This article proposes five stages in the progression of diabetes, each of which is characterized by different changes in β-cell mass, phenotype, and function. Stage 1 is compensation: insulin secretion increases to maintain normoglycemia in the face of insulin resistance and/or decreasing β-cell mass. This stage is characterized by maintenance of differentiated function with intact acute glucose-stimulated insulin secretion (GSIS). Stage 2 occurs when glucose levels start to rise, reaching ∼5.0–6.5 mmol/l; this is a stable state of β-cell adaptation with loss of β-cell mass and disruption of function as evidenced by diminished GSIS and β-cell dedifferentiation. Stage 3 is a transient unstable period of early decompensation in which glucose levels rise relatively rapidly to the frank diabetes of stage 4, which is characterized as stable decompensation with more severe β-cell dedifferentiation. Finally, stage 5 is characterized by severe decompensation representing a profound reduction in β-cell mass with progression to ketosis. Movement across stages 1–4 can be in either direction. For example, individuals with treated type 2 diabetes can move from stage 4 to stage 1 or stage 2. For type 1 diabetes, as remission develops, progression from stage 4 to stage 2 is typically found. Delineation of these stages provides insight into the pathophysiology of both progression and remission of diabetes.

A major obstacle to successful islet transplantation for both type 1 and 2 diabetes is an inadequate supply of insulin-producing tissue. This need for transplantable human islets has stimulated efforts to expand existing pancreatic islets and/or grow new ones. To test the hypothesis that human adult duct tissue could be expanded and differentiated in vitro to form islet cells, digested pancreatic tissue that is normally discarded from eight human islet isolations was cultured under conditions that allowed expansion of the ductal cells as a monolayer whereupon the cells were overlaid with a thin layer of Matrigel. With this manipulation, the monolayer of epithelial cells formed three-dimensional structures of ductal cysts from which 50-to 150-μm diameter islet-like clusters of pancreatic endocrine cells budded. Over 3–4 weeks culture the insulin content per flask increased 10- to 15-fold as the DNA content increased up to 7-fold. The cultivated human islet buds were shown by immunofluorescence to consist of cytokeratin 19-positive duct cells and hormone-positive islet cells. Double staining of insulin and non-β cell hormones in occasional cells indicated immature cells still in the process of differentiation. Insulin secretion studies were done over 24 h in culture. Compared with their basal secretion at 5 mM glucose, cysts/cultivated human islet buds exposed to stimulatory 20 mM glucose had a 2.3-fold increase in secreted insulin. Thus, duct tissue from human pancreas can be expanded in culture and then be directed to differentiate into glucose responsive islet tissue in vitro . This approach may provide a potential new source of pancreatic islet cells for transplantation.

The regenerative process in the pancreas is of particular interest because diabetes results from an inadequate number of insulin-producing beta cells and pancreatic cancer may arise from the uncontrolled growth of progenitor/stem cells. Continued and substantial growth of islet tissue occurs after birth in rodents and humans, with additional compensatory growth in response to increased demand. In rodents there is clear evidence of pancreatic regeneration after some types of injury, with proliferation of preexisting differentiated cell types accounting for some replacement. Additionally, neogenesis or the budding of new islet cells from pancreatic ducts has been reported, but the existence and identity of a progenitor cell have been debated. We hypothesized that the progenitor cells are duct epithelial cells that after replication undergo a regression to a less differentiated state and then can form new endocrine and exocrine pancreas. To directly test whether ductal cells serve as pancreatic progenitors after birth and give rise to new islets, we generated transgenic mice expressing human carbonic anhydrase II (CAII) promoter: Cre recombinase (Cre) or inducible CreER ^TM to cross with ROSA26 loxP-Stop-loxP LacZ reporter mice. We show that CAII-expressing cells within the pancreas act as progenitors that give rise to both new islets and acini normally after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor of all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes.

Inadequate beta-cell function is an essential component of all forms of diabetes. The most obvious problem is a failure to maintain sufficient beta-cell mass and function to cope with whatever insulin resistance is present. The most striking functional defect is a loss of acute glucose-induced insulin secretion (GIIS). This review discusses the ways in which beta-cells successfully adapt to increased demand and then decompensate as diabetes develops. Successful adaptation is achieved through increased beta-cell mass and increased insulin secretion. The hypothesis is explored that beta-cells exposed to the diabetic milieu lose their differentiation, which leads to loss of specialized functions such as GIIS. This concept has been strengthened by the finding of dedifferentiation of beta-cells in a rat model of partial pancreatectomy that includes a reduction of insulin gene expression, which may further contribute to decreased insulin production. Another finding was increased expression of c-Myc, which probably contributes to an increase in the expression of lactate dehydrogenase and the development of beta-cell hypertrophy. Arguments are developed that the beta-cell changes found in diabetes are better correlated with increased glucose levels than with non-esterified fatty acid levels, thus supporting the importance of glucose toxicity.

To define the consequences of a known reduction of B cell mass in rats, 90% partial pancreatectomies were performed. For the 6 wk following surgery moderate hyperglycemia was maintained in the fed state but there were no differences in body weight nor plasma insulin concentrations compared with sham-pancreatectomized controls. 8-10 wk following surgery regeneration of the remnant was evident with remnant weight being 26%, B cell mass being 42%, and non-B cell mass being 47% of values found for control whole pancreas. There were comparable increases in the remnant content of insulin, glucagon, and somatostatin. Following meal challenges, intraperitoneal and intravenous glucose tolerance tests and intravenous arginine challenge given 6-7 wk after surgery, the insulin responses to glucose were blunted or absent but the responses following the meals or arginine were intact. Similarly, when the pancreatic remnant was perfused in vitro, insulin release after challenge with 300 mg/dl glucose was markedly reduced whereas intact responsiveness to 10 mM arginine was retained. These data suggest that the chronic stimulation of a reduced B cell mass can lead to a selective loss of glucose-induced insulin secretion.