Endogenous GIP signaling is indispensable for DPP‐4 inhibitor‐mediated metabolic control in mice

ABSTRACT

Aims/Introduction

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors enhance circulating levels of biologically intact incretins, yet the relative contribution of glucose‐dependent insulinotropic polypeptide (GIP) to their metabolic effects remains incompletely understood. While glucagon‐like peptide‐1 (GLP‐1) has long been emphasized in incretin biology, emerging evidence suggests important physiological roles for GIP. This study investigated whether endogenous GIP signaling is indispensable for the glucose‐lowering and anti‐obesity effects of DPP‐4 inhibition.

Materials and Methods

Male Gipr ^+/+ and Gipr ^−/− mice were treated with anagliptin or linagliptin under normal diet or high‐fat diet (HFD) conditions. Glucose tolerance, insulin secretion, incretin levels, body weight, and adiposity were assessed. To confirm GLP‐1 pathway integrity, dulaglutide was administered to a subset of animals.

Results

DPP‐4 inhibition significantly improved glucose tolerance and attenuated body‐weight gain in HFD‐fed Gipr ^+/+ mice, without affecting food intake. These effects were abolished in Gipr ^−/− mice, despite similar elevations in circulating biologically intact GIP and GLP‐1. Under normal diet, DPP‐4 inhibitors enhanced early‐phase insulin secretion and lowered glucose levels in Gipr ^+/+ mice, but not in Gipr ^−/− mice. Importantly, dulaglutide restored glucose‐lowering effects in Gipr ^−/− mice, confirming preserved GLP‐1 receptor function.

Conclusions

Endogenous GIP signaling is essential for both glucose‐lowering and anti‐obesity actions of DPP‐4 inhibitors in mice. GLP‐1 elevation alone is insufficient to compensate for GIP receptor deficiency. These findings refined the mechanistic understanding of DPP‐4 inhibitors, highlighted the physiological importance of GIP, and suggested context‐dependent metabolic actions of incretins.

This study reveals that the metabolic benefits of DPP‐4 inhibitors, including improved glucose tolerance and reduced body weight, are completely abolished in GIP receptor‐deficient mice. These findings establish that endogenous GIP signaling, rather than GLP‐1, is the indispensable key player for the efficacy of this drug class.

INTRODUCTION

Incretins are gut‐derived hormones secreted in response to nutrient ingestion and play a pivotal role in glucose homeostasis by enhancing glucose‐dependent insulin secretion from pancreatic β‐cells. The two major incretins, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), act through their respective receptors to coordinate postprandial glucose regulation and exert metabolic effects in multiple organs, including the brain, adipose tissue, and gastrointestinal tract ¹ , ² .

In recent years, clinical advances in incretin‐based therapies have largely emphasized GLP‐1 receptor agonists, which demonstrate potent glucose‐lowering and weight‐reducing effects in individuals with type 2 diabetes and obesity. In contrast, DPP‐4 inhibitors, which increase circulating levels of both active GLP‐1 and GIP by inhibiting their degradation, are widely regarded as weight‐neutral, despite their glucose‐lowering benefits ³ . Accordingly, GLP‐1 has remained at the forefront of incretin research and drug development, whereas the physiological and pharmacological significance of GIP has long been underappreciated. However, it is critical to acknowledge that the therapeutic potential of GIP signaling was not entirely overlooked. Indeed, early work on GIP receptor (GIPR) agonists demonstrated clear benefits in rodent models of diabetes ⁴ , ⁵ , ⁶ . Despite these early suggestions of GIP's potential, the specific contribution of GIP signaling to the metabolic actions of DPP‐4 inhibitors remains insufficiently defined.

Accumulating evidence now suggests that GIP signaling may have beneficial metabolic effects depending on physiological context. GIP receptor agonists and GIP/GLP‐1 dual receptor agonist tirzepatide have demonstrated robust glycemic and weight‐lowering properties, leading to renewed interest in the physiological role of GIP in energy balance and glucose metabolism ⁷ , ⁸ , ⁹ . This renewed focus, however, has also spurred ongoing academic debate regarding the optimal pharmacological approach to targeting GIP signaling—specifically, whether GIPR agonism or antagonism is therapeutically more beneficial in different metabolic contexts ¹⁰ , ¹¹ , ¹² . These observations highlight the need to re‐examine GIP biology in the setting of incretin‐based therapy.

