Increased Gluconeogenesis is One Cause of Cystic Fibrosis Related Diabetes (CFRD)
Condition: Cystic Fibrosis; Diabetes Mellitus
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): Stable isotopes
Intervention type(s): Other
Intervention description(s): Stable isotopes were used to quantify gluconeogenesis GNG, hepatic glucose production (HGP), and protein breakdown.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic