Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Hill, David

Affiliation

Lawson Health Research Institute

Abstract

This study investigated whether pancreatic alpha-to-beta-cell transdifferentiation contributes to beta-cell recovery after a partial beta cell depletion using streptozotocin in either neonatal or adult Glucagon-Cre or Glucagon-CreERT2/Rosa26-eYFP transgenic mice. Pancreas immunofluorescence was performed at 2, 14, and 30 days post-treatment. Lineage tracing of alpha-cells showed increased bi-hormonal (YFP+Ins+Gluc+) and transdifferentiated (YFP+Ins+Gluc-) cells in both age groups following STZ, being highest in neonates. However, the greatest functional recovery was detected in adult females following a glucose tolerance test. Despite increased alpha-to-beta-cell transdifferentiation following STZ, beta-cell abundance did not recover to control levels at either age. The relationship between age and islet cell plasticity was further explored in an observational study through immunofluorescence analysis of human pancreas which revealed that bi-hormonal cells are present in non-diabetic individuals throughout the lifespan. These findings highlight islet cell plasticity that is retained to adulthood and its potential for endogenous regenerative therapies for diabetic patients.

Summary for Lay Audience

Diabetes is on the rise globally, and researchers are seeking ways to restore the insulin-producing beta-cells in the pancreas, which are crucial for regulating blood sugar. This study aimed to see if the pancreas can internally generate beta-cells during diabetes through the conversion of alpha-cells, another cell type in the pancreas, and whether this process is influenced by age.

To explore this, we injected a toxin called streptozotocin to specifically reduce the population of beta-cells in newborn and adult mice in order to mimic diabetes. We then examined their pancreas at 2, 14, and 30 days after the treatment. Both strains of mice were designed so that the alpha-cells contained a fluorescent signal, allowing the detection of their transformation into beta-cells. The results showed that, in a diabetic setting, more alpha-cells converted into beta-cells, whether they still retained the characteristics of alpha-cells or fully transformed into insulin-producing cells. This transformation was more pronounced in newborn mice, suggesting the possibility that younger animals have a greater capacity for cellular conversion in the pancreas. However, when assessing ability to lower blood sugar as a functional indicator of beta-cell population recovery, adult female mice showed the greatest improvement. Overall, even with the increase in converted alpha-cells, the beta-cell population did not return to normal levels at 30 days after inducing diabetes in either the young or adult mice.

We also studied pancreatic cells undergoing conversion in humans by analyzing pancreatic samples from non-diabetic donors between 0 to 79 years old. In individuals of all ages, we observed the presence of different cell types producing more than one pancreatic hormone as an indicator of cellular conversion. We also found that one of the cell types producing the two hormones, glucagon and somatostatin, decreased with age. This particular cell type has not been extensively studied, and its implications in diabetes is currently unknown.

These findings highlight that the pancreas retains regenerative abilities in adulthood in both mice and humans. This ability to transform cells within the pancreas could potentially be harnessed to develop new regenerative therapies for diabetes for patients at various ages.

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