Previous studies using Glp1r ^−/− , Gipr ^−/−, and Glp1r ^−/− ; Gipr ^−/− mice have shown that both receptors contribute to the insulinotropic effects of DPP‐4 inhibition ¹³ , ¹⁴ . Notably, the glucose‐lowering effect of DPP‐4 inhibitors has been reported to persist in Glp1r ^−/− mice ¹⁵ , suggesting that GIP signaling may play a predominant role. Yet, despite the clinical relevance of DPP‐4 inhibitors and the increasing recognition of GIP biology, it remains unknown whether DPP‐4 inhibitors retain their efficacy in Gipr ^−/− mice. This represents a critical gap in our understanding of incretin pharmacology.

Therefore, in this study, we investigated the metabolic effects of chronic DPP‐4 inhibition in Gipr ^−/− mice to delineate the contribution of endogenous GIP signaling to glucose regulation and body weight control. By evaluating both glucose tolerance and diet‐induced obesity phenotypes, we aimed to clarify the mechanistic role of GIP in mediating the metabolic benefits of DPP‐4 inhibitors.

METHODS

Animals

Male Gipr ^−/− mice on a C57BL/6 background ¹⁶ and age‐matched wild‐type Gipr ^+/+ mice (C57BL/6 SLC Japan, Shizuoka, Japan) were used in all experiments. Unless otherwise indicated, animals had ad libitum access to water and food and were maintained under a 12‐h light/dark cycle. Mice were housed at 23 ± 3°C, with 40–70% relative humidity and provided a standard chow diet (CE‐2; CLEA Japan, Tokyo, Japan).

Diet and treatment

Mice were fed either a normal diet (ND; 10% kcal from fat; D12450J, Research Diets, Inc., New Brunswick, USA) or a high‐fat diet (HFD; 60% kcal from fat; D12492, Research Diets, Inc.). The DPP‐4 inhibitors anagliptin and linagliptin were kindly provided by Sanwa Kagaku Kenkyusho Co., Ltd. (Nagoya, Japan) and Nippon Boehringer Ingelheim Co., Ltd. (Tokyo, Japan), respectively. Drug doses were determined with reference to previous reports and pharmacokinetic/pharmacodynamic data ¹⁷ , ¹⁸ . Diets containing 0.3% (w/w) anagliptin or 0.003% (w/w) linagliptin were custom prepared by Research Diets, Inc. and administered to the mice.

Oral glucose tolerance test (OGTT)

OGTTs were performed after a 16‐h fast. Blood samples were collected at 0, 15, 30, 60, and 120 min after oral glucose administration by oral gavage. Blood glucose levels were immediately measured using the glucose oxidase method (Mint Sensor II, Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan). Samples were centrifuged immediately, and plasma was stored at −80°C until analysis of insulin and incretin concentrations. Plasma insulin was measured using an Ultra Sensitive Mouse Insulin ELISA kit (Cat# M1104, Morinaga BioScience, Inc., Yokohama, Japan), biologically intact GIP was measured using the Mouse GIP, Active form (high sensitivity) Assay Kit (Cat# 27702, Immuno‐Biological Laboratories Co., Ltd., Fujioka, Japan), and biologically intact GLP‐1 was measured using the V‐PLEX GLP‐1 Active Kit (Cat# K1503OD‐2, Meso Scale Diagnostics, LLC, Rockville, MD, USA).

Effects of DPP‐4 inhibitors under ND conditions

Seven‐week‐old Gipr ^−/− and Gipr ^+/+ mice were randomly assigned to an anagliptin‐treated group or a control group. Anagliptin was administered via the diet for 5 weeks. At 12 weeks of age, glucose tolerance was evaluated by OGTT (2 g/kg body weight). Blood glucose, insulin, biologically intact GIP, and biologically intact GLP‐1 levels were measured. Body weight and food intake were monitored regularly throughout the study period. To confirm these findings with a different DPP‐4 inhibitor, a separate 5‐week experiment was conducted using linagliptin. All procedures were similar, with the exception that a glucose dose of 1 g/kg body weight was used for the OGTT.

