Preface

An adaptive metabolic axis has been a major evolutionary advantage in allowing humans to colonize every part of the globe from arid deserts to permanent ice fields. Prior to an effective food supply chain, metabolic plasticity evolved to deal with seasonal famines balanced by times of plenty, and a greater diversity of diets than perhaps any other mammalian species. In the developed world there are new challenges to metabolic plasticity including food over-abundance, unbalanced diets, child and adult obesity, and an increasing rate of type 1 and 2 diabetes. A plasticity of pancreatic β-cell mass and function are key to metabolic adaption. The β-cell mass normally increases proportionally to fetal and child growth, in response to the added metabolic stress of pregnancy, and in response to the nutritional stress of an obesogenic diet. Yet, in the face of the autoimmune challenge of type 1 diabetes or the glucotoxicity of type 2 diabetes there is a net loss of β-cells with limited potential for endogenous regeneration. Thus lies the paradox. How can a highly physiologically-adaptive β-cell mass prove so difficult to manipulate following the pathological loss that accompanies diabetes?

Key to creating and testing strategies for the therapeutic manipulation of β-cell number is to know their developmental origins and normal ontogeny. The first section of this volume addresses current knowledge around the developmental origins of pancreatic β-cells, and how β-cell mass and proliferation change throughout the human lifespan. The second section explores the mechanisms responsible for β-cell plasticity, drawing from animal models and clinical studies revealing environmental, epigenetic, endocrine and paracrine regulators that contribute to the normal homeostatic processes, and the delicate balance of proliferation vs. apoptotic loss that optimizes β-cell mass during normal metabolic homeostasis. The final section examines the presence and potential of resident stem cells within the pancreas or bone marrow, β-cell progenitors, and the potential for pancreatic endocrine cell differentiation or trans-differentiation.

Underlying each of these chapters is the assumption that β-cells can potentially be replaced endogenously, but only through a thorough understanding of normal development and the exploitation of existing, but perhaps sub-optimal adaptive physiology. There is great reason for confidence. In humans there is reproducible histological evidence of β-cell turnover involving mitogenesis and apoptosis throughout life, including both children and adults with type 1 or type 2 diabetes [1-5]. The regenerative potential of human β-cells may normally be age-limited, since new cells were not generated in the short-term in patients aged over 50 following surgical reduction of pancreatic mass [6]. However, insulin release had improved between 2-4 years post-surgery, suggesting that even in older individuals a slower adaptive replacement of β-cells can occur [7]. Overcoming such physiological limitations to optimize β-cell mass and function to match metabolic demand will likely be a major focus for diabetes research in the coming decade.