Imaging Insulin Secretion from Mouse Pancreas by MRI Is Improved by Use of a Zinc-Responsive MRI Sensor with Lower Affinity for Zn 2+ Ions

J Am Chem Soc. 2018 Dec 19;140(50):17456-17464. doi: 10.1021/jacs.8b07607. Epub 2018 Dec 11.

Abstract

It has been demonstrated that divalent zinc ions packaged with insulin in β-cell granules can be detected by MRI during glucose-stimulated insulin secretion using a gadolinium-based Zn2+-sensitive agent. This study was designed to evaluate whether a simpler agent design having single Zn2+-sensing moieties but with variable Zn2+ binding affinities might also detect insulin secretion from the pancreas. Using an implanted MR-compatible window designed to hold the pancreas in a fixed position for imaging, we now demonstrate that focally intense "hot spots" can be detected in the tail of the pancreas using these agents after administration of glucose to stimulate insulin secretion. Histological staining of the same tissue verified that the hot spots identified by imaging correspond to clusters of islets, perhaps reflecting first-responder islets that are most responsive to a sudden increase in glucose. A comparison of images obtained when using a high-affinity Zn2+ sensor versus a lower-affinity sensor showed that the lower-affinity sensors produced the best image contrast. An equilibrium model that considers all possible complexes formed between Zn2+, the GdL sensor, and HSA predicts that a GdL sensor with lower affinity for Zn2+ generates a lower background signal from endogenous Zn2+ prior to glucose-stimulated insulin secretion (GSIS) and that the weaker binding affinity agent is more responsive to a further increase in Zn2+ concentration near β-cells after GSIS. These model predictions are consistent with the in vivo imaging observations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Contrast Media / chemical synthesis
  • Contrast Media / chemistry*
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Gadolinium / chemistry
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion / physiology*
  • Insulin-Secreting Cells / metabolism
  • Magnetic Resonance Imaging / methods
  • Male
  • Mice, Inbred C57BL
  • Pancreas / cytology
  • Pancreas / metabolism*
  • Protein Binding
  • Serum Albumin, Human / chemistry
  • Serum Albumin, Human / metabolism
  • Zinc / chemistry
  • Zinc / metabolism*

Substances

  • Contrast Media
  • Coordination Complexes
  • Insulin
  • Gadolinium
  • Zinc
  • Serum Albumin, Human