Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice

Abstract

Previous studies have reported that dual drug combinations consisting of γ-aminobutyric acid (GABA) together with a dipeptidyl-peptidase-4 inhibitor (DPP-4i), also a DPP-4i with a proton pump inhibitor (PPI), could improve pancreatic β-cell function and ameliorate diabetes in diabetic mice. In this study, we sought to determine if a triple drug combination of GABA, a DPP-4i and a PPI might have superior therapeutic effects compared with double drug therapies in the prevention and reversal of diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes (T1D). In a diabetes prevention arm of the study, the triple drug combination of GABA, a DPP-4i, and a PPI exhibited superior therapeutic effects in preventing the onset of diabetes compared with all the double drug combinations and placebo. Also, the triple drug combination significantly increased circulating C-peptide and serum insulin levels in the mice. In a diabetes reversal arm of the study, the triple drug combination was superior to all of the double drug combinations in reducing hyperglycemia in the mice. In addition, the triple drug combination was the most effective in increasing circulating levels of C-peptide and serum insulin, thereby significantly reducing exogenous insulin needs. The combination of GABA, a DPP-4i and a PPI appears to be a promising and easily scalable therapy for the treatment and prevention of T1D.

Efficacy of combination therapy with GABA, a DPP-4i and a PPI as an adjunct to insulin therapy in patients with type 1 diabetes

“…The above clinical outcomes reported here are consistent with our findings in a recent study of this combination of GABA, a DPP-4i, and a PPI in NOD mice, an animal model for human T1D ( 16 ). Importantly, the combination of all three drugs prevented and reversed autoimmune diabetes in the NOD mice, whereas all two-drug combinations were less or not effective.…”

“…Recently, it was reported that the combination of GABA and GAD-alum, in a 12-month, double-blind, randomized T1D pediatric trial, significantly reduced fasting and meal-stimulated serum glucagon, but preservation of the C-peptide response was not attained, however the safety of GABA was confirmed ( 15 ). We have recently reported that a three-drug combination therapy consisting of the neurotransmitter GABA, a DPP-4i and a PPI can prevent and reverse diabetes in non-obese diabetic (NOD) mice, an animal model for human T1D, whereas all two-drug combinations were less or not effective ( 16 ). The objective of the study reported here was to determine whether glycemic control in patients with T1D could be improved by adding a combination of GABA, DPP-4i, and PPI to a standard insulin treatment regimen in these patients, in a real-world clinical setting.…”

A comprehensive review on potential drug–drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP‐4 inhibitors

“…In nonobese diabetic mice, normoglycemia was shown to be restored when sitagliptin and omeprazole were combined, increasing the synergistic effect of the two medications. 29 Pantoprazole ✓ According to a recent study, sitagliptin and pantoprazole are well tolerated, safe, and may help certain islet transplant recipients who had early graft insufficiency regain their insulin independence. However, this improvement did not last once the medication was stopped.…”

Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review

“…For example, it has been reported that the combination therapy of GLP-1 receptor agonists (exendin-4) and PPI (omeprazole) is closely related to the enhanced insulin sensitization actions in streptozotocin (STZ)-induced T1D model mice ( 70 ). The study found that triple drug therapy with GABA, DPP-4 inhibitors (sitagliptin), and PPI (omeprazole) has an encouraging therapeutic effect in ameliorating β cell function and managing T1D in non-obese diabetic (NOD) mice ( 71 ). In the STZ-induced young and old diabetic mice models, the drug combination therapy consisting of melatonin and DPP-4 inhibitors (sitagliptin) could effectively provoke β cell proliferation in mice, and then ameliorate diabetic manifestations by reducing fasting blood glucose levels, enhancing glucose tolerance, and plasma insulin levels ( 72 ).…”