Exercise and the dipeptidyl‐peptidase IV inhibitor sitagliptin do not improve beta‐cell function and glucose homeostasis in long‐lasting type 1 diabetes—A randomised open‐label study

Abstract

Background Increasing evidence points to beta‐cell regeneration in individuals with type 1 diabetes mellitus (type 1 DM) at all stages of the disease. Exercise and glucagon‐like peptide‐1 (GLP‐1) independently improve beta‐cell function and glucose homeostasis in animal studies and in clinical trials in individuals with type 2 diabetes mellitus (type 2 DM). Whether a combination of both, exercise and GLP‐1, induces a similar effect in individuals with long‐lasting type 1 DM remains to be investigated. Methods In an open‐label study, participants with long‐standing type 1 DM were randomly assigned to oral sitagliptin 100 mg daily for 12 weeks in combination with or without an exercise intervention. The primary end‐point was change in the area under the concentration‐time curve of C‐peptide during a mixed meal tolerance test before and after 12 weeks of intervention. Results A total of 24 participants were included in the study and treated with sitagliptin, 12 participants were allocated to a 12‐week exercise intervention. After 12 weeks, there was no difference in the change of AUC C‐peptide between groups (exercise: 0 [−1424 to 1870], no exercise: 2091 [283‐17 434]; P = 0.09). HDL improved in the exercise intervention group compared to the group with sitagliptin only (exercise: 0.11 [−0.09 to 0.27]; no exercise: −0.18 [−0.24 to 0.01]; P = 0.04). AUC glucose was numerically slightly lower in the exercise intervention group but this did not translate into changes in HbA1c. Conclusion The combination of exercise and sitagliptin had no effect on beta‐cell function in individuals with long‐lasting type 1 DM.

Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus

“…A healthy and functional mass of pancreatic beta cells is necessary for normal glucose homeostasis, and DM is accompanied with varying levels of beta-cell dysfunction [44,45]. A progressive loss of beta-cell mass and function is a major contributor for developing DM [46].…”

“…Chronic hyperglycemia induces free radical generation in islets through several molecular pathways such as an increase of cytosolic calcium and protein kinase activation [50,54]. Since beta cells have a low capacity of the antioxidant defense system, oxidative stress in beta cells is prevalent in DM and plays an important role for the loss of their function in both T1DM and T2DM [45,48,55].…”

Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis

“…Sitagliptin had no effect on β cell function in individuals with long-standing T1DM [ 90 ], but it improved β cell functionality [ 91 , 92 ] and insulin sensitivity in subjects with LADA [ 91 ], inducing changes of T cell phenotype and gene expression profile [ 93 ]; indeed, DPP4-I treatment is nowadays considered as a therapeutic option in LADA subjects [ 36 ].…”