One of the causes of type 2 diabetes is a defect of β-cells that reside in islets of Langerhans within the pancreatic gland. The excessive demands for insulin from obese or ageing body are believed to impair the biochemical reactions linking glucose to ATP, the main ‘energy currency’ of a living cell thereby unbundling the stimulus (glucose) from secretion (insulin). The mechanisms of the defect are difficult to study, as it becomes detectable at a late stage of the disease. Pregnancy presents a natural equivalent of diabetes, that comes and goes: an increasing insulin demand makes some mothers-to-be temporally diabetic. Gestational diabetes is observed in experimental animals (mice) and hence can be studied in the laboratory. Despite obvious importance for people with diabetes, little is known about the how and how fast the elevated body weight and levels of circulating ‘pregnancy hormones’, estrogen and progesterone, change glucose handling in β-cells.
Our hypothesis is that pregnancy temporarily makes β-cell energy-related reactions more sensitive to glucose, thereby increasing insulin secretion when needed. This comes at a price of damage to main energetic organelle, mitochondria. We aim to test the hypothesis by imaging how the biochemical reactions induced by glucose progress in pregnant mice or islets that were kept at high concentrations of estrogen/progesterone.
Using fluorescence microscopy we will study:
1. How glucose impacts cellular energy metabolites, such as fructose-1,6-bisphosphate, ATP, NAD(P)H, different forms of oxygen in islets from mice with gestational diabetes.
2. How physiologically important compounds (glucose, GLP-1, GIP, somatostatin) impact intracellular signals (Ca2+ and cAMP). We will also assess:
3. Hormone secretory function and
4. Food intake, body weight, blood insulin and glucose of the experimental mice.
We expect to get a detailed information on changes in islet biochemistry in pregnancy and elucidate how and how fast they are induced.
Please note: Applications for more than one PhD studentship are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission. If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship. In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this project.
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