The ratio of proinsulin and insulin and that of proinsulin and C-peptide have been proposed as clinical markers of pancreatic beta cell function [Citation1,Citation2]. Many studies have utilized these indicators to evaluate the effects of antidiabetic agents on beta cell. Nagai et al. recently reported the effects of 24 weeks of treatment with ipragliflozin on beta cell function, assessed using the proinsulin/insulin ratio and the proinsulin/C-peptide ratio, in 19 Japanese patients with type 2 diabetes mellitus [Citation3]. In that study, the proinsulin/C-peptide ratio decreased significantly. This finding suggested that ipragliflozin might have a beneficial effect on pancreatic beta cells. The significant point to be emphasized is that the study had been designed to investigate the effects of ipragliflozin on beta cell function as the primary end point. We read this article with great interest and were prompted to examine the factors that influenced the amelioration of beta cell function by administration of ipragliflozin.
We previously showed the ameliorating effects on body composition, visceral adipose tissue volume, and fatty liver in Japanese patients with type 2 diabetes after 16 weeks of treatment with ipragliflozin [Citation4,Citation5]. In this study, fasting insulin, C-peptide, and proinsulin levels significantly decreased. As expected, the fasting proinsulin/C-peptide ratio decreased significantly after 16 weeks of treatment (proinsulin (10−3)/C-peptide ratio from 36.5 ± 20.0 to 30.4 ± 15.7, P = 0.0144), which was consistent with the above report [Citation3]. Fat mass, fasting insulin, C-peptide, proinsulin, and the proinsulin/C-peptide ratio before treatment showed significant negative correlations with changes in the proinsulin/C-peptide ratio. Moreover, changes in fasting insulin, C-peptide, and proinsulin levels showed significant positive correlations with changes in the proinsulin/C-peptide ratio. These results indicated that hyperinsulinemia and hyperproinsulinemia before treatment with ipragliflozin and their amelioration after ipragliflozin treatment were associated with a decrease in the proinsulin/C-peptide ratio.
Proinsulin is synthesized by the secreting granule of pancreatic beta cells and is a precursor molecule for insulin and C-peptide. Physiologically, almost all proinsulin molecules are intracellularly cleaved into insulin and C-peptide [Citation1]. Therefore, serum proinsulin levels are greatly lower than those of insulin and C-peptide in healthy people. Presumably hyperproinsulinemia might be caused by inefficient proinsulin processing within the beta cell secretory granule, leading to an increased release of immature insulin precursors, or alternatively caused by an increased secretary demand on beta cells, leading to an increased insulin secretion from the reserve insulin granule pool, which could contain greater amounts of immature insulin precursors [Citation2,Citation6]. Our findings would support the latter explanation, since our results suggest that treatment with ipragliflozin ameliorated the increased demand for insulin, resulting in a decrease in the proinsulin/C-peptide ratio. Therefore, ipragliflozin treatment could improve beta cell function by reducing beta cell overload.
The reduction in the proinsulin/C-peptide ratio was significantly greater in patients with type 2 diabetes mellitus treated with canagliflozin, another sodium/glucose cotransporter 2 (SGLT2) inhibitors, compared with placebo in a 24-week, randomized, double-blind study [Citation7]. Another group also showed a similar effect with sitagliptin, one of the dipeptidyl peptidase-4 (DPP4) inhibitors, on the proinsulin/C-peptide ratio in patients with type 2 diabetes mellitus receiving a combination of oral antidiabetics and basal insulin [Citation8]. Interestingly, a recent mechanistic study indicated that treatment with empagliflozin improved the insulin/proinsulin ratio and addition of linagliptin to empagliflozin tended to further improve this ratio [Citation9]. Conversely, another recent study showed that canagliflozin administered as an add-on therapy to teneligliptin decreased the proinsulin/C-peptide ratio [Citation10]. These findings suggest that the mechanism behind decreasing serum proinsulin levels with DPP4 inhibitors could be different from that of SGLT2 inhibitors. As described earlier, SGLT2 inhibitors could decrease the proinsulin/C-peptide ratio by ameliorating the increased demand for insulin, while DPP4 inhibitors could decrease the proinsulin/C-peptide ratio by stimulating the conversion of proinsulin into insulin and C-peptide [Citation11].
Accordingly, combination of an SGLT2 inhibitor and a DPP4 inhibitor might have synergic effect on improving pancreatic beta cell function in patients with type 2 diabetes mellitus in daily clinical practice.
Declaration of Interest
A Nakamura has received research funding from Mitsubishi Tanabe Pharma and Ono Pharmaceutical Co.,Ltd. H Miyoshi has received honoraria for lectures from Astellas Pharma Inc., AstraZeneca, Dainippon Pharma Co, Eli Lilly and Company, Kissei, Mitsubishi Tanabe Pharma Co., Merck Sharp and Dohme, Novartis Pharma, Novo Nordisk Pharma, Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Sanofi and has received research funding from Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Dainippon Pharma Co., Eli Lilly and Company, Mitsubishi Tanabe Pharma Co., Merck Sharp and Dohme, Novo Nordisk Pharma, Sanofi, Takeda Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and Taisho Toyama Pharmaceutical Co., Ltd. T Atsumi has received honoraria for lectures from Mitsubishi Tanabe Pharma Co., UCB Japan Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Eli Lilly and Company, Bristol-Myers Squibb, AbbVie Inc. and Eisai Co., Ltd., and has received research funding from Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co. Ltd., Bayer Yakuhin, Ltd., and Eisai Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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References
- Pfützner A, Forst T. Elevated intact proinsulin levels are indicative of beta-cell dysfunction, insulin resistance, and cardiovascular risk: impact of the antidiabetic agent pioglitazone. J Diabetes Sci Technol. 2011;5:784–793.
- Loopstra-Masters RC, Haffner SM, Lorenzo C, et al. Proinsulin-to-C-peptide ratio versus proinsulin-to-insulin ratio in the prediction of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetologia. 2011;54:3047–3054.
- Nagai Y, Ohta A, Sada Y, et al. Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes. Expert Opin Pharmacother. 2017;18:13–17.
- Yamamoto C, Miyoshi H, Ono K, et al. Ipragliflozin effectively reduced visceral fat in Japanese patients with type 2 diabetes under adequate diet therapy. Endocr J. 2016;63:589–596.
- Takase T, Nakamura A, Miyoshi H, et al. Amelioration of fatty liver index in patients with type 2 diabetes on ipragliflozin: an association with glucose-lowering effects. Endocr J. 2017;64:363–367.
- Breuer TG, Menge BA, Banasch M, et al. Proinsulin levels in patients with pancreatic diabetes are associated with functional changes in insulin secretion rather than pancreatic beta-cell area. Eur J Endocrinol. 2010;163:551–558.
- Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother. 2014;15:1501–1515.
- Asai S, Ohta A, Kato H, et al. Effect of sitagliptin on glycemic control and beta cell function in Japanese patients given basal-supported oral therapy for type 2 diabetes. Endocr J. 2014;61:1213–1220.
- Forst T, Falk A, Andersen G, et al. Effects on α- and β-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: an exploratory mechanistic study. Diabetes Obes Metab. 2017;19:489–495.
- Kadowaki T, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24-week, randomised, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2017;19:874–882.
- Forst T, Dworak M, Berndt-Zipfel C, et al. Effect of vildagliptin compared to glimepiride on postprandial proinsulin processing in the β cell of patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:576–579.