Investigating the Incretin Effect in Cystic Fibrosis

Study Overview
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Brief Summary
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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.

Official Title
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Investigating the Incretin Effect in Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Oral Glucose Tolerance test (75g 2-hour)
* Drug: Modified Oral Glucose Tolerance Test (50g 4-hours)
* Drug: Matched isoglycemic clamp
* Drug: Hyperglycemic clamp with concurrent GLP-1 infusion
* Drug: Hyperglycemic Clamp with concurrent GIP infusion
* Drug: Hyperglycemic clamp with placebo infusion
* Other: Liquid Meal Test (Carbohydrate-rich)
* Other: Liquid Meal Test (Fat-rich)
* Other: Liquid Meal Test (Mixed)
* Device: Continuous Glucose Monitoring


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cystic Fibrosis<br>Adult patients with confirmed cystic fibrosis who are clinically stable. Interventions: 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) Continuous Glucose Monitoring | Drug: Oral Glucose Tolerance test (75g 2-hour)<br>* 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<br>* Other names: OGTT;Drug: Modified Oral Glucose Tolerance Test (50g 4-hours)<br>* 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.<br>* Other names: 50g OGTT;Drug: Matched isoglycemic clamp<br>* 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<br>* Other names: isoglycemic clamp;Drug: Hyperglycemic clamp with concurrent GLP-1 infusion<br>* 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.<br>* Other names: Glucagon-like peptide-1;Drug: Hyperglycemic Clamp with concurrent GIP infusion<br>* 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.<br>* Other names: glucose-dependent insulinotropic peptide;Drug: Hyperglycemic clamp with placebo infusion<br>* 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.<br>* Other names: Hyperglycemic clamp with normal saline (0.9%) infusion;Other: Liquid Meal Test (Carbohydrate-rich)<br>* 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.<br>Other: Liquid Meal Test (Fat-rich)<br>* 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.<br>Other: Liquid Meal Test (Mixed)<br>* 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.<br>Device: Continuous Glucose Monitoring<br>* 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.<br>* Other names: CGMS;|
| Controls<br>Adult Non-CF subjects matched for age and body mass index with normal glucose tolerance. 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) | Drug: Oral Glucose Tolerance test (75g 2-hour)<br>* 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<br>* Other names: OGTT;Drug: Modified Oral Glucose Tolerance Test (50g 4-hours)<br>* 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.<br>* Other names: 50g OGTT;Drug: Matched isoglycemic clamp<br>* 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<br>* Other names: isoglycemic clamp;Drug: Hyperglycemic clamp with concurrent GLP-1 infusion<br>* 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.<br>* Other names: Glucagon-like peptide-1;Drug: Hyperglycemic Clamp with concurrent GIP infusion<br>* 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.<br>* Other names: glucose-dependent insulinotropic peptide;Drug: Hyperglycemic clamp with placebo infusion<br>* 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.<br>* Other names: Hyperglycemic clamp with normal saline (0.9%) infusion;Other: Liquid Meal Test (Carbohydrate-rich)<br>* 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.<br>Other: Liquid Meal Test (Fat-rich)<br>* 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.<br>Other: Liquid Meal Test (Mixed)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) of Insulin & C-peptide secretion during a matched isoglycemic clamp | Differences in Insulin & C-peptide secretion will be measured over a 4-hour period following an oral glucose tolerance test and then separately over the same period during a matched isoglycemic glucose infusion (which will recreate the glucose values obtained during the oral glucose tolerance test). The difference in these values can be wholly attributed to the effect of incretin hormones. | 4 hours | 
| Volume of intravenous glucose required to maintain a hyperglycemic clamp at 180-216mg/dL | A hyperglycemic clamp uses an intravenous glucose infusion to fix blood sugar at a certain level. We will use such a technique to fix blood sugar levels at 180-216mg/dL (10-12 mmol/l) for one hour then infuse either an incretin hormone (GLP-1/GIP) or placebo (sodium chloride) for a further two hours. The excess volume of intravenous glucose required during the last two hours of the test (compared to the first) will allow us to calculate what if any effect the incretin hormones have on the pancreas in patients with Cystic Fibrosis | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum DPP-4 levels | We will measure serum DPP-4 levels on 2 separate occasions in both CF and control groups to establish if there are any differences in how rapidly the incretin hormones are deactivated between the groups | 0 mins | 
| AUC incretin hormone levels (GLP-1/GIP) | Incretin hormone levels (GLP-1/GIP) will be measured in response to an oral glucose tolerance test, an intravenous isoglycemic glucose infusion as well as in response to standardised meals of different composition (fat-rich, carbohydrate rich & mixed). | 4 hours |