In insulin-resistant states, pancreatic islets usually respond by increasing insulin secretion to maintain normoglycemia, a process termed β cell compensation. The mechanisms involved are not fully understood, but it is apparent from rodent studies that both expansion of the β cell mass (10
, S5) and enhanced β cell function are important (12
). Increased β cell mass has been observed in the pancreata of obese compared with lean nondiabetic subjects (8
), although the fold increase (about 50%) is less than seen in rodents, especially mice. The stimulating factors implicated in the compensatory islet responses likely include increased nutrient supply (particularly glucose and FFAs), insulin and other growth factor signaling, and increased levels of and sensitivity to incretin hormones such as glucagon-like peptide 1 (GLP-1) (Figure ).
Mechanisms of β cell compensation for insulin resistance.
For compensatory β cell mass expansion, increased nutrient supply in the blood is important as a stimulant, with considerable evidence for roles for both glucose (10
, S6) and FFAs (10
, S7) (Figure ). Increased enteric nutrient supply, particularly in the form of fat, may also result in β cell mass expansion through increased GLP-1 production from L cells in the intestine (15
). Interestingly, a study in dogs fed a high-fat diet showed β cell compensation even though glucose levels were not elevated, even postprandially, suggesting that glucose is not the primary cause of β cell compensation in that model; increased GLP-1 and FFA signaling were proposed as the stimulants (15
Evidence points to important roles for various growth factor signaling pathways in compensatory β cell growth. Roles have been proposed for insulin and insulin-like growth factors 1 and 2 acting via insulin receptor substrate–2 (IRS-2) (17
). IRS-2 signaling through PKB phosphorylation and inactivation of the forkhead-O transcription factor 1 (FOXO1) increases expression of the homeodomain protein pancreas-duodenum homeobox–1
) gene, an important β cell proliferation and survival factor (11
, S8–S10). Activated PKB provides protection from apoptosis through phosphorylation and inhibition of proapoptotic proteins such as BAD (11
). The major support for this cascade in β cell growth was based on in vitro studies and knockout mouse models. A recent study in Zucker fatty (ZF) rats has provided strong support for PKB activation in the β cell growth response to insulin resistance in this normoglycemic model (11
GLP-1 enhances β cell proliferation and acts as a survival factor by signaling through multiple pathways. GLP-1 can activate IRS-2 and PKB via the cAMP response element–binding protein (CREB) (19
, S11) and transactivation of the EGFR with activation of PKB in a PI3K- and PKC-ζ–dependent manner (20
, S12, S13). FFA signaling via GPR40, also known as FFA receptor 1 (FFAR1), a G protein–coupled receptor that acts as a FA receptor and is highly expressed in islet β cells (21
, S14), might also have a proliferative effect, as was recently described for oleate in breast cancer cells (22
There is considerable debate in the literature with respect to the source of cells for islet expansion in adults. The possibilities include proliferation of existing β cells, including cells in close proximity to ductules, and/or neogenesis from pancreatic ductal cells (8
, S15). The relevance of this debate to human T2D also needs to be carefully considered, as the capacity for human β cell proliferation and neogenesis, particularly in adults, may be much less than in the rodent models that are mostly studied.