Dextrose-Sulfonylurea Challenge as a Screening Test for Monogenic Diabetes in Patients Diagnosed with Type 1 Diabetes

Monogenic diabetes due to ABCC8, KCNJ11, HNF1A and HNF4 can be treated with sulfonylurea (SU). The SEARCH for Diabetes in Youth confirmed most patients with monogenic diabetes are misdiagnosed with T1DM, and that family history and fasting C-peptide do not reliably increase pre-test probability for diagnosis. Confirmatory genetic testing is expensive and methods to improve cost-benefit ratio do not exist. As such, we developed a dextrose-SU challenge to assess C-peptide response to SU as indication of clinically significant underlying β-cell excitation defects. We postulate negative response to hyperglycemia with positive response to SU indicates presence of a genetic defect in glucose-stimulated insulin secretion. This challenge has been completed on 42 subjects with TIDM on insulin therapy. Blood glucose (BG) and C-peptide were obtained at regular intervals prior to and after a 0.5 g/kg IV dextrose bolus, a single dose of glipizide was given 20 minutes after dextrose (0.3 mg/kg max 15mg if <50 kg; 40 mg if >50 kg) and BG and C-peptide were obtained until study completion. Twenty of the 42 subjects had undetectable C-peptide. Twenty-two subjects had detectable C-peptide, 13 of which showed preferential C-peptide response to glipizide (ΔC-peptide 0.41 ± 0.45 ng/mL) compared to hyperglycemia (Δ 0.05 ± 0.03 ng/mL). This suggests islets may show modest but specific response to SU in TIDM. Nine of the 13 who showed preferential response to glipizide completed a dextrose-only challenge 6 months later and retained marginal C-peptide response to hyperglycemia alone (Δ 0.05 ± 0.04 ng/mL). Whole exome sequencing is pending on these subjects. These data suggest the challenge may serve to elicit and stratify C-peptide response to SU, assist in categorizing residual β-cell function, support screening for monogenic diabetes, and increase consideration of SU therapy for appropriate patients.