Alpha-cell-mediated beta-like cell regeneration as a putative therapeutic pathway for type 1 diabetes

Anja Pfeifer, Keith Al-Hasani, Monica Courtney, Nouha Ben-Othman, Elisabet Gjernes, Andhira Vieira, Patrick Collombat

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

Abstract

The human body requires the maintenance of stable and balanced blood glucose levels. This state of homeostasis is strictly regulated by the antagonistic actions of pancreatic peptide hormones, including insulin and glucagon. The mature pancreas consists of two compartments with distinct functions: the exocrine tissue, where digestive enzymes are produced and transported into the duodenum via a widely branched ductal system, and the endocrine compartment that consists of highly vascularized cell-agglomerates, called islets of Langerhans. These functional units include insulin-producing beta-cells and glucagon- secreting alpha-cells. Specifically, upon increased blood sugar levels, insulin is released and induces fat-, muscle-, and red blood cells, to store and/or metabolize glucose. Conversely, glucagon, which is released by alpha-cells in response to low levels of blood glucose, predominantly promotes liver cells to release/synthesize glucose. Should the strictly regulated interplay between insulin and glucagon be impaired, the required narrow range of blood glucose levels can no longer be preserved, and severe diseases, such as diabetes, may arise. Diabetes mellitus, which is the result of a cell-mediated autoimmune destruction of beta-cells, has become one of the most widespread metabolic diseases, affecting almost 6% of the world's population. The absolute or relative deficiency of insulin results in the development of Type 1 Diabetes Mellitus (T1DM) or Type 2 Diabetes Mellitus (T2DM), respectively. Although insulin-based therapy can provide a measure of control of the glycemia in T1DM patients, exogenous insulin can still not ensure physiologically stable blood glucose levels. Differences in diet, age and/or exercise can indeed cause significant variations in the glycemia. Such fluctuations represent a major burden, since they can, over time, lead to a wide range of complications, including micro- and macro-vascular damages, blindness, amputation and/or death. Alternative therapies, such as islet transplantation or in vitro generation of beta-cells, present a number of disadvantages, including life-long immunosuppression, the scarcity of cadaveric donors, or technical inefficiencies. Importantly, using the mouse as a model, a new alternative was recently described in vivo. Indeed, it was demonstrated that glucagon-producing alpha-cells could be continuously regenerated and subsequently converted into functional insulin-expressing beta-like cells, such cells being capable of reversing the consequences of chemically-induced hyperglycemia. This chapter will therefore focus on the potential of alpha-to-beta-like cell transdifferentiation as a therapy for T1DM.

Original languageEnglish
Title of host publicationGlucagon
Subtitle of host publicationStructure, Biosynthesis and Physiological Effects
PublisherNova Science Publishers
Pages149-160
Number of pages12
ISBN (Print)9781626181472
Publication statusPublished - Apr 2013
Externally publishedYes

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