From the pancreatic beta cell to the endothelium:Pathophysiological aspects of Type 2 Diabetes

The incidence of Diabetes Mellitus increases globally in epidemic proportions. Type 2 Diabetes is the most prevalent form of Diabetes, comprising 90% of the patients. In Type 2 Diabetes, two processes contribute to the development of the disease: insufficient insulin secretion from the pancreatic ?-cell and insulin resistance of the target organs. This leads to loss of control of blood glucose levels, which characterize Diabetes. Even while blood glucose levels can be controlled by a variety of life-style and pharmacological interventions, complications often arise. These complications include cardiovascular disease, retinopathy, neuropathy, and nephropathy. In this thesis, different aspects of pathophysiological mechanisms in Type 2 Diabetes were studied. The aims were (i) to identify the voltage-gated calcium channel that is coupled to glucose-stimulated insulin secretion in the rat clonal ?-cell line INS-1 832/13; (ii) to investigate the mechanism of ?-cell adaptation in the C57BL/6J mouse model of insulin resistance; (iii) to determine whether spontaneous glucose tolerance was a feature in the RIP2-Cre mouse model which is often used for ?-cell specific knockout of genes; and (iv) to study the presence of insulin receptors and IGF-I receptors in human endothelial cells of different origin. It was established that CaV1.2 was the main voltage-gated calcium channel coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells, confirming previous results obtained from mouse ?-cells. C57BL/6J mice on a high-fat diet become insulin resistant but do not develop Diabetes. The hypersecretion of insulin from the ?-cells of these animals is due to a shift in metabolic fuels from glucose to fatty acids and amino acids. The ?-cells of these mice have a high fat content that might interfere with the function of glucose transporters. Furthermore, an increase in mitochondrial mass was observed in the ?-cells of insulin-resistant C57BL/6J mice. All these alterations are part of the ?-cell adaptation, which enables the mice to secrete sufficient insulin in order to prevent the development of overt Diabetes. C57BL/6J mice were also used to backcross RIP2-Cre mice onto. Absence of the recently reported five-exon deletion in the nnt gene in the C57BL/6J mice used, contributed to normal glucose tolerance in both mice strains studied. The expression of Cre recombinase did not affect glucose tolerance and this mouse strain on this background can be used in ?-cell specific knockout studies. Human endothelial cells from coronary artery and umbilical vein expressed more IGF-I receptors than insulin receptors. Indications for the presence of insulin/IGF-I hybrid receptors were found in both endothelial cell types. These results reflect the importance of IGF-I in the development of vascular complications of Diabetes Mellitus

Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes

Objective: Gene expression alterations, especially in target tissues of insulin, have been associated with type 2 diabetes (T2D). In this study, we examined if genes involved in oxidative phosphorylation (OXPHOS) show differential gene expression and DNA methylation in pancreatic islets from patients with T2D compared with non-diabetic donors. Design and methods: Gene expression was analyzed in human pancreatic islets from 55 non-diabetic donors and nine T2D donors using microarray. Results: While the expected number of OXPHOS genes with reduced gene expression is 7.21, we identified 21 downregulated OXPHOS genes in pancreatic islets from patients with T2D using microarray analysis. This gives a ratio of observed over expected OXPHOS genes of 26.37 by a χ-test with P=2.81 × 10. The microarray data was validated by qRT-PCR for four selected OXPHOS genes: NDUFA5, NDUFA10, COX11, and ATP6V1H. All four OXPHOS genes were significantly downregulated in islets from patients with T2D compared with non-diabetic donors using qRT-PCR (P≤0.01). Furthermore, HbAlc levels correlated negatively with gene expression of NDUFA5, COX11, and ATP6V1H (

Maternal health and the placental microbiome

Over the past decade, the role of the microbiome in regulating metabolism, immune function and behavior in humans has become apparent. It has become clear that the placenta is not a sterile organ, but rather has its own endogenous microbiome. The composition of the placental microbiome is distinct from that of the vagina and has been reported to resemble the oral microbiome. Compared to the gut microbiome, the placental microbiome exhibits limited microbial diversity. This review will focus on the current understanding of the placental microbiota in normal healthy pregnancy and also in disease states including preterm birth, chorioamnionitis and maternal conditions such as obesity, gestational diabetes mellitus and preeclampsia. Factors known to alter the composition of the placental microbiota will be discussed in the final part of this review

