Reversal of diabetes in patients through islet cell transplant is quickly becoming a reality. However, cadaver organ donations, the current source of islets for transplant, do not provide sufficient islets to transplant all those affected by this disease. Attempts to drive insulin-secreting beta-cells to divide have met with limited, but promising results. Investigating a key cell cycle transcription factor, E2F, we found that human pancreata have low expression of E2Fs which drive proliferation (E2F1-3), but have an abundance of E2Fs (E2F4-6) that inhibit cell division. When compared to expression of E2Fs in proliferative insulinomas, we see the inhibitory E2Fs are nearly absent and E2F3 is highly overexpressed. Using this pattern of E2F expression as a roadmap to drive proliferation, we overexpress E2F3 inducing significant (26% ± 5.7) proliferation of insulin positive cells compared to controls (2.88% ± 0.21), p=0.0046. In human islets, uninfected and LacZ infected beta-cells show little proliferation, 0.5208% ± 0.0579 and 1.504% ± 0.22 respectively, while E2F3 overexpression increased proliferation rates to 7.158% ± 0.4776, p=0.0004. When infected rat islets are transplanted into streptozotocin-induced diabetic nude mice they are able to reverse diabetes, obtaining an average blood glucose of 184.2 ± 30.4 mg/dL with E2F3 infected islets, compared to 280.1 ± 30.4 mg/dL with uninfected islets, p=0.007. Additionally, these mice have an enhanced ability to clear glucose as measured by IPGTT, with an AUC of 24390 mg/dL/min for E2F3 infected islets compared to 42654 mg/dL/min for uninfected, p=0.047. Refinement of this approach may increase the available islets for transplant and research. Furthermore, better understanding of the human beta-cell cycle could provide in vivo regeneration therapies for individuals progressing to diabetes.
To cite this abstract in AMA style:Rady B, Chen Y, Vaca P, Wang Q, Wang Y, Oberholzer J. Human Insulinoma Expression of E2F Reveals a Role in Beta-Cell Proliferation and Quiescence [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/human-insulinoma-expression-of-e2f-reveals-a-role-in-beta-cell-proliferation-and-quiescence/. Accessed August 21, 2018.
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