Impact of obesity severity and duration on pancreatic [beta]- and [alpha]-cell dynamics in normoglycemic non-human primates

Obesity is associated with high insulin and glucagon plasma levels. Enhanced [beta]-cell function and [beta]-cell expansion are responsible for insulin hypersecretion. It is unknown whether hyperglucagonemia is due to α-cell hypersecretion or to an increase in α-cell mass. In this study, we investigated the dynamics of the [beta]-cell and α-cell function and mass in pancreas of obese normoglycemic baboons. Pancreatic [beta]- and α-cell volumes were measured in 51 normoglycemic baboons divided into six groups according to overweight severity or duration. Islets morphometric parameters were correlated to overweight and to diverse metabolic and laboratory parameters. Relative α-cell volume (RαV) and relative islet α-cell volume (RIαV) increased significantly with both overweight duration and severity. Conversely, in spite of the induction of insulin resistance, overweight produced only modest effects on relative [beta]-cell volume (R[beta]V) and relative islet [beta]-cell volume (RI[beta]V). Of note, RI[beta]V did not increase neither with overweight duration nor with overweight severity, supposedly because of the concomitant, greater increase in RIαV. Baboons' body weights correlated with serum levels of interleukin-6 and tumor necrosis factor-α soluble receptors, demonstrating that overweight induces abnormal activation of the signaling of two cytokines known to impact differently [beta]- and α-cell viability and replication. In conclusion, overweight and insulin resistance induce in baboons a significant increase in α-cell volumes (RαV, RIαV), whereas have minimal effects on the [beta] cells. This study suggests that an increase in the α-cell mass may precede the loss of [beta] cells and the transition to overt hyperglycemia and diabetes.