الفهرس 
scope, aims and thesis outlineOnly 14 pages are availabe for public view
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Abstract
Diabetes is a major public health problem that is now affecting nearly half a billion people worldwide, and considered one of the top ten causes of death. Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is the hormone that regulates the blood glucose level. Hyperglycemia is the common feature of uncontrolled diabetes, and over time it affects almost every cell in the body and causes serious damage to many of the body systems. The main categories of diabetes are type 1, type 2 and gestational diabetes mellitus (GDM).
GDM is the most common medical complication of pregnancy. It defined as any degree of glucose intolerance with onset or first recognition during pregnancy. As the global epidemic of diabetes continues to expand, prevalence of GDM increased to affect almost 16 % of pregnancies worldwide. Failure to adapt the metabolic demands of pregnancy due to inadequate insulin secretion and/or peripheral insulin resistance is the major determinant of GDM progression. GDM is associated with multiple adverse pregnancy outcomes. Women with GDM are at subsequent high risk of type 2 diabetes mellitus (T2DM) and cardiovascular disorders later in their life. Exposure to hyperglycemia in utero predisposes children to an elevated risk of obesity, insulin resistance, cardiometabolic disorders and the development of T2DM at the adulthood.
Current treatment strategies for GDM include lifestyle change (healthy diet and physical activity) and/or insulin injections. If those fail to sustain normoglycemia, the oral antidiabetic drugs of T2DM (as glyburide, metformin or their combination) are prescribed. The use of these medications during pregnancy is still a matter of great debate due to several adverse effects, and even less is known about their impact on the long-term health of mothers and offspring, proposing further investigations. Therefore, it is desirable to find effective new alternatives. Natural antioxidants usage is increasingly observed during pregnancy, but this requires evidence-based assessment for their effects. Cinnamaldehyde (Ci), as being a natural antioxidant and antidiabetic agent, was first tested by our group for its effect on GDM using the fat-sucrose diet/streptozotocin rat model that simulates many of the clinical characteristics of the human disease. Ci alleviated the maternal and fetal glycemia, increased the insulin secretion and sensitivity, inhibited the induction of oxidative stress and inflammation, and restored the maternal reproductive performance.
The main aim of this PhD research is to provide a deeper understanding of GDM pathophysiology using genome-wide transcriptome, targeted biochemical, metabolome, metal analysis and histopathology in order to develop safe and efficient therapies to protect from the negative impact of GDM on pregnancy and offspring health.
The specific aims of this PhD study were as following:
1. To evaluate the possible vasoprotective effect of Ci on GDM-induced placental vascular dysfunction, as the placenta is the primary interface between maternal and fetal circulations and plays an essential role for the proper fetal growth.
2. To investigate the possible hepatoprotective effect of Ci on both maternal and fetal liver structure and function, as the liver is the focal organ of carbohydrate metabolism, blood glucose homeostasis and detoxifying processes.
3. To assess the long-term therapeutic significance of maternal intake of Ci during the gestation and lactation times on the protection from the transgenerational diabetic risk of GDM on the adult offspring.
4. To detect whether cinnamaldehyde passes through the placental barriers to fetal circulation, as well as into the breast milk or not.
5. To compare the antidiabetic efficacy of Ci to that of the commonly prescribed oral hypoglycemic medication for GDM; glyburide/metformin-HCl (Gly/Met).
The research work done during the course of this PhD study is described in the following chapters:
Chapter 1: In this chapter we reviewed the literature on GDM pathophysiology and the treatment strategies highlighting the current knowledge and unmet needs.
Chapter 2: Here we explored the efficacy of the antidiabetic action of Ci on mitigating placental vascular dysfunction induced by GDM, and protection from the associated fetal hypoxia. Our multi-level analysis revealed five possible factors that occurred in combination and resulted in a decrease in oxygen delivery to the fetuses in GDM: (1) placental hypervascularization/vasoconstrictive remodelling that might cause a decrease in the blood flow to the fetus, (2) placental active metabolism that possibly increased the placenta oxygen consumption, (3) placental oxidative stress that might lead to an impairment in the placenta functions, (4) fetal hyperglycemia and hyperinsulinemia that could exacerbate the fetal oxygen consumption by activating the aerobic metabolism, and (5) fetal hepatic iron deficiency that might hamper the fetal erythropoiesis. Combining the transcript profiling with biochemical and histopathological approaches provided an integrative insight into the mechanism of Ci action that indicated potent effects on multiple control points. Ci improved the materno-fetal glycemia, diminished the placenta vasculopathy and oxidative stress, alleviated placental metabolism, and restored fetal liver iron content, and thus, protecting the fetuses from hypoxia. Lack of the effectiveness of the hypoglycemic targeted drug ”Gly/Met” on the impaired placental vascular performance draws the medical community’s attention to the vital role of the placenta in developing effective medications for GDM.
Chapter 3: In this chapter we studied the possible hepatoprotective effect of Ci on both maternal and fetal liver injury caused by GDM. GDM induced serious maternal and fetal hepatic structural and functional abnormalities that included prominent oxidative stress, impairment of the antioxidant defenses, in addition to hepatic fatty depositions, inflammation, necrosis, fibrosis and congested veins. A depletion of the storable glycogen and proteins, elevation of the proliferating cell nuclear antigen (PCNA) expression in the hepatocellular nuclei, along with the increase in serum lipids and transaminases activity were also detected. Moreover, maternal and fetal pancreatic islets showed structural and morphometric alterations, reflecting maladaptation of the islets to pregnancy requirements. Effectively, maternal treatment with Ci decreased the circulating lipids and transaminases, attenuated the liver oxidative stress, restored the normal islets and hepatic configurations, prevented the abnormal hepatocellular proliferation, and normalized the hepatic glycogen and proteins contents. While Gly/Met intake achieved potent glycemic control than Ci, it did not provide the sufficient hepatic redox balance in both maternal and fetal compartments. This chapter also showed for the first time that Ci and its metabolites do not transfer across the placenta to fetal circulation, reflecting its safe antidiabetic properties.
Chapter 4: This chapter highlights the importance of the therapeutic intervention in GDM during pregnancy and lactation for the long-term health of the upcoming generation. We found that fetal environmental exposures to GDM primed the adult offspring to metabolic risks of T2DM and obesity even with the low energy diet intake postnatally. GDM induced overweight, insulin resistance, hepatic steatosis and oxidative stress in the adult offspring. In addition, islets’ number and size were increased reflecting functional impairment of the endocrine pancreas at adulthood. Results revealed that the early maternal treatment with Ci increased the insulin sensitivity, improved β-cells functionality, protected against the liver metabolic derangements, and diminished the susceptibility to oxidative stress in the adult offspring effectively more than Gly/Met. As well, by using the sensitive Ultra-Performance Liquid chromatography-Electrospray Ionization tandem Mass Spectrometry (UPLC-ESI MS/MS) we were unable to detect Ci or its metabolites in the breast milk, suggesting that they do not transfer from maternal circulation to the milk and thus reflects the safety of Ci intake during the lactation period.
Chapter 5: This chapter contains a general discussion, summarizing the main results and giving an overview of the impact of GDM on mothers and offspring health. In addition, it providing an integrative insight into the therapeutic benefits of Ci in the management of GDM complications, and presenting a common conclusion and future perspectives drawn from all the findings.
Key words: Gestational diabetes, placental dysfunction, hepatic injury, pancreatic maladaptation, oxidative stress, gene expression, transgenerational complications, metabolic disorders, cinnamaldehyde.