Abstract
Effects of combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor on β-cells are still unclear, although combination agent of these two drugs has become common in clinical practice. Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old db/db mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2 weeks with oral administration of linagliptin, empagliflozin, linagliptin + empagliflozin (L + E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L + E group were significantly lower than Cont group after treatment. In addition, β-cell mass in L + E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive β-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L + E group in an early phase. Furthermore, mRNA expression levels related to β-cell differentiation and proliferation were significantly increased only in L + E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on β-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.
Highlights
Diabetes is the most prevalent metabolic disease, which causes serious complications such as micro and/or macroangiopathy
Combination drugs of both inhibitors became commercially available in clinical practice very recently and it is drawing much attention from the point of its cost-effectiveness and improvement of patients’ adherence. It is still poorly understood whether combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors has more beneficial effects on β-cell mass and function compared to each medication and whether there are any different effects on pancreatic β-cells when these medications are administered between in an early phase and an advanced phase of diabetes
Linagliptin, empagliflozin and combination therapy did not alter serum insulin and glucagon levels in both an early and advanced phase of diabetes (Fig. 1b,c,f,g). This result suggested that glucose-lowering effect of empagliflozin and combination therapy was mainly attributed to urinary glucose excretion but not insulin action
Summary
Diabetes is the most prevalent metabolic disease, which causes serious complications such as micro and/or macroangiopathy. Our group elucidated that luseogliflozin exerts more beneficial effects on β-cells when administered in an early phase of diabetes rather than in an advanced phase of d iabetes[8,9,10] In addition to these backgrounds, DPP-4 inhibitors have become commonly used in many patients with T2DM recently as they exert good glucose-lowering effect with low risk of hypoglycaemia. Combination drugs of both inhibitors became commercially available in clinical practice very recently and it is drawing much attention from the point of its cost-effectiveness and improvement of patients’ adherence It is still poorly understood whether combination therapy of DPP-4 inhibitors and SGLT2 inhibitors has more beneficial effects on β-cell mass and function compared to each medication and whether there are any different effects on pancreatic β-cells when these medications are administered between in an early phase and an advanced phase of diabetes.
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