Clinical trial NCT01975259: Investigating the Incretin Effect in Cystic Fibrosis
Official title: Investigating the Incretin Effect in Cystic Fibrosis
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cystic Fibrosis
Lead sponsor: Liverpool Heart and Chest Hospital NHS Foundation Trust
Sponsor class: OTHER
First posted: 2013-11-03
Enrollment: 50
Sex: ALL
Minimum age (years): 17
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The CF Cohort will be recruited from the population of Patients attending Adult CF Service at Liverpool Heart \& Chest Hospital, Liverpool, United Kingdom

The control group will be invited to participate from the general public. We will advertise our study through the Liverpool Heart \& Chest Hospital and also via GP surgeries (Primary care clinics) in both electronic \& paper forms.

Brief summary: 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

Primary outcomes:
measure: Area Under Curve (AUC) of Insulin & C-peptide secretion during a matched isoglycemic clamp
timeFrame: 4 hours
measure: Volume of intravenous glucose required to maintain a hyperglycemic clamp at 180-216mg/dL
timeFrame: 3 hours
Secondary outcomes:
measure: Serum DPP-4 levels
timeFrame: 0 mins
measure: AUC incretin hormone levels (GLP-1/GIP)
timeFrame: 4 hours
Other outcomes:
Locations:
city: Liverpool
country: United Kingdom
facility: Liverpool Heart and Chest Hospital
Study officials:
affiliation: Liverpool Heart and Chest Hospital
name: Gareth H Jones, MBChB
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7. doi: 10.1172/JCI116186.
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citation: Hameed S, Morton JR, Jaffe A, Field PI, Belessis Y, Yoong T, Katz T, Verge CF. Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain. Diabetes Care. 2010 Feb;33(2):221-6. doi: 10.2337/dc09-1492. Epub 2009 Nov 12.
citation: Dobson L, Sheldon CD, Hattersley AT. Validation of interstitial fluid continuous glucose monitoring in cystic fibrosis. Diabetes Care. 2003 Jun;26(6):1940-1. doi: 10.2337/diacare.26.6.1940-a. No abstract available.
citation: Costa M, Potvin S, Hammana I, Malet A, Berthiaume Y, Jeanneret A, Lavoie A, Levesque R, Perrier J, Poisson D, Karelis AD, Chiasson JL, Rabasa-Lhoret R. Increased glucose excursion in cystic fibrosis and its association with a worse clinical status. J Cyst Fibros. 2007 Nov 30;6(6):376-83. doi: 10.1016/j.jcf.2007.02.005. Epub 2007 Apr 3.
citation: Hillman M, Eriksson L, Mared L, Helgesson K, Landin-Olsson M. Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus. J Cyst Fibros. 2012 Mar;11(2):144-9. doi: 10.1016/j.jcf.2011.11.001. Epub 2011 Dec 3.
citation: Anzeneder L, Kircher F, Feghelm N, Fischer R, Seissler J. Kinetics of insulin secretion and glucose intolerance in adult patients with cystic fibrosis. Horm Metab Res. 2011 May;43(5):355-60. doi: 10.1055/s-0031-1275270. Epub 2011 Mar 29.
citation: Lanng S, Thorsteinsson B, Roder ME, Orskov C, Holst JJ, Nerup J, Koch C. Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance. Acta Endocrinol (Copenh). 1993 Mar;128(3):207-14. doi: 10.1530/acta.0.1280207.