Contact:
Dr
Gary Adams
University of Nottingham Medical School,
Queens Medical Centre
Nottingham NG 7 2UH
Tel: +44 (0) 115 823 0901
Email: gary.adams@nottingham.ac.uk
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Contact: |
Research Profile
Background
Diabetes mellitus is arguably the most important metabolic disease in humans
and it is predicted that the number of people presenting with diabetes will
exceed 350 million by 2010 resulting in more than 5-6% of the world’s
population being affected.
Two principle forms of this disease are recognised as Type 1 (T1DM) and Type
2 (T1DM). Type 1 is widely accepted to be caused by a reduction in the number
of insulin-secreting β-cells because of insulitis, which occurs typically
in childhood and is due to the destruction of pancreatic beta cells as a result
of auto-immunity. Type 2 begins as a syndrome of insulin resistance, where
the target tissues fail to respond appropriately to insulin.
My main research activity to date, therefore, has been in the development of an insulin-secreting glucose-responsive organoid, which has the ability to produce insulin in a physiologically relevant manner.
My current main research interests fall into:
Diabetes Mellitus
Use Of Biodegradable Polymeric Scaffolds To Regenerate Pancreatic Insulin-Secreting
Tissue
Encapsulation Of Insulin-Secreting Like Tissue
Manipulation Of Embryonic Stem Cells In The Production Of Insulin
Manipulation Of NES2Y Cells In The Production Of Insulin
Physical Characterisation Of Insulin
(I) Use Of Biodegradable Polymeric Scaffolds To Regenerate Pancreatic Insulin-Secreting
Tissue
A major factor that has prevented the successful transplantation of insulin-producing
islets has been the insufficient quantities of pancreatic islet tissue. The
use of biodegradable polymeric scaffolds to regenerate human tissue has been
highlighted as one of the most promising areas of materials/biomedical research.
It is hypothesised that surface engineered three-dimensional biodegradable
scaffolds can be developed that control specific integrin-mediated interactions
with islet-producing stem cells (IPSC). This will, in turn, enable the proliferation
and differentiation of these stem cells to be directed with the aim of generating
large quantities of engineered islets. This work examines the development of
a novel islet-cell tissue, utilising biomimetic templates to control pancreatic
stem cell differentiation and proliferation.
(II) Encapsulation Of Insulin-Secreting Like Tissue
Future in vitro examination will establish the effectiveness and efficacy of
insulin-producing like tissue under encapsulation conditions. Using a variety
of nano-and-microencapsulates, it is intended this encapsulate will constrain
the components of the gel spatially and provide an alternative controlled drug
delivery device for type I insulin-dependent diabetics, a device superior to
previous alginate based delivery systems.
(III) Manipulation Of Embryonic Stem Cells In The Production Of Insulin
This proposal builds on our preliminary studies demonstrating an approach where
we are able to manipulate embryonic stem (ES) cells in the production of insulin,
which when challenged with glucose is responsive to the circulating glycaemic
environment. While others have shown differentiation of ES cells towards the
pancreatic islet lineage, including expression of insulin, it has not always
been clear how much or even if insulin was being actively made by the cells
or simply taken up from the culture medium. Here we have developed a systematic
process that is both robust and effective for manipulating and quantifying
differentiation of ES cell differentiation into pancreatic islet- like clusters.
(IV) Manipulation Of NES2Y Cells In The Production Of Insulin
The NES2Y cell line exhibits characteristics typical of islet cells derived
from PHHI patients: enhanced insulin secretion but no KATP channel activity.
As a result, insulin secretion occurs at constitutively high levels in the
absence of glucose. In addition, they exhibit impaired expression of the
homeodomain transcription factor PDX1, which is a key component of the signaling
pathway linking nutrient metabolism to the regulation of insulin gene expression.
The researchers are manipulating the ability of NES2Y cells to grow continuously
in culture. As a result of this continual growth, the NES2Y cell is considered
to be immortal and it expresses cytoplasmic insulin and possesses characteristics
of a beta cell and/or endocrine stem cell.
(V) Physical Characterisation Of Insulin
Recent findings provide evidence that the physiological bioeffectiveness and
bioavailability of insulin in Type 1/2 diabetic patients is compromised as
a result of ligand-dependent structural changes in insulin, undermining its
physiological solute transport. This work will carry forward work on biomolecular
and protein-ligand interactions with the aim of determining the interaction
of insulin with appropriate cell types and characterising the binding parameters
of insulin. This will require a detailed understanding of the mechanism of
self-assembly of insulin with various cell types. This knowledge will be
exploited to generate appropriate insulin receptor-mediated responses and
bioavailability.
Techniques
Isolation and manipulation of isolated islets of Langerhans
In vitro insulin secretion studies
RT-PCR, real time PCR
Protein chemistry (separation and quantification); one- and two-dimensional
electrophoresis, Western blot
Spectrophotometry (UV and visible), Fluorophotometry, Bio-luminescence
High performance liquid chromatography
ELISA
Confocal imaging
Tissue culture
Immunocytochemistry, Immunoblotting, electron microscopy
Rheological assessment
Selected Publications in Peer Reviewed Journals
Cui, Y-X., Shakesheff, K.M., Adams, G.G. (2006) Encapsulation of RIN-m5F cells within Ba2+ cross-linked alginate beads affects proliferation and insulin secretion. J Microencapsul 23: 663-676. PubMed
Adams G.G., Cui, Y., Mitchell, J.H. and Taylor, M.J. (2006) Rheological and
Diffusion properties of a dextran-con A polymer in the presence of insulin
and magnesium Rheologica Acta 45: 611-620
Langley, J., Adams, G.G. (2007) Insulin-based regimens decrease mortality rates in critically ill patients: a systematic review. Diabetes Metab Res Rev 23: 184-192. PubMed
Vaughn, N., Randle, J. and Adams, G.G. (2006) Clostridium difficile: Infection Control Link Professionals’ Knowledge British Journal of Infection Control Nurs Times 103: 42-43. PubMed
Adams, G.G., Wang, N., Cui, Y. (2005) Future alternative therapies in a quest to halt aberrations in diabetes mellitus. Biomed Pharmacother 59: 296-301. PubMed
Adams, G.G., Jan Clark, Tarsem Sahota, Sangeeta Tanna, and M.Joan Taylor, (2000)
Diabetes mellitus and and Closed-loop Insulin Delivery Biotechnology and
Genetic
Engineering Review Vol. 17 pp 455-49
Research Group – Insulin and Diabetes Experimental Research
group (IDER)