Human β-cell proliferation and intracellular signaling: driving in the dark without a road map

Abstract

A major goal in diabetes research is to find ways to enhance the mass and function of insulin secreting β-cells in the endocrine pancreas to prevent and/or delay the onset or even reverse overt diabetes. In this Perspectives in Diabetes article, we highlight the contrast between the relatively large body of information that is available in regard to signaling pathways, proteins, and mechanisms that together provide a road map for efforts to regenerate β-cells in rodents versus the scant information in human β-cells. To reverse the state of ignorance regarding human β-cell signaling, we suggest a series of questions for consideration by the scientific community to construct a human β-cell proliferation road map. The hope is that the knowledge from the new studies will allow the community to move faster towards developing therapeutic approaches to enhance human β-cell mass in the long-term goal of preventing and/or curing type 1 and type 2 diabetes.

FIG. 1.

A working model depicting some of the multiple signaling pathways that have been reported to modulate cell-cycle activation and/or proliferation in rodent β-cells. Note that although this model is reasonably robust, it is nonetheless preliminary and will require amendment and addition over time. The growth factors (insulin, IGF-I, HGF) and the incretin hormone GLP-1 are linked to the IRS/PI3K pathway, which in turn signals via PDK-1 to modulate Akt and FoxO1. Nutrients have also been reported to modulate PI3K, block AMP-activated protein kinase, and modulate mTORC1. PI3K activation following HGF binding to its tyrosine kinase receptor, c-Met, results in the production of phosphatidylinositol trisphosphate that directly binds to the pleckstrin homology domain of PDK-1. PDK-1 then attaches to the hydrophobic motif of PKCζ, phosphorylates Thr410, and exposes the kinase domain to autophosphorylation of Thr560, a phosphorylation required for full catalytic activity. PKCζ activation leads to inactivation of GSK3β and increased phosphorylation and activation of mTORC1. Activation of mTORC1 is required for PKCζ-mediated induction of rodent β-cell proliferation. Lactogen signaling is activated by the prolactin receptor and acts via Jak2/Stat5 and/or Jak2/Bcl6/menin and/or tryptophan hydroxylases, which generate serotonin. Serotonin is assumed to act via the HTR2b receptor to modulate intracellular calcium and PKC or PI3K members. The FoxO proteins, downstream targets of Akt, are reported to regulate the cell cycle, although it is unclear how this directly impacts β-cell cycle control. Transcriptional repression of cyclin D is required for FoxO-mediated inhibition of cell-cycle progression and transformation, and FoxO proteins have been reported to upregulate the transcription of p27Kip1. The phosphorylation of FoxO1 by Akt is reported to prevent the transcription factor Foxa2 from driving the expression of Pdx1, which mediates the proliferation/differentiation of β-cells in response to FoxO1 (90). Akt can also downregulate p21Cip1 activity indirectly through MDM2/p53. Insulin and IGF-I can also promote proliferation independently of the PI3K pathway by acting through proteins that act by extracellular signal–related kinase-dependent and -independent (Raf1) pathways. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

The rodent and human β-cell G₁/S molecule road map. These are the ultimate targets of upstream mitogenic signaling molecules. Those that activate cell-cycle progression (cyclins and cyclin-dependent kinases) are shown in green, and those that inhibit cell-cycle progression (the pocket proteins, INK4s, and the CIP/KIP families of cell-cycle inhibitors) are shown in red. The two wiring diagrams in rodents and human β-cells appear to be similar, with two exceptions (cyclin D2 and cdk6), indicated in black: 1) human islets have little cyclin D2, whereas this is abundant and critical in rodent β-cells; and 2) human islets contain abundant cdk6, a cdk that is absent in rodent β-cells. See text and references (–66,71) for details. Modified from Cozar-Castellano et al. (66). (A high-quality color representation of this figure is available in the online issue.)

FIG. 3.

Examples of reported upstream signaling pathways that activate cell-cycle progression in the rodent β-cell. This figure illustrates that there are many different ways in which a growth factor or nutrient can activate cell-cycle progression. Please note that the figure is oversimplified for clarity and is also incompletely defined. The Akt/PKB, PKCζ STAT5s, and β-catenin activate one or more cyclins and cdk proteins. MAPK has been reported to modulate Ezh2 to act via p16. CREB/cAMP response element modulator, Nkx6.1 and Pdx1 have been reported to act via the “late” cdks and cyclins, cdk1/2 and cyclins A/E. FoxM1 (91) has been reported to inhibit the Cip/Kip proteins, and menin, activate cMyc, and regulate Skp2 (92,93). PKCζ activation in rodent β-cells leads to upregulation of cyclin Ds and A and diminished expression of p21. Modulation of one or more of these cell-cycle proteins is critical for phosphorylation and inactivation of pRb so that it can release the E2F transcription factors that are required for cell-cycle progression. Several additional β-cell mitogenic signaling pathways likely exist, including those activated by estrogen/progesterone receptors, and JUN kinase (depicted as “?”). Green indicates proteins that promote proliferation, whereas red indicates proteins that inhibit proliferation. (A high-quality color representation of this figure is available in the online issue.)

FIG. 4.

The rudimentary human β-cell mitogenic signaling road map. Contrast this figure to Fig. 1. The gray lines are molecules and pathways that are known to exist in rodents but are unstudied in human β-cells. The human β-cell signaling road map is underdeveloped: Although the human G₁/S molecules are reasonably well-characterized in the human β-cell (66), only a handful of growth factor receptors (e.g., IR, IGF-1R, and c-Met) and signaling molecules (IRS-1, IRS-2, PI3K, Akt, PKCζ, and GSK3β) are known to be present in human β-cell, and the majority of the proteins involved in signaling have not been studied.