Glucose Metabolism in Cystic Fibrosis Related Diabetes (CFRD)

This is a mechanistic observational study. A physiological challenge of a single mixed meal tolerance test (MMTT) is administered, which will enable a comprehensive assessment of multiple parameters of glucose turnover, insulin secretion, insulin sensitivity and lipolysis in individuals with CFRD. The MMTT is the gold standard for measuring both insulin action and secretion simultaneously with glucose kinetics. The pilot study aims to test whether use of CFTR modulators (ETI) improves fasting and post prandial glycemia by enhancing disposition index (DI) in individuals with CFRD with CFTR +ve mutation (at least one copy of F508del) on CFTR modulator (ETI) therapy (CFRDF508del+ETI).

We plan to gather critical preliminary data on the following aspects of CFRD:

• Abnormalities in specific components (basal vs. static vs. dynamic) of beta-cell function in CFRDF508del+ETI and in CFRD-ETI individuals.
• Effects of ETI on components of beta cell function.
• Effects of CFTR mutation and of CFTR modulators (CFRDF508del+ETI) on insulin sensitivity and post prandial glucose turnover in CFRD.

Inclusion criteria

• Diagnosis of Cystic Fibrosis Related Diabetes (CFRD)
• Age 21-75 years at time of consent
• BMI 19-50 kg/m2 (In Asians BMI is ~ 2 points lower for comparison so it is 17-48 kg/m2)
• Creatinine ≤ 1.4 mg/dl in women and ≤ 1.5 mg/dl in men
• HbA1c ≤ 11% lifestyle treatment or mono/combination therapy with oral hypoglycemic agents (e.g. metformin or sulphonylurea or SGLT2i) and preferably on insulin pump therapy (i.e., SAP, HCL) with or without CGM will be recruited. However, use of MDI (Multiple Daily Injections) of insulin, i.e., on basal-bolus insulin therapy will also be included. Most of our patients are on insulin therapy with very few on oral antidiabetes medications but we would like to offer them the choice of participation.
• Subjects on FDA approved/recommended full doses of ETI will be offered participation. If dose adjustments of ETI are made after enrollment a discussion will be done with the primary care provider and HCSTOC as required.
• Willing to be at a stable weight for duration of the study.
• An understanding of and willingness to follow the protocol and sign the informed consent

Subjects meeting any of the exclusion criteria at baseline will be excluded from study participation:

Exclusion criteria

• Debilitating chronic disease
• Anemia <10.0 gm/dL in females and <11.0 gm/dL in males
• Symptoms of undiagnosed illness on history/exam
• Abuse of alcohol or recreational drugs
• Pregnancy
• Active hepatic disease (we will include only if less than 3X ULN for liver enzymes and no fibrosis on ultrasound). Transient elevations of liver enzymes will not exclude participation but will be discussed with the primary care provider and HCSTOC as required.
• Current use of the following drugs and supplements:

i. Corticosteroids ii. Benzodiazepines iii. Opiates iv. Barbiturates v. Anticoagulant therapy vi. Any other medication that the investigator believes is a contraindication to the subject's participation