has not been systematically evaluated. We systematically retrieved relevant studies from PubMed, Embase, and the Web of Science, and performed stratified analyses and regression analyses. Thirteen studies were analyzed, comprising 1 547 154 individuals from nine retrospective studies, three prospective studies, and one case–control study. Increased exposure to particulate matter ≤2.5 µm in diameter (PM2.5) was not associated with the increased risk of GDM (adjusted OR 1.03, 95% CI 0.99 to 1.06). However, subgroup analysis showed positive correlation of PM2.5 exposure in the second trimester with an increased risk of GDM (combined OR 1.07, 95% CI 1.00 to 1.13). Among pollutants other than PM2.5, significant association between GDM and nitrogen dioxide (NO2) (OR 1.05, 95% CI 1.01 to 1.10), nitrogen oxide (NOx) (OR 1.03, 95% CI 1.01 to 1.05), and sulfur dioxide (SO2) (OR 1.09, 95% CI 1.03 to 1.15) was noted. There was no significant association between exposure to black carbon or ozone or carbon monoxide or particulate matter ≤10 µm in diameter and GDM. Thus, systematic review of existing evidence demonstrated association of exposure to NO2, NOx, and SO2, and the second trimester exposure of PM2.5 with the increased risk of GDM. Caution may be exercised while deriving conclusions from existing evidence base because of the limited number and the observational nature of studies.

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Gestational Diabetes Mellitus (GDM): Current concept and a short Review

Bangladesh Journal of Pathology ◽

10.3329/bjpath.v24i1.2877 ◽

1970 ◽

Vol 24 (1) ◽

pp. 16-20 ◽

Cited By ~ 1

Author(s):

MT Rahman ◽

T Tahmin ◽

S Ferdousi ◽

SN Bela

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Later Life ◽

Short Review ◽

Current Concept ◽

Increased Risk ◽

Develop Type

Gestational Diabetes Mellitus (GDM) is a very common and important disease occurring during pregnancy and has detrimental effect on both the mother and the baby. The mother is at increased risk of developing obstetric complications like prolonged labour, prone to develop type 2 diabetes in future and the baby is born with overweight, cause of childhood obesity and later life development of type 2 diabetes. A short review and current concept of GDM is discussed. Key words: GDM, Type 2 diabetes, Obesity, Macrosomia, Complications doi: 10.3329/bjpath.v24i1.2877 Bangladesh J Pathol 24 (1) : 16-20

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Gestational diabetes mellitus and the role of intercurrent type 2 diabetes on long-term risk of cardiovascular events

Scientific Reports ◽

10.1038/s41598-021-99993-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jiyu Sun ◽

Gyu Ri Kim ◽

Su Jin Lee ◽

Hyeon Chang Kim

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Cardiovascular Events ◽

Cvd Risk ◽

Increased Risk ◽

Incident Cases

AbstractRecent studies have shown that gestational diabetes mellitus (GDM) is associated with an increased risk for cardiovascular disease. GDM has also been shown to be a risk factor for type 2 diabetes (T2DM) after pregnancy. However, there is limited evidence regarding the role of intercurrent T2DM on the relationship between GDM and future CVD. Thus, we investigated the risks of incident cardiovascular events among women with GDM during pregnancy compared to women without GDM and whether the increased CVD risk is dependent on intercurrent development of T2DM. We conducted a population-based retrospective cohort study using the Korean National Health Insurance Service claims database. Outcomes were the first occurrence of any CVD (myocardial infarction, treatment with coronary revascularization, heart failure, and cerebrovascular disease). Cox proportional hazard models were used to assess the association between GDM and incident CVD events, using landmark analysis at 4 years. A total of 1,500,168 parous women were included in the analysis, of which 159,066 (10.60%) had GDM. At a median follow-up of 12.8 years, 13,222 incident cases of total CVD were observed. Multivariable-adjusted hazard ratio for total CVD among women with prior GDM, compared with those without GDM, was 1.08 (95% CI 1.02–1.14). Further classifying GDM by progression to T2DM in relation to total CVD risk indicated a positive association for GDM with progression to T2DM vs no GDM or T2DM (HR 1.74; 95% CI 1.40–2.15), and no statistically significant association for GDM only (HR 1.06; 95% CI 1.00–1.12). GDM with subsequent progression to T2DM were linked with an increased risk of cardiovascular diseases. These findings highlight the need for more vigilant postpartum screening for diabetes and the implementation of diabetes interventions in women with a history of GDM to reduce future CVD risk.

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Trans-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

10.1101/2021.10.11.21264235 ◽

2021 ◽

Author(s):

Natalia Pervjakova ◽

Gunn-Helen Moen ◽

Maria-Carolina Borges ◽

Teresa Ferreira ◽

James P Cook ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Increased Risk ◽

In Pregnancy

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5,485 women with GDM and 347,856 without GDM. Through trans-ancestry meta-analysis, we identified five loci with genome-wide significant association (p<5×10-8) with GDM, mapping to/near MTNR1B (p=4.3×10-54), TCF7L2 (p=4.0×10-16), CDKAL1 (p=1.6×10-14), CDKN2A-CDKN2B (p=4.1×10-9) and HKDC1 (p=2.9×10-8). Multiple lines of evidence pointed to genetic contributions to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.

