Investigating the Incretin Effect in Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Observational

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.
    


Intervention name(s): Oral Glucose Tolerance test (75g 2-hour); Modified Oral Glucose Tolerance Test (50g 4-hours); Matched isoglycemic clamp; Hyperglycemic clamp with concurrent GLP-1 infusion; Hyperglycemic Clamp with concurrent GIP infusion; Hyperglycemic clamp with placebo infusion; Liquid Meal Test (Carbohydrate-rich); Liquid Meal Test (Fat-rich); Liquid Meal Test (Mixed); Continuous Glucose Monitoring
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Other; Other; Other; Device
Intervention description(s): A standard 2-hour oral glucose tolerance test where fasted patients (10hours overnight) consume a 75g glucose solution & have glucose levels recorded up to every 30 mins for 2hours; A 4-hour version of the oral glucose tolerance test where fasted patients (10hours overnight) consume a 50g of glucose solution & have glucose levels recorded up to every 5mins as well pancreatic and incretin responses at 10 fixed time points.; A glucose drip will be infused at a variable rate that recreates the individual subjects blood glucose values obtained during their 4-hour modified oral glucose tolerance test. This test will therefore last 4-hours and again subjects will be fasted (10hours overnight) at the time of the test. The same blood tests will be performed at the same time points as the modified glucose tolerance test; An intravenous glucose infusion will be infused at a rate that maintains blood glucose at a level of 180-216mg/dL (10-12 mmol/l) (hyperglycemic clamp). After 60mins an infusion of GLP-1 will be commenced at a rate of 0.25pmol/kg/min for 60mins and then continued at a rate of 1.2pmol/kg/min for a further 60mins. Subjects will be blinded to what infusion they are receiving.; An intravenous glucose infusion will be infused at a rate that maintains blood glucose at a level of 180-216mg/dL (10-12 mmol/l) (hyperglycemic clamp). After 60mins an infusion of GIP will be commenced at a rate of 1pmol/kg/min for 60mins and then continued at a rate of 4pmol/kg/min for a further 60mins. Subjects will be blinded to what infusion they are receiving.; An intravenous glucose infusion will be infused at a rate that maintains blood glucose at a level of 180-216mg/dL (10-12 mmol/l) (hyperglycemic clamp).
After 60mins an infusion of normal saline will be commenced as a placebo infusion. It will be infused at a rate so that the total volume of fluid is similar to that infused during the other two hyperglycemic clamp interventions. Subjects will be blinded to what infusion they are receiving.; A standardised liquid meal (carbohydrate-rich) containing approximately 500kcal would be administered to patients who had fasted overnight (10hrs). Over the next 4hours bloods would be sampled at 10 fixed time points to measure features of the incretin response to this type of meal.; A standardised liquid meal (fat-rich) containing approximately 500kcal would be administered to patients who had fasted overnight (10hrs). Over the next 4hours bloods would be sampled at 10 fixed time points to measure features of the incretin response to this type of meal.; A standardised liquid meal (mixed) containing approximately 500kcal would be administered to patients who had fasted overnight (10hrs). Over the next 4hours bloods would be sampled at 10 fixed time points to measure features of the incretin response to this type of meal.; Continuous glucose monitoring entails wearing a small portable device, usually on the upper arm, for a period of three days. The device uses a small plastic tube to record the glucose level from interstitial fluid & every minute wirelessly transmits this information to a base unit to enable a very accurate estimate of average blood sugar control to be defined.
Other intervention name(s): OGTT; Modified OGTT; 50g OGTT; isoglycemic clamp; Glucagon-like peptide-1; gastric inhibitory polypeptide; glucose-dependent insulinotropic peptide; Hyperglycemic clamp with normal saline (0.9%) infusion; CGM; CGMS
Intervention MeSH terms: Glucagon; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1
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.
      
Biospecimen description: 
      Blood