The role of innervation for hormone secretion in human islets

Project: Research project

Description

There is a fundamental gap in understanding how the islets of Langerhans function in vivo, either in the native
environment in the pancreas or after transplantation to treat type 1 diabetes. Most studies on islet function
have been performed in vitro, and as a consequence little is known about the role of innervation on islet
hormone secretion. The long-term goal of our research is to understand the cell biology of islets of
Langerhans in the living organism. The objective of this particular application is to determine the role
innervation plays in the secretion of islet hormones using a new technological platform allowing in vivo imaging
of vascularized and reinnervated islets after transplantation. In this new technology, islets are transplanted into
the anterior chamber of the eye, and their function is recorded locally and systemically after manipulation of the
eye's neural input. The central hypothesis is that in mouse islets the autonomic nervous system modulates
insulin secretion via parasympathetic cholinergic fibers and glucagon secretion via sympathetic noradrenergic
fibers, but that for human islet function this innervation and its in vivo influence is limited. In this view, mouse
islets are heavily dependent on nervous input, whereas human islets regulate hormone secretion almost
autonomously. The rationale for the proposed research is that the results will contribute a missing,
fundamental element to basic knowledge, without which the biology of human islets cannot be understood.
The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of
fundamental knowledge about the nature and behavior of living systems. Guided by strong preliminary data,
this hypothesis will be tested by pursuing three specific aims: 1) Identify species differences in the innervation
patterns of pancreatic islets in vitro;2) Establish that intraocular islet grafts determine their own innervation
pattern;and 3) Establish the role of neural input on glucose homeostasis in vivo. Under the first aim, the
innervation patterns of islets and the neurotransmitter receptor profiles of the innervated endocrine cell types
will be systematically examined in mouse and human islets using immunohistochemistry and imaging of
intracellular [Ca2+]. Under the second aim, intraocular human and mouse islet grafts will be compared in terms
of immunohistochemical staining patterns and in vivo tracing of autonomic nervous fibers. Under the third aim,
local islet cell responses and regulation of glucose homeostasis by mouse and human islet grafts will be
challenged by activating the parasympathetic and sympathetic components of the pupillary reflex, by
pharmacological blockade, and by selective elimination of the neural input. The proposed work is innovative
because it capitalizes on a new technological platform that allows for the first time in vivo imaging the function
of innervated human and mouse islet. The proposed research is significant because it is expected to advance
and expand current models of the regulation of glucose homeostasis by pancreatic islets.
StatusFinished
Effective start/end date7/1/093/31/17

Funding

  • National Institutes of Health: $36,069.00
  • National Institutes of Health: $330,725.00
  • National Institutes of Health: $342,720.00
  • National Institutes of Health: $115,125.00
  • National Institutes of Health: $191,250.00
  • National Institutes of Health: $383,401.00
  • National Institutes of Health: $342,720.00

Fingerprint

Islets of Langerhans
Hormones
Homeostasis
Glucose
Endocrine Cells
Research
Transplants
Pupillary Reflex
Neurotransmitter Receptor
Islets of Langerhans Transplantation
Anterior Chamber
Type 1 Diabetes Mellitus
Autonomic Nervous System
Axons
Pancreas
Autonomic Pathways
Pericytes
Cell Biology
Transplantation
Immunohistochemistry

ASJC

  • Medicine(all)