Clinical Trials

Inclusion Criteria:

• Men and women age 18-85 years.
• Cases: Individuals in the Penn Medicine BioBank or Mayo Clinic with variants of DPP4 with predicted loss of function or related variants that may impact DPP4 antigen and/or activity or related pathways.
• Controls: Matched as much as possible to cases by age, gender, race, BMI and medication use that may affect outcomes of interest.
• Patients must be able to understand English.
• Specific to the pilot study only: pre-diabetes or diabetes based on clinical laboratory data available or prior medical history. Clinical laboratory data include: fasting plasma glucose ≥ 100mg/dL, plasma glucose of ≥ 140mg/dL two hours after a 75g glucose load, or hemoglobin A1C ≥ 5.7%. Individuals without pre-diabetes or diabetes may participate in the phenotyping case-control study (main study) only. To clarify, those with pre-diabetes or type 2 diabetes may participate in either just phenotyping or in the small pilot study (phenotyping during placebo and sitagliptin).

Exclusion Criteria:

• Chronic oral glucocorticoid use, use of oral or injected steroids within the past three weeks, use of high-dose inhaled steroids (> 1000mcg/day) within the past month, or use of atypical antipsychotics within the past month.
• History of gastrointestinal impairment such that would potentially affect absorption of oral glucose or endogenous GLP-1 release (for example gastrectomy, jejunectomy, Roux-en-Y gastric bypass).
• Significant hemoglobinopathy or anemia requiring blood transfusions within the past 3 months.
• Hemophelia.
• Systemic chemotherapy administration within the past 3 weeks.
• Acute illness that may impact insulin and glucose dynamics (for example recent heart failure exacerbation, ongoing respiratory infection).
• Pregnant.
• Hypothalamic obesity or genetic disorder of metabolism that impacts glucose or insulin dynamics.
• Participation in a clinical trial within five half-lives of the study drug.
• Major organ system illness or any underlying condition requiring regular medication or treatment that could make implementation of the protocol or interpretation of the study results difficult.
• Inability to consent or comply with study protocol.
• Need for prandial insulin therapy or current use of oral anti-diabetic agent other than metformin (thus type 1 diabetes is exclusionary).
• Current use of GLP-1 agonist therapy.
• Hemoglobin A1C ≥  8.5%.
• Additional exclusion criteria not otherwise listed, but unique for the (optional) MRI participants: impaired renal function (eGFR < 50mL/min/1.73m^2), contrast allergy, metal device or implant, or other related wound or implant not cleared through radiologic evaluation.
• Additional exclusion criteria for the pilot study: Impaired renal function (eGFR < 50mL/min/1.73m^2), history of pancreatitis, history of angioedema or allergy to sitagliptin, breastfeeding.