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Etiology, Detection, Diagnosis, and Clinical Management of Gestational Diabetes Mellitus

Journal of Pharmacy Practice ◽

10.1177/089719009901200108 ◽

1999 ◽

Vol 12 (1) ◽

pp. 65-71

Author(s):

Beverly A. Sullivan ◽

Scott T. Henderson ◽

Julie M. Davis ◽

Martin B. Steffenson

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Health Care Providers ◽

Close Monitoring ◽

Care Providers ◽

Treatment Interventions ◽

Increased Risk ◽

Mother And Child

Healthy outcomes for both mother and child are expected and fortunately seen in most pregnancies. In some cases, serious or potentially serious problems arise during the pregnancy that mandate a need for both close monitoring and treatment interventions by health care providers. Gestational diabetes mellitus (GDM) is such a condition that may evolve during pregnancy. Women who experienced gestational diabetes during pregnancy are at increased risk of developing Type 2 diabetes as are their offspring. As defined, GDM is a type of diabetes restricted to pregnant women in whom the recognition of glucose intolerance first occurs during pregnancy.1 Physicians and pharmacists who are trained in the management of diabetes can help guide the patient with GDM through the pregnancy and after delivery, monitor her and the infant. This article reviews the current concepts pertaining to the basic pathophysiology, detection, diagnosis, and management of gestational diabetes mellitus.

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Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome

10.2337/figshare.14488899.v1 ◽

2021 ◽

Author(s):

Mickaël Canouil ◽

Amna Khamis ◽

Elina Keikkala ◽

Sandra Hummel ◽

Stephane Lobbens ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Blood ◽

Epigenetic Effect ◽

Epigenetic Effects ◽

Increased Risk ◽

Design And Methods

Objective: Gestational diabetes mellitus (GDM) is associated with a future offspring risk for the development of obesity and insulin resistance in Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycaemic exposure. Research Design and Methods: We explored the association of GDM exposure on maternal blood and newborn cord-blood methylation of 536 mother-offspring pairs from the prospective FinnGeDi cohort, using Illumina’s methylationEPIC BeadChip 850K arrays. We assessed two hypotheses First, we tested for shared maternal and offspring epigenetic effects due to GDM exposure. Second, we tested whether GDM exposure and maternal methylation has an epigenetic effect on the offspring. Results: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (FDR = 1.38 x 10-2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), plus cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, cg11493553 located in the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI and cg23355087, within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. Conclusion: Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM exposure, but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.

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High pre-pregnancy BMI with a history of gestational diabetes mellitus is associated with an increased risk of type 2 diabetes in Korean women

PLoS ONE ◽

10.1371/journal.pone.0252442 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252442

Author(s):

Dayeon Shin ◽

Kyung Won Lee

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Healthy Weight ◽

Korean Women ◽

Increased Risk ◽

The Future ◽

History Of

Despite the importance of pre-pregnancy body mass index (BMI) and a history of gestational diabetes mellitus (GDM) in the progression of GDM to type 2 diabetes, few studies have evaluated the combined effect of high pre-pregnancy BMI and GDM status on the future development of type 2 diabetes in Korean women. This study aimed to examine the relationship of pre-pregnancy BMI and GDM history with the risk of type 2 diabetes among Korean women. In addition, the effects of pre-pregnancy BMI and current BMI on the risk of type 2 diabetes were evaluated. Women who gave birth in the Health Examinees Study of the Korean Genome and Epidemiology Study from 2004 to 2013 (n = 59,258) were included in this study. Multivariable logistic regression was used to examine the association of pre-pregnancy BMI categories (underweight: <18.5 kg/m2; normal: 18.5–22.9 kg/m2; overweight: 23.0–24.9 kg/m2; obese: ≥25.0 kg/m2) and GDM history with the risk of type 2 diabetes after controlling for the following covariates: age, education, income, smoking status before the first pregnancy, alcohol consumption, regular exercise, menarche age, first pregnancy age, and first pregnancy outcome. Compared to women with normal pre-pregnancy BMIs, women with overweight and obese pre-pregnancy BMIs had higher odds of developing type 2 diabetes (adjusted odds ratio [AOR]: 1.13, 95% confidence interval [CI]: 1.02–1.25 and AOR: 1.29, 95% CI: 1.10–1.50, respectively) after controlling for covariates. Women with pre-pregnancy BMIs <23 kg/m2 and current BMIs ≥23 kg/m2 had increased odds of developing type 2 diabetes (AOR: 1.64, 95% CI: 1.51–1.78) compared to those with pre-pregnancy BMIs <23 kg/m2 and current BMIs <23 kg/m2. Among women without a history of GDM, those with overweight and obese pre-pregnancy BMIs had increased odds of developing type 2 diabetes compared to those with normal pre-pregnancy BMIs (AOR: 1.12, 95% CI: 1.01–1.24 and AOR: 1.23, 95% CI: 1.05–1.44, respectively). Among women with GDM, those with obese pre-pregnancy BMIs had increased odds of developing type 2 diabetes (AOR: 3.84, 95% CI: 1.52–9.87). This study showed that there was a higher likelihood of developing type 2 diabetes in women who were overweight or obese before pregnancy with a history of GDM compared to their counterparts without a history of GDM. Furthermore, high pre-pregnancy BMI or high current BMI increased the risk of type 2 diabetes in Korean women, regardless of GDM history. This emphasizes the importance of maintaining a healthy weight status before and after pregnancy to prevent the future risk of type 2 diabetes.

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