Pancreatic β-cell proliferation in obesity

Abstract

Because obesity rates have increased dramatically over the past 3 decades, type 2 diabetes has become increasingly prevalent as well. Type 2 diabetes is associated with decreased pancreatic β-cell mass and function, resulting in inadequate insulin production. Conversely, in nondiabetic obesity, an expansion in β-cell mass occurs to provide sufficient insulin and to prevent hyperglycemia. This expansion is at least in part due to β-cell proliferation. This review focuses on the mechanisms regulating obesity-induced β-cell proliferation in humans and mice. Many factors have potential roles in the regulation of obesity-driven β-cell proliferation, including nutrients, insulin, incretins, hepatocyte growth factor, and recently identified liver-derived secreted factors. Much is still unknown about the regulation of β-cell replication, especially in humans. The extracellular signals that activate proliferative pathways in obesity, the relative importance of each of these pathways, and the extent of cross-talk between these pathways are important areas of future study.

FIGURE 1

Differences in β-cell volume in human subjects. With obesity, there is an expansion of β-cells. However, individuals with type 2 diabetes have overall reduced β-cell numbers compared with their nondiabetic counterparts. Values are means ± SDs, n = 4–7. P values were calculated by using the Mann-Whitney test. Plotted from tabular data in reference with permission from publisher S. Karger AG, Basel.

FIGURE 2

Three possible timelines resulting in diminished β-cell mass in type 2 diabetes at the time of autopsy. In the top panel, a failure to achieve adequate β-cell mass during development or early childhood expansion results in decreased β-cell mass that persists throughout life, increasing susceptibility to type 2 diabetes. In the middle panel, a failure to expand β-cell mass in adult life in response to obesity and insulin resistance results in failure to produce adequate insulin and the development of type 2 diabetes. In the bottom panel, compensatory expansion occurs, but then there is increased loss of β-cells that results in lower β-cell mass when measured at autopsy. The dotted lines represent the timeline in an individual with increased susceptibility to diabetes.

FIGURE 3

Multiple pathways can stimulate β-cell replication in obesity, and there is overlap of many of the downstream activators. GLP-1 signals through the GLPR (red arrow) and leads to increased intracellular cAMP, which activates PKA. PKA then phosphorylates and activates the transcription factor CREB. Glucose metabolism (green arrows) increases cAMP levels and can activate the same pathway. PKA also inhibits GSK3-β, which is an activator of the cell cycle inhibitor p27. Glucose metabolism (green arrows) results in production of ATP and membrane depolarization, which leads to an influx of calcium ions. These calcium ions activate CAMK4, which then also phosphorylates and activates CREB. CREB stimulates transcription of IRS-2, which then provides IRS-2 protein necessary for insulin signaling. Insulin signals through the insulin receptor to phosphorylate and activate IRS-2 (purple arrow), leading to activation of PI3K and Akt. Akt inhibits GSK3-β. Akt is also necessary to phosphorylate the inhibitory transcription factor FoxO1 and promote its exclusion from the nucleus. When FoxO1 inhibition is released, transcription of Pdx1 and other genes promoting cell growth can be expressed. GLP-1 signaling can also transactivate EGFR (yellow arrow) and lead to activation of PI3K, ultimately signaling through the same pathways. HGF signaling through its receptor c-Met also stimulates PI3K (orange arrow). Therefore, there is great overlap in the downstream pathways that are involved in signaling in response to GLP-1, glucose metabolism, insulin, and HGF. The cAMP/PKA, GSK3-β, CREB, and IRS-2/PI3K/Akt/FoxO1 pathways are used by multiple upstream mitogenic signals (blue arrows). This overlap suggests that perhaps multiple activators must be present to trigger β-cell proliferation physiologically, but additionally highlights the challenges of interpreting the importance of 1 upstream factor when a downstream target is manipulated experimentally. CAMK4, calcium/calmodulin-dependent kinase; CREB, cAMP response element binding protein; EGFR, epithelial growth factor receptor; FoxO1, forkhead box O1; GLP-1, glucagon-like peptide-1; GLPR, glucagon-like peptide-1 receptor; GSK3-β, glycogen synthase kinase 3-β HGF, hepatocyte growth factor; IRS-2, insulin receptor substrate 2; Pdx1, pancreatic and duodenal homeobox 1; PI3K, phosphoinositide-3 kinase; PKA, protein kinase A.