Increased Gluconeogenesis is One Cause of Cystic Fibrosis Related Diabetes (CFRD)

Increased Gluconeogenesis is One Cause of CFRD

People with CF have a high incidence of diabetes, called CFRD. CFRD is an important cause of worsened morbidity and mortality, thus understanding the pathophysiology underlying its development is imperative. Insulin deficiency has been well recognized as one cause of CFRD; however the clinical presentation and studies of pathogenesis indicate that the etiology is more complex. There is strong evidence that normal metabolism of carbohydrate, protein and fat is altered in CF. We believe that the inflammatory response to chronic underlying lung disease is responsible for insulin resistance and alters substrate metabolism, and that these changes, in addition to insulin deficiency cause CFRD. Our global hypothesis is that hyperglycemia is caused, in part, by high rates of gluconeogenesis resulting from excessive amino acid substrate availability caused by cytokine-mediated protein catabolism. We further hypothesize that inflammation alters normal fatty acid metabolism leading to lipogenesis, an energy wasteful pathway. We will recruit 24 adult CF subjects and 10 controls (similar in distribution in lean tissue mass, age and gender) and will categorize them according to glucose tolerance (OGTT), as well as insulin secretion and insulin sensitivity using the Tolbutamide-stimulated IVGTT and the Minimal Model. Clinical status will be characterized by measuring pulmonary function and modified NIH scores, in addition to measuring levels of circulating cytokines. Gluconeogenesis (GNG) will be quantified by measuring the incorporation 2H into the 2nd, 5th and 6th carbons of glucose. Amino acid turnover rates will be measured using stable isotopes of lactate and alanine and whole body protein turnover (WBPT) will be measured using [1-13C]leucine and [15N2]urea. Fat metabolism will be evaluated by measuring ketone body turnover using stable isotopes, and by quantifying lipogenesis using the isotopomer equilibration method. Key enzymes of fatty acid metabolism will also be measured. We will utilize indirect calorimetry to measure resting energy expenditure. Subjects will be recruited from the CF centers at the University of Texas- Southwestern and the South Central CF Consortium.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Cystic Fibrosis
• Intervention / Treatment: Other: Stable isotopes

Detailed Description

People with CF have a high incidence of diabetes, called CFRD. CFRD is an important cause of worsened morbidity and mortality, thus understanding the pathophysiology underlying its development is imperative. Insulin deficiency has been well recognized as one cause of CFRD; however the clinical presentation and studies of pathogenesis indicate that the etiology is more complex. There is strong evidence that normal metabolism of carbohydrate, protein and fat is altered in CF. We believe that the inflammatory response to chronic underlying lung disease is responsible for insulin resistance and alters substrate metabolism, and that these changes, in addition to insulin deficiency cause CFRD. Our global hypothesis is that hyperglycemia is caused, in part, by high rates of gluconeogenesis resulting from excessive amino acid substrate availability caused by cytokine-mediated protein catabolism. We further hypothesize that inflammation alters normal fatty acid metabolism leading to lipogenesis, an energy wasteful pathway. We will recruit 24 adult CF subjects and 10 controls (similar in distribution in lean tissue mass, age and gender) and will categorize them according to glucose tolerance (OGTT), as well as insulin secretion and insulin sensitivity using the Tolbutamide-stimulated IVGTT and the Minimal Model. Clinical status will be characterized by measuring pulmonary function and modified NIH scores, in addition to measuring levels of circulating cytokines. Gluconeogenesis (GNG) will be quantified by measuring the incorporation 2H into the 2nd, 5th and 6th carbons of glucose. Amino acid turnover rates will be measured using stable isotopes of lactate and alanine and whole body protein turnover (WBPT) will be measured using [1-13C]leucine and [15N2]urea. Fat metabolism will be evaluated by measuring ketone body turnover using stable isotopes, and by quantifying lipogenesis using the isotopomer equilibration method. Key enzymes of fatty acid metabolism will also be measured. We will utilize indirect calorimetry to measure resting energy expenditure. Subjects will be recruited from the CF centers at the University of Texas- Southwestern and the South Central CF Consortium.

Our proposal is intended to better describe the unique metabolism of people with CF, and to provide a comprehensive evaluation of pathophysiologic changes which contribute to the development of CFRD and to wasting; and are part of the applicant's long-range goal which is to identify the underlying causes of CF related diabetes and catabolism so that disease-specific therapies can be developed. We fully expect that the proposed studies will provide new and important information.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390-9063
      • University of Texas Southwestern

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

cystic fibrosis with any type of glucose tolerance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Healthy volunteers	Other: Stable isotopes; Stable isotopes were used to quantify gluconeogenesis GNG, hepatic glucose production (HGP), and protein breakdown.
Experimental: Cystic fibrosis (CF)	Other: Stable isotopes; Stable isotopes were used to quantify gluconeogenesis GNG, hepatic glucose production (HGP), and protein breakdown.

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Dana S Hardin, MD, University of Texas

Publications and helpful links

General Publications

• Hardin DS, Ahn C, Rice J, Rice M, Rosenblatt R. Elevated gluconeogenesis and lack of suppression by insulin contribute to cystic fibrosis-related diabetes. J Investig Med. 2008 Mar;56(3):567-73. doi: 10.2310/JIM.0b013e3181671788.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2003
• Primary Completion (Actual): March 1, 2005
• Study Completion (Actual): March 1, 2005

Study Registration Dates

• First Submitted: May 3, 2004
• First Submitted That Met QC Criteria: May 4, 2004
• First Posted (Estimate): May 5, 2004

Study Record Updates

• Last Update Posted (Actual): March 14, 2018
• Last Update Submitted That Met QC Criteria: March 12, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: 58603DK (completed); R01DK058603 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No