Investigating the Incretin Effect in Cystic Fibrosis

Most Cystic fibrosis (CF) patients now commonly live well into adulthood, this means they are progressively accumulating damage to the insulin-secreting cells inside their pancreas. This explains why most adult patients have some degree of abnormal sugar regulation \& rates of diabetes rise significantly with age. CF related diabetes is categorically different from other types of diabetes \& its development is serious as it heralds a faster decline in lung function \& a reduced life expectancy.

The hallmark of abnormal sugar handling in CF is high glucose levels after meals as the damaged pancreas responds abnormally slowly. Over 70% of the initial response of a healthy pancreas is induced, not by glucose alone, but by hormones released from the bowel known as incretins. We want to establish whether incretins are important in blood sugar handling in CF as specific drugs that enhance their effect are now available.

The study hypothesis is that the incretin system will function normally in patients with Cystic Fibrosis. To show this we will measure how much insulin secretion is dependant on incretin hormones in CF patients by comparing levels after a sugary drink test and then an intravenous glucose drip test (run at a rate that mimics the blood sugar levels obtained during the first test to make it a fair comparison ) - as incretins will only be produced in the first test when the sugar passes through the bowel any extra insulin produced will be due to these hormones. To detect resistance to the incretin hormones we will separately measure responses to direct infusions of the hormones themselves. We will explore which components of meals cause incretin hormone release from the bowel wall by measuring blood levels after different types of meals are consumed. Finally we will measure levels of the enzyme that breaks down the incretin hormones (DPP-4) to know if they are deactivated more quickly in people with CF. By describing the incretin system in CF we will considerably improve our understanding of this important condition as well as potentially highlighting new ways to treat it.


Eligibility Criteria:
Inclusion Criteria:

* Cystic fibrosis as diagnosed by EITHER Cystic fibrosis transmembrane conductance regulator (CFTR) mutation on genotyping OR Positive sweat test (Chloride ≥60mmol/L after pilocarpine iontophoresis) AND Clinical features in keeping with a diagnosis of Cystic Fibrosis
* Clinically stable for at least 4 weeks without inpatient or outpatient treatment for an infective exacerbation - including antibiotics (other than long-term prophylactic therapy) or steroids

Exclusion Criteria:

* Active Pregnancy or \<12 months Post-partum
* Clinically unstable patients
* Patients on long-term steroids
* Patients with known gastroparesis or previous surgery to the gastrointestinal tract (including vagotomy)
* History of organ transplant or planned organ transplant awaited
* Non-CF related diabetes (e.g. Type 1 or 2 Diabetes Mellitus)
* Active malignancy
* Clinically significant derangements in haematological or biochemical indices
* Clinical symptoms of malabsorption (frequent bowel motions/passing of undigested foodstuffs or steatorrhoea)
* Known difficult venous access
* Use of bile acid sequestrants in the previous 4 weeks