Introduction and Objective: Glucose transporter type 4 (GLUT4), encoded by SLC2A4, is essential for glucose metabolism. In T2DM, insulin-stimulated GLUT4 translocation is impaired, causing insulin resistance in adipose tissue and skeletal muscle. Despite this, no monogenic diabetes forms have been attributed to pathogenic variants in SLC2A4 or GLUT4-regulatory genes. The Rare and Atypical DIAbetes NeTwork (RADIANT) is a multicenter study aimed at understanding individuals with atypical diabetes. Therefore, we utilized this cohort to determine whether rare heterozygous variants in this pathway contribute to the pathogenesis of atypical insulin insufficient diabetes. Methods: Participants underwent oral glucose tolerance testing (OGTT) and genome sequencing (GS). We identified 5 participants with heterozygous, predicted deleterious variants absent or nearly absent from population databases in SLC2A4 or GLUT4-regulatory genes. Results: Two participants had predicted deleterious missense variants (p.G92V and p.T326I) in SLC2A4, diagnosed at ages 36 and 29. Two carried predicted null variants (p.P232Hfs*31 and p.E119Afs*43) in TRIP10, diagnosed at ages 28 and 17. One participant (diagnosed at age 50) carried a predicted deleterious missense variant (p.V17A) in RAB31. Four of five were non-obese (mean BMI 25.6 kg/m²); one SLC2A4 carrier had BMI 38.8 kg/m². Glycemic control was good (mean HbA1c 6.7%, range 5.9-8.0%); participants used various oral agents, with one on insulin, and one on no medications. All had intact C-peptide secretion (mean peak C-peptide 5.59 ng/mL, range 2.61-10.18 ng/dL). Conclusion: We hypothesize that heterozygous loss-of-function in SLC2A4 or GLUT4-regulatory genes underlies insulin resistance and postprandial hyperglycemia in these individuals, potentially representing novel monogenic diabetes. GLUT4-related diabetes may be under-recognized due to phenotypic overlap with T2DM, mild-moderate severity, and absence of syndromic features. Disclosure S.I. Stone: None. R. Gandica: None. J. Lonier: Advisory Panel; Ended; Vertex Pharmaceuticals Incorporated. Research Support; Current; Sanofi. S.W. Greeley: None. A. Balasubramanyam: None. E.A. Oral: Research Support; Current; Regeneron Pharmaceuticals Inc. Advisory Panel; Current; Regeneron Pharmaceuticals Inc. Research Support; Current; Ionis Pharmaceuticals, Chiesi USA, Inc. Consultant; Current; Chiesi USA, Inc. Other - Intellectual property; Current; Chiesi USA, Inc. Research Support; Current; Rhythm Pharmaceuticals, Inc. Research Support; Ended; Novo Nordisk. Advisory Panel; Ended; Novo Nordisk. Research Support; Current; Morphic Medical. S.D. Gage: None. C. Thornton: None. J. Flannick: None. T.I. Pollin: Research Support; Current; Regeneron Pharmaceuticals Inc. Consultant; Current; Ionis Pharmaceuticals. F. Urano: Research Support; Current; Amylyx Pharmaceuticals, Prilenia. Advisory Panel; Current; Emerald Biotherapeutics/Camelot. Board Member; Ended; CURE4Wolfram. Funding National Institutes of Health (U54DK118612)
Stone et al. (Fri,) studied this question.