35-OR: Incretin Production Is Impaired in Atypical Low BMI Diabetes Mellitus Free

Introduction: Atypical Low BMI Diabetes Mellitus (ALBDM) constitutes an unclassified form of diabetes that is likely to be prevalent in low- and middle-income countries. Recently, we reported in Diabetes Care that such individuals demonstrate striking defects in insulin secretion, despite absence of visible pancreatic pathology (PMID: 35522035). This study aims to determine whether defects in the incretin axis might contribute to impaired insulin secretion in ALBDM.

Methodology: We assessed the glucagon and incretin (GLP-1, GIP, and Oxyntomodulin) responses to an oral glucose tolerance test (OGTT) in patients with ALBDM. Ten male subjects demonstrating features of ALBDM (n=10, age 33±8.3 years, BMI 18.5±1.1 kg/m², HbA1c 7.5±0.7%) were compared with 7 healthy BMI-matched normoglycemic (HbA1c: 5.0±0.3%) controls. All subjects underwent an OGTT, with blood sampling for C-peptide and incretin levels at nine specific time points. Insulin secretion rate (ISR) was calculated by C-peptide deconvolution using ISEC software, and total secretion rate for incretins were calculated as area under the curve (AUC) using the Trapezoid method with linear interpolation.

Results: As we previously reported, ALBDM subjects displayed impaired insulin secretion (50% reduction in post-OGTT insulin AUC, p=0.007). There was a profound reduction of OGTT-stimulated rise in the incretins GLP-1 (80% reduction; p=0.055), GIP (79% reduction; p=0.02) and oxyntomodulin (75% reduction; p=0.007) in ALBDM subjects compared to controls. In ALBDM subjects, mild hyperglucagonemia was observed in the early postprandial phase at 15 min of the OGTT followed by slow postprandial suppression.

Conclusions: Significant reductions in levels of GLP-1, GIP and Oxyntomodulin and an accompanying early phase of hyperglucagonemia suggest potential defects in development and/or function of enteroendocrine cells, which may contribute to defective insulin secretion and hyperglycemia in patients with Atypical Low BMI Diabetes Mellitus.