It's easy to say we are what we eat, but this simple statement belies the complexity of metabolic signalling that goes into balancing food intake with energy expenditure. One hormone in particular—insulin—is a critically important regulator of whole body energy metabolism. It is secreted from the pancreas when blood glucose levels are high, and it acts to maintain glucose homeostasis by promoting glucose uptake and storage in muscle, fat, and liver. When insulin secretion is absent or reduced, or when peripheral tissues fail to respond to insulin, the result is hyperglycaemia leading ultimately to diabetes. Diabetes affects more than 170 million people worldwide and is associated with several long-term complications including nerve damage, kidney failure, microcirculatory impairment, and a greater risk for heart disease and stroke.
There are two types of secretion: exocrine and endocrine. In endocrine secretion, the secreted molecules end up in the blood and they reach their target cells throughout the body via the circulation. By contrast, exocrine secretion does not involve the circulation and the products are released directly into the outside world. Most of the pancreas serves the exocrine function of secreting digestive enzymes into the gut. Less than 1% of the pancreatic tissue is devoted to an endocrine function. The endocrine tissue of the pancreas is organized as cell clusters, called the islets of Langerhans, which are dispersed throughout the pancreatic exocrine tissue and receive a rich vascular (blood vessel) supply ( Figure 1). A pancreatic islet comprises three main cell types. Pancreatic α cells (15%) occupy the islet periphery and secrete glucagon in response to low blood glucose. Glucagon opposes the actions of insulin, thereby increasing circulating glucose levels. Pancreatic δ cells, the least abundant cell type (5%), are dispersed throughout the islet and secrete somatostatin, which has important paracrine effects that suppress insulin and glucagon secretion. The insulin-secreting β cells are the most abundant cell type (80%) and comprise the islet core.
During development, the pancreas arises as an off-branching of early gut tissues, and develops as a set of branching tubules which give rise to clusters of endocrine and exocrine cells. Studies have shown that the cytokine TGF-β plays a major role in the development of pancreatic β cells during development of the organ [ 1, 2], and a paper by Smart et al. in this issue of PLoS Biology [ 3] demonstrates that TGF-β signalling is also critical in the maintenance of β cell functional identity in the adult. Smart and her colleagues were able to show that loss of TGF-β signalling in these cells causes reversion of these cells to an immature differentiated state and resulted in diabetes. Therefore, TGF-β is important for maintaining the functional characteristics of β cells.
In type 1 diabetes, the less common but more severe form of the disease, pancreatic β cells are destroyed by an autoimmune reaction. Type 2 diabetes accounts for greater than 85% of the cases of diabetes. In this form of the disease, the β cells persist, but for reasons that remain to be established they fail to secrete insulin in sufficient quantities to maintain blood glucose within the normal range. Disrupted insulin secretion is observed prior to onset of type 2 diabetes [ 4], and when combined with the development of insulin resistance in peripheral tissues, results in chronic hyperglycaemia. Further deterioration of β cell function contributes to the progression of type 2 diabetes [ 5]. Type 2 diabetes is believed to result from an unfortunate combination of variants (polymorphisms) in several diabetes susceptibility genes [ 6]. Rarer monogenic forms of the disease result from mutations in genes encoding proteins that are critical to glucose-sensing in the β cell [ 7]. Thus, an appreciation of the mechanisms regulating β cell function and insulin secretion is crucial towards understanding the pathogenesis of type 2 diabetes.