Predictors of preeclampsia in women in the metformin in gestational diabetes (MiG) study

Background: Gestational Diabetes Mellitus (GDM), maternal obesity and pregnancy weight gain are associated with an increased risk of developing Preeclampsia (PE). The aim of this study was to examine the predictors of PE in women commencing pharmacotherapy for GDM in the Metformin in Gestational diabetes trial.Methods: Descriptive and logistic regression analyses examined the relationship between maternal enrolment characteristics and later development of PE.Results: 46 (6.3%) of 703 women developed PE. At enrolment ((30 (SD3.2) weeks gestation), women who later developed PE had higher HbA1c (6.14% (95% CI 5.84, 6.45) vs. 5.73% (95% CI 5.67, 5.78), P = 0.003), fasting triglycerides (2.93 mmol/L (95% CI 2.57, 3.29) vs. 2.55mmol/L (95% CI 2.47, 2.62), P = 0.03) and blood pressure. Their infants were born 9 days earlier (P < 0.001) but were otherwise not different. In univariate analysis, the strongest positive predictors for PE were Polynesian ethnicity (OR 2.75 (95% CI 1.48, 5.09), P= 0.001), personal or family history of PE (OR 2.65 (95% CI 1.36, 5.16), P=0.004), maternal HbA1c (OR 1.96 (95% CI 1.35, 2.89), P< 0.001), triglycerides (OR 1.45 (95% CI 1.07,1.97), P=0.002), and weight gain from early pregnancy (OR 1.09 (95% CI 1.03,1.17), P=0.01). HDL-C was a negative predictor of PE (OR 0.29 (95% CI 0.09, 0.94), P= 0.04).Following adjustment for Polynesian ethnicity and personal or family history of PE, and when further adjusted for HbA1c or early pregnancy BMI, these variables remained significant.Conclusion: Treatment allocation and BMI were not associated with risk of PE. Personal or family history of PE, Polynesian ethnicity, degree of hyperglycemia, maternal triglycerides and weight gain prior to treatment signal increased risk of subsequent PE in women needing pharmacotherapy for GDM

Review: Placental mitochondrial function and structure in gestational disorders

The aetiology of many gestational disorders is still unknown. However, insufficient trans-placental nutrient and oxygen transfer due to abnormal placentation is characteristic of several pathologies, and may alter the function of placental mitochondria. Mitochondria are multifunctional organelles that respond to a wide range of stimuli - such as physiological changes in cellular energy demands or various pathologies - by reshaping via fusion or fission, increasing/decreasing in number, altering oxidative phosphorylation, and signalling cellular functions such as apoptosis. Mitochondrial function is integral to tissue functions including energy production, metabolism, and regulation of various cellular responses including response to oxidative stress. This review details the functions of placental mitochondria and investigates mitochondrial function and structure in gestational disorders including preeclampsia, intrauterine growth restriction, diabetes mellitus, and obesity. Placental mitochondrial dysfunction may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health

SPRING: an RCT study of probiotics in the prevention of gestational diabetes mellitus in overweight and obese women

Background: Obesity is increasing in the child-bearing population as are the rates of gestational diabetes. Gestational diabetes is associated with higher rates of Cesarean Section for the mother and increased risks of macrosomia, higher body fat mass, respiratory distress and hypoglycemia for the infant. Prevention of gestational diabetes through life style intervention has proven to be difficult. A Finnish study showed that ingestion of specific probiotics altered the composition of the gut microbiome and thereby metabolism from early gestation and decreased rates of gestational diabetes in normal weight women. In SPRING (the Study of Probiotics IN the prevention of Gestational diabetes), the effectiveness of probiotics ingestion for the prevention of gestational diabetes will be assessed in overweight and obese women