Implications of Integrated Pancreatic Microcirculation: Crosstalk between Endocrine and Exocrine Compartments

Abstract

The endocrine and exocrine pancreas have been studied separately by endocrinologists and gastroenterologists as two organ systems. The pancreatic islet, consisting of 1-2% mass of the whole pancreas, has long been believed to be regulated independently from the surrounding exocrine tissues. Particularly, islet blood flow has been consistently illustrated as one-way flow from arteriole(s) to venule(s) with no integration of the capillary network between the endocrine and exocrine pancreas. It is likely linked to the long-standing dogma that the rodent islet has a mantle of non-β-cells and that the islet is completely separated from the exocrine compartment. A new model of islet microcirculation is built on the basis of analyses of in vivo blood flow measurements in mice and an in situ three-dimensional structure of the capillary network in mice and humans. The deduced integrated blood flow throughout the entire pancreas suggests direct interactions between islet endocrine cells and surrounding cells as well as the bidirectional blood flow between the endocrine and exocrine pancreas, not necessarily a unidirectional blood flow as in a so-called insuloacinar portal system. In this perspective, we discuss how this conceptual transformation could potentially affect our current understanding of the biology, physiology, and pathogenesis of the islet and pancreas.

Figure 1

Three models of islet blood flow. Adapted from Dybala et al. (4).

Figure 2

Islet formation: Exocrine pancreas plays a pivotal role during early development. A: Expression of transcription factors Pdx1 and Ptf1a during early foregut endoderm development. B: In healthy mice (left), islets are distributed throughout the pancreas and integrated with the acinar tissue of the exocrine pancreas. In Ptf1a knockout (KO) mice (right), the pancreas fails to form, and endocrine cells are found randomly scattered throughout the spleen. E, embryonic day; PP, pancreatic polypeptide.

Figure 3

Two distinct models of islet formation. A: Islet aggregation model. Endocrine and exocrine precursor cells line the BM and ECM of the epithelium in the developing pancreas. Endocrine (islet) precursors pass through the BM and ECM before reaggregating into islets in the mesenchyme. B: Fission model of islet formation during fetal and neonatal development. a: Endocrine cells (β-cells in red, α-cells in green) proliferate contiguously, forming branching cord-like structures. b: Islet formation progresses with fission of branched cords. Note the random distribution of islet size. c: Further expansion of β-cells within the newly formed islets leads to the observed α-cell proportion of 5–10%. Adapted from Miller et al. (24).

Figure 4

Small pancreas in patients with T1D. Lack of insulin may affect exocrine pancreatic volume as a growth factor. Functional islets in healthy patients (left) are integrated with the exocrine pancreas, providing sufficient insulin for normal growth and function. In patients with T1D (right), β-cells are lost, and insulin perfusion in the exocrine tissue is reduced with decreased exocrine and whole-pancreas volume. PP, pancreatic polypeptide.

Figure 5

Exocrine inflammation directly affects β-cell/islet function through the integrated pancreatic blood flow. Normal function of the exocrine pancreas is disrupted in CFRD and T3c diabetes, leading to β-cell/islet dysfunction. Inflammatory cytokines associated with exocrine pancreatic disease, such as IL-6 in CFRD, travel throughout the pancreas to the islets, eventually leading to progressive endocrine hormone deficiency. Normal bidirectional blood flow between endocrine and exocrine pancreas facilitates the exchange of cytokines central to the pathogenesis of CFRD and T3c diabetes.