Contribution of Pancreatic Alpha-Cell Function to Insulin Sensitivity and Glucose Variability in Type 1 Diabetes Patients

Abstract

In type 1 diabetes (T1D) patients, relationships between pancreatic alpha cell function and glucose metabolism remain elusive. Therefore, we aimed to reveal the contribution of alpha cell function to insulin sensitivity, hepatic glucose uptake (HGU), and glucose variability, including the dawn phenomenon, in T1D patients. We recruited forty Japanese T1D patients with a median (interquartile range) BMI of 21.0 (19.3-22.7) kg/m2, diabetes duration of 2.6 (0.1-10.3) years, and HbA1c level of 8.2 (7.4-10.3) %. We measured the arginine-stimulated glucagon secretion using RIA and double-sandwich ELISA and subsequently assessed the dawn phenomenon using an artificial pancreas (STG-55®, Nikkiso, Japan) and performed a hyperinsulinemic-euglycemic clamp followed by oral glucose loading to evaluate insulin sensitivity and HGU. Glycemic variability was analyzed with continuous glucose monitoring (CGM). The median areas under the curve of glucagon measured by RIA (AUCglcRIA) and ELISA (AUCglcELISA) were 3.7 (2.6-4.6) × 104 and 1.9 (0.8-4.3) × 103 pg/mL × min, respectively. The glucose infusion rate (GIR) during the euglycemic clamp was inversely correlated with AUCglcRIA and AUCglcELISA (R2 = 0.21 and 0.44, P = 0.033 and 0.038, respectively, adjusted for age, sex, and BMI). In addition, the median GIR was significantly lower in the high glucagon response group than in the low glucagon response group [7.3 (5.1-8.4) vs. 9.2 (7.0-11.7), P = 0.049]. The dawn index (ratio of insulin requirements between 4:00-8:00 and 0:00-04:00) and HGU did not correlate AUCglcRIA and AUCglcELISA. The standard deviation of glucose levels determined by CGM significantly correlated with AUCglcRIA (R2 = 0.28, P = 0.015) but not with AUCglcELISA (R2 = 0.01, P = 0.62). In conslusion, alpha cell function may contribute to insulin sensitivity in T1D, and its relationship with glycemic variability may be affected by the procedure of the glucagon assay used. Disclosure N. Takahashi: None. D. Chujo: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Sanofi K.K., Kyowa Hakko Kirin Co., Ltd.. H. Kajio: None. K. Ueki: Speaker's Bureau; Self; Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Novo Nordisk Inc., Mitsubishi Tanabe Pharma Corporation, Kyowa Hakko Kirin Co., Ltd., Takeda. Research Support; Self; Takeda, Astellas, Novo Nordisk Inc..