Abstract
Disclosure: S.I. Stone: None. T.I. Pollin: None. J. Flannick: None. S. Gage: None. A. Balasubramanyam: None. F. Urano: None.
The glucose transporter GLUT4, encoded by the SLC2A4 gene, is essential for glucose metabolism. In patients with type 2 diabetes mellitus (T2DM) expression levels of SLC2A4 are normal; however, there is decreased GLUT4 translocation in response to insulin. This decrease in GLUT4 translocation leads to the adipose tissue and skeletal muscle insulin resistance seen in patients with T2DM. Despite the well-known importance of GLUT4 in relation to glucose homeostasis, no monogenic forms of diabetes have yet been identified that are caused by SLC2A4 variants. The Rare and Atypical Diabetes Network (RADIANT) Study is a multicenter study aimed at understanding patients with atypical presentations of diabetes. Study measures include an oral glucose tolerance test, genome sequencing (GS), RNA sequencing, and metabolomics. We report 2 unrelated individuals who were found to have rare variants in SLC2A4 suspected to cause their diabetes. Case 1 is a 58-year-old Asian male who was diagnosed with diabetes at 36 years. At the time, his BMI was 18 kg/m2 and his glucose was 400 mg/dL. His HbA1c is now 8.0% and he is managed with glyburide monotherapy. Case 2 is a 39-year-old white woman with history of obesity (BMI 38.8 kg/m2) and polycystic ovary syndrome. She was diagnosed with diabetes at 29 years. Her HbA1c is 6.6% on insulin degludec, insulin aspart, pioglitazone, metformin, and glimepiride. A 75-gram Oral Glucose Tolerance (OGTT) testing demonstrated substantial insulin secretory capacity in both individuals. Case 1 had peak glucose and C-peptide concentrations of 374 mg/dL and 4.38 ng/mL respectively (C-peptide Index (CPI 1.16)). Case 2 demonstrated peak glucose and C-peptide concentrations of 314 mg/dL and 5.89 ng/mL respectively (CPI 0.45). Both participants had a distinctive pattern of C-peptide response in the OGTT, with the levels continuing to rise at the 120-minute timepoint. GS demonstrated novel, heterozygous variants in SLC2A4. Both the c.275G>T (p.Gly92Val) (Case 1) and c.977C>T (p.Thr326Ile) (Case 2) missense variants are absent from the general population, predicted to be damaging (REVEL scores of 0.803 and 0.897 respectively) and occur at highly conserved residues previously reported to disrupt function when altered in vitro. Peripheral blood mononuclear cells have been isolated from both participants for further study of patient-specific differentiated cells (adipocytes and myocytes). We hypothesize that their SLC2A4 variants contribute to insulin resistance and post-prandial hyperglycemia in these individuals, potentially representing a novel monogenic form of diabetes caused by structural changes in GLUT4. It is possible that cases of GLUT4-related diabetes are under-recognized due to phenotypic overlap with T2DM, onset of disease in young adulthood, mild to moderate severity, and lack of other syndromic features.
Presentation: Monday, July 14, 2025