Dataset Information

Formation of a human ?-cell population within pancreatic islets is set early in life.

ABSTRACT:

Context

Insulin resistance can be compensated by increased functional pancreatic ?-cell mass; otherwise, diabetes ensues. Such compensation depends not only on environmental and genetic factors but also on the baseline ?-cell mass from which the expansion originates.

Objective

Little is known about assembly of a baseline ?-cell mass in humans. Here, we examined formation of ?-cell populations relative to other pancreatic islet cell types and associated neurons throughout the normal human lifespan.

Design and methods

Human pancreatic sections derived from normal cadavers aged 24 wk premature to 72 yr were examined by immunofluorescence. Insulin, glucagon, and somatostatin were used as markers for ?-, ?-, and ?-cells, respectively. Cytokeratin-19 marked ductal cells, Ki67 cell proliferation, and Tuj1 (neuronal class III ?-tubulin) marked neurons.

Results

Most ?-cell neogenesis was observed preterm with a burst of ?-cell proliferation peaking within the first 2 yr of life. Thereafter, little indication of ?-cell growth was observed. Postnatal proliferation of ?- and ?-cells was rarely seen, but a wave of ductal cell proliferation was found mostly associated with exocrine cell expansion. The ?-cell to ?-cell ratio doubled neonatally, reflecting increased growth of ?-cells, but during childhood, there was a 7-fold change in the ?-cell to ?-cell ratio, reflecting an additional loss of ?-cells. A close association of neurons to pancreatic islets was noted developmentally and retained throughout adulthood. Negligible neuronal association to exocrine pancreas was observed.

Conclusion

Human baseline ?-cell population and appropriate association with other islet cell types is established before 5 yr of age.

SUBMITTER: Gregg BE

PROVIDER: S-EPMC3431572 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Formation of a human β-cell population within pancreatic islets is set early in life.

Gregg Brigid E BE Moore Patrick C PC Demozay Damien D Hall Ben A BA Li Mei M Husain Aliya A Wright Amy J AJ Atkinson Mark A MA Rhodes Christopher J CJ

The Journal of clinical endocrinology and metabolism 20120628 9

<h4>Context</h4>Insulin resistance can be compensated by increased functional pancreatic β-cell mass; otherwise, diabetes ensues. Such compensation depends not only on environmental and genetic factors but also on the baseline β-cell mass from which the expansion originates.<h4>Objective</h4>Little is known about assembly of a baseline β-cell mass in humans. Here, we examined formation of β-cell populations relative to other pancreatic islet cell types and associated neurons throughout the norma ...[more]

PMID: 22745242

Similar Datasets

Project description:Type 1 diabetes (T1D) occurs as a consequence of the autoimmune destruction of insulin-producing pancreatic beta (β) cells and commonly presents with insulin deficiency and unregulated glycemic control. Despite improvements in the medical management of T1D, life-threatening complications are still common. Beta-cell replication to replace lost cells may be achieved by using small-molecule mitogenic drugs, like harmine. However, the safe and effective delivery of such drugs to beta cells remains a challenge. This work aims to deploy an antibody conjugated nanocarrier platform to achieve cell-specific delivery of candidate therapeutic and imaging agents to pancreatic endocrine cells. We approached this goal by generating core-shell type micellar nanocarriers composed of the tri-block copolymer, Pluronic®F127 (PEO100-PPO65-PEO100). We decorated these nanocarriers with a pancreatic endocrine cell-selective monoclonal antibody (HPi1), with preference for beta cells, to achieve active targeting. The PPO-based hydrophobic core allows encapsulation of various hydrophobic cargoes, whereas the PEO-based hydrophilic shell curbs the protein adhesion, hence prolonging the nanocarriers' systemic circulation time. The nancarriers were loaded with quantum dots (QDots) that allowed nanocarrier detection both in-vitro and in-vivo. In-vitro studies revealed that HPi1 conjugated nanocarriers could target endocrine cells in dispersed islet cell preparations with a high degree of specificity, with beta cells exhibiting a fluorescent quantum dot signal that was approximately five orders of magnitude greater than the signal associated with alpha cells. In vivo endocrine cell targeting studies demonstrated that the HPi1 conjugated nanocarriers could significantly accumulate at the islet xenograft site. For drug delivery studies, the nanocarriers were loaded with harmine. We demonstrated that HPi1 conjugated nanocarriers successfully targeted and delivered harmine to human endocrine cells in a human islet xenograft model. In this model, targeted harmine delivery yielded an ~ 41-fold increase in the number of BrdU positive cells in the human islet xenograft than that observed in untreated control mice. By contrast, non-targeted harmine yielded an ~ 9-fold increase in BrdU positive cells. We conclude that the nanocarrier platform enabled cell-selective targeting of xenografted human pancreatic endocrine cells and the selective delivery of the hydrophobic drug harmine to those cells. Further, the dramatic increase in proliferation with targeted harmine, a likely consequence of achieving higher local drug concentrations, supports the concept that targeted drug delivery may promote more potent biological responses when using harmine and/or other drugs than non-targeting approaches. These results suggest that this targeted drug delivery platform may apply in drug screening, beta cell regenerative therapies, and/or diagnostic imaging in patients with type 1 diabetes.