Islet cell dynamics and metabolites variations throughout the spectrum of β-cells deficit

Number of pages52
Imprimatur date2023-08
Defense date2023-07

The main feature of type 1 diabetes (T1D) is the autoimmune destruction of the insulin-producing β-cells in the islets of Langerhans. This process of destruction is progressive, following different stages and can take months or even years, eventually leading to severe insulin deficiency and overt diabetes. However, there is a gap of knowledge regarding the number of β-cells that needs to be lost to progress through the different diabetes stages as well as markers that follow this destruction. In the latest stages, the marked insulin deficiency leads to chronic hyperglycaemia, as well as increasing the risk of severe complications. In addition, the other islet cell types (α-, δ- and γ-cells) are also impacted by the loss of β-cells and present dysregulated hormone secretion, contributing to the physiopathology of diabetes, and hampering glycaemic management. TD1 patients α cells secrete more glucagon and δ-cells tend to secrete more somatostatin under hypoglycaemic condition.

The main objectives of the project are to understand the link between β cell mass and glucose homeostasis impairment as well as characterise the impacts on δ cells. To understand how the gradual loss of β-cells affects glycemia and δ-cells morphology, we are using a transgenic mouse model (RIP-DTR) that enables us to specifically ablate β-cells by injecting a precise dose of diphtheria toxin. Using this model, we can artificially mimic the different stages leading to type 1 diabetes. This will allow us to assess the dynamics of metabolic markers of diabetes loss already used in clinic (proinsulin and ketone bodies) as well as δ-cell function (by assessing plasmatic somatostatin) during the different β-cell loss stages. The adaptations of δ-cells to the loss of β-cell were also assessed by immunofluorescence.

We have observed that a loss of more than 80% of β cells is necessary for the first symptoms associated with hyperglycaemia to appear (weight loss, blood glucose levels above 12mM). At this stage, the blood concentration of many metabolites (proinsulin, ketone bodies) is altered. Moreover, while the secretion of somatostatin does not appear to be altered in hyperglycemia condition, we found several cellular adaptations of this cell type upon β-cell loss. Specifically, we found an increase in δ cells proliferation, which lead to an increased δ-cell number per islet. They also present an increase in size or hypertrophy compared to δ-cells of non-diabetic mice.

The dynamics of cellular changes within the pancreatic islets suggest that there is reorganisation of structure and communication between endocrine cells, either to compensate for or in response to the loss of insulin-producing cells. These modifications of δ cell behaviours don’t impact somatostatin secretion at high glucose level.

By analysing these dynamics, and with the help of complementary methods such as imaging, we can devise effective ways of monitoring the quantity and function of β-cells to enable early detection of patients at risk of developing type 1 diabetes. By understanding precisely, the adaptative responses of δ cells to β cell loss, we could modulate this response to improve hormonal control and islet functions.

Citation (ISO format)
KINTZINGER, Mélanie Mugette Rolande. Islet cell dynamics and metabolites variations throughout the spectrum of β-cells deficit. 2023.
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Master thesis
  • PID : unige:171024

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Creation08/23/2023 10:29:16 AM
First validation08/30/2023 8:47:46 AM
Update time08/30/2023 8:47:46 AM
Status update08/30/2023 8:47:46 AM
Last indexation08/31/2023 12:16:44 PM
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