Introduction and Objective: Thyroid Hormone Interacting Protein 10 (TRIP10), also known as CDC42-Interacting Protein 4 (CIP4) is required for insulin mediated translocation of GLUT4 to the plasma membrane in response to insulin signaling. However, no monogenic forms of diabetes have been attributed to this gene. The Rare and Atypical DIAbetes NeTwork (RADIANT) is a multicenter study aimed at understanding patients with atypical diabetes.Methods: Two RADIANT participants had whole genome sequencing (WGS) and comprehensive phenotyping. Review of WGS identified loss of function variants in TRIP10 as the suspected cause for diabetes.Results: Case 1 is a 64-year-old Jamaican man who was diagnosed with diabetes at 28 years (HbA1c 10.0%). He maintains an HbA1c in the 6% range with glimepiride, strict diet, and exercise (BMI 22.1 kg/m2). Case 2 is a 41-year-old Ashkenazi Jewish man initially diagnosed with diabetes at age 17 (HbA1c 9.6%). He currently takes metformin, empagliflozin, and oral semaglutide with HbA1c of 5.7% (BMI 23.6 kg/m2). 75-gram Oral Glucose Tolerance Testing demonstrated insulin resistance. In both participants, C-peptide continued to rise at the 120-minute timepoint. WGS demonstrated novel, heterozygous variants in TRIP10(NM_001288962.2). Both the c.995del (p.Pro332HisfsTer31) (Case 1) and c.348_355dup (p.Glu119AlafsTer43) (Case 2) variants are absent (c.995del) or nearly absent (c.348_355dup: 2/1,614,136 alleles) in gnomAD v4.1. These variants are predicted to result in a premature termination codon and nonsense-mediated decay.Conclusion: We hypothesize that heterozygous loss of TRIP10 contributes to insulin resistance and postprandial hyperglycemia in these individuals, potentially representing a novel monogenic form of diabetes. Cases of TRIP10-related diabetes may be under-recognized due to phenotypic overlap with type 2 diabetes, young adult onset, mild to moderate severity, and lack of syndromic features.
S.I. Stone: None. R. Gandica: None. J. Lonier: None. T.I. Pollin: None.
National Institutes of Health (U54DK118612)
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