Sympathetic neurons engage in "cross talk" with cells in the pancreas during early development

Main Category: Diabetes
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Sympathetic neurons engage in "cross talk" with cells in the pancreas during early development

The human body is a complicated system of blood vessels, nerves, organs, tissue and cells each with a specific job to do. When all are working together, it's a symphony of form and function as each instrument plays its intended roles.

Biologist Rejji Kuruvilla and her fellow researchers uncovered what happens when one instrument is not playing its part.

Kuruvilla along with graduate students Philip Borden and Jessica Houtz, both from the Biology Department at Johns Hopkins University's Krieger School of Arts and Sciences, and Dr. Steven Leach from the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins School of Medicine, recently published a paper in the journal Cell Reports exploring whether "cross-talk" or reciprocal signaling, takes place between the neurons in the sympathetic nervous system and the tissues that the nerves connect to. In this case the targeted tissue called islets, were in the pancreas.

"We knew that sympathetic neurons need molecular signals from the tissues that they connect with, to grow and survive," said Kuruvilla. "What we did not know was whether the neurons would reciprocally signal to the target tissues to instruct them to grow and mature. It made sense to focus on the pancreas because of previous studies done in diabetic animal models where sympathetic nerves within the pancreas were found to retract early on in the disease, suggesting that dysfunction of the nerves could be an early trigger for pancreatic defects."

The researchers spent approximately three years working with lab mice to test the various scenarios in which signaling between sympathetic neurons and islet cells might take place. The experiments focused on what effects removing the sympathetic nerves would have on pancreas development in newborn mice.

Previous studies had shown that pancreatic cells release a signal of their own, a nerve growth protein, that directs the sympathetic nerves toward the pancreas and provides necessary nutrition to sustain the nerves.

In turn, Kuruvilla's team found that in mutant mice, the removal of the sympathetic neurons resulted in deformities in the architecture of the pancreatic islet cells and defects in insulin secretion and glucose metabolism.

Pancreatic islets are highly organized functional micro-organs with a defined size, shape and distinctive arrangement of endocrine cells. It's this marriage of form and function that result in cells clustered close together, that creates greater, more efficient islet cell function.

However, the mutant mice, with their sympathetic neurons removed, had islet formations that were misshapen, sported lesions and developed in a patchy, uneven manner. Because of their dysfunctional islet cell development, postnatal mice did not secrete enough insulin when confronted with high glucose, and had high blood glucose levels as a result. Increased levels of blood glucose in humans is a hallmark of diabetes.

It's known in neuroscience that the neurons in question from the sympathetic nervous system control the body's "flight or fight" response and communicate with connected tissues by releasing a chemical messenger called norepinephrine. The release of norepinephrine also plays an important role in the development and maturation of islets, said Kuruvilla.

Using sympathetic neurons and islet cells grown together in a culture dish, the researchers observed that islet cells move toward the nerves and identified norepinephrine as the nerve signal that causes the movement of the islet cells.

"Seeing how these islet cells were responding to sympathetic neurons both in a dish and the effects of removing the nerves in a whole animal on islet shape and functions were pretty remarkable," said Borden, lead author of the paper. "It was clear to us that sympathetic neurons were key to how islets were developing, something no one else had shown."

Kuruvilla said these studies, identifying sympathetic nerves as a critical player in organizing pancreatic cells during development and influencing their later function, could add to a better understanding of treating diabetes in the future. The research also lends support to the value in considering the importance of external factors such as nerves and blood vessels when transplanting islet cells for the treatment of diabetes in patients.

"This study reveals interactions between two co-developing systems, sympathetic neurons and pancreatic islet cells, that has important implications for peripheral organ development, and for regeneration of these tissues following injury or disease," said Kuruvilla.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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We need to engage GPs in developing primary care

A distinctive feature of CCGs is that they harness the clinical expertise of their GP members. Photograph: Hongqi Zhang /Alamy

The creation of clinical commissioning groups (CCGs) is at the heart of the government's reforms to health and social care in England. On 1 April 2013, these newly formed, clinically led groups were handed control of around two-thirds of the English NHS budget, and responsibility for commissioning secondary and community care services for their local population. Much attention has been given to their commissioning role, but CCGs have another distinct role to play in supporting quality improvement in general practice. CCGs are in the unique position of being membership organisations, which presents an opportunity for GPs to be more closely involved in transforming primary care.

Will CCGs be able to influence changes needed in primary care when they do not oversee the NHS contracts for primary care? Success here will be dependent on strong engagement with GP members.

The King's Fund and The Nuffield Trust have been working together to study six CCG case study sites, focusing on governance processes and structures as well as emerging relationships. A distinctive feature of CCGs is that they harness the clinical expertise of their GP members. Our research explores how this is being done in practice – how members are involved in their CCGs, what influence they have over commissioning decisions and how leaders and members are working together to develop primary care locally. Findings from the first year of the research reveal the opportunities that CCGs have and challenges they face.

Our research suggests a great deal of enthusiasm at grassroots level, with GPs generally wanting CCGs to succeed, and a lot of energy and enthusiasm among leaders. CCGs have brought local clinicians together, in many cases formalising and building on collaborations between practices that existed more loosely under practice-based commissioning; but in other cases through the creation of new networks and relationships. We heard from GPs who felt positive about being in it together.

More than two-fifths of general practice respondents to our survey felt they could influence the work of their CCG – far higher than the number who thought they could have influenced primary care trusts (PCT) in the past system. Interviews suggested that the GP voice is better represented in CCGs than it was in PCTs.

Importantly, the majority of GPs believed that CCGs have a legitimate role in influencing their members in terms of referrals, prescribing, and other issues – although some felt wary about the form that this involvement could take. There was concern that the financial environment that the NHS is facing, with significant savings needed over the coming years, may lead to CCGs performing a rationing function that could damage GP-patient relationships.

Reconciling this role with the need to maintain clinical engagement and member ownership will therefore be a delicate balance for CCG leaders to strike. Most CCGs are emphasising their intention to take a supportive approach, particularly through provision of comparative performance data to member practices, and by facilitating various forms of peer-to-peer dialogue.

Our survey also highlighted that engagement – awareness, support and involvement – among CCG members is not universal. Nearly half of our survey respondents without a formal role in the CCG feel disengaged in its work – lack of time and capacity being the most frequently cited reasons. CCG members are also less likely than leaders to believe the CCG is owned by its members. Low GP engagement was a major barrier to the success of previous models of clinical commissioning. It is therefore critical that CCGs continue and build momentum on engaging GP members. Driving service changes that will win the support of the clinical community may be important here.

Over the next two years, our case study sites will shed further light on whether and how CCGs are building on the enthusiasm at grassroots level and harnessing the support of their GP members in order to develop and change primary care.

Shilpa Ross is a researcher for the King's Fund and Dr Louise Marshall is specialty registrar of public health for the Nuffield Trust

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