Effects of DPP‐4 inhibitors under HFD conditions

Seven‐week‐old Gipr ^−/− and Gipr ^+/+ mice were randomly assigned to an anagliptin‐treated group or a control group. Anagliptin was administered via a HFD for 8 weeks. Body weight and food intake were monitored throughout the experimental period, as in the ND condition. At 15 weeks of age, glucose tolerance was evaluated by OGTT (2 g/kg body weight), followed by measurement of plasma glucose, insulin, biologically intact GIP, and biologically intact GLP‐1 levels. At 16 weeks of age, mice were euthanized, and epididymal fat, mesenteric fat, and skeletal muscle tissues were collected. Random incretin levels were also assessed at this time point. To validate these results, a similar 8‐week experiment was conducted in a separate cohort of HFD‐fed mice using linagliptin.

GLP‐1RA administration and study design

Seven‐week‐old Gipr ^−/− and Gipr ^+/+ mice were maintained on a HFD with or without anagliptin for 5 weeks. After this period, mice receiving HFD with anagliptin were allocated to two groups: HFD + anagliptin, and HFD + anagliptin + dulaglutide. Beginning at 12 weeks of age, mice in the HFD + anagliptin + dulaglutide group received intraperitoneal injections of dulaglutide (0.6 mg/kg body weight), a GLP‐1 receptor agonist, twice weekly for 3 weeks, according to previously established protocols ¹⁹ , ²⁰ . Mice in the HFD + anagliptin and HFD control groups received an equivalent volume of saline. Body weight was monitored throughout the study. At 15 weeks of age, glucose tolerance was evaluated by OGTT.

Statistical analysis

Unless otherwise specified, data are presented as mean ± SEM. For comparisons between two groups, an unpaired Student's t‐test or the Mann–Whitney U test was used, as appropriate. For comparisons among three or more groups, one‐way analysis of variance (anova) followed by Tukey's post hoc test was performed. A P value <0.05 was considered statistically significant. All analyses were conducted using GraphPad Prism version 9 (GraphPad Software, San Diego, CA, USA).

Ethical statement

All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, NIH Publication No. 8023, revised 1978). All procedures were approved by the Animal Care and Use Committee of Gifu University Graduate School of Medicine (Approval No. AG‐P‐N‐20240128).

RESULT

DPP‐4 inhibition improves glucose tolerance in Gipr^+/+ but not Gipr ^−/− mice under ND

To evaluate whether the metabolic effects of DPP‐4 inhibition depend on GIP signaling, we administered anagliptin to Gipr ^+/+ and Gipr ^−/− mice maintained on a ND. In Gipr ^+/+ mice, anagliptin treatment did not alter body weight or food intake (Figure 1a,b). OGTT revealed significantly lower glucose levels at 15 and 30 min and reduced AUC_{0–120 min} glucose (Figure 1c). Although postprandial insulin levels were unchanged, the insulinogenic index tended to increase (Figure 1d,e). In striking contrast, anagliptin did not improve glucose tolerance or insulin secretion in Gipr ^−/− mice, with no changes in body weight or food intake (Figure 1a–e). Biologically intact GIP(1–42) and GLP‐1(7–36) amide levels increased in both genotypes following anagliptin (Figure 1f,g). Similar results were obtained with linagliptin. In Gipr ^+/+ mice, linagliptin improved glucose tolerance and tended to enhance early‐phase insulin secretion without affecting body weight or food intake (Figure S1a–e). In contrast, linagliptin produced no metabolic effects in Gipr ^−/− mice (Figure S1a–e), despite significantly elevating GLP‐1 and GIP in both genotypes (Figure S1f,g).

Figure 1.

Effects of anagliptin on glucose metabolism in normal diet–fed Gipr ^+/+ and Gipr ^−/− mice. Seven‐week‐old Gipr ^+/+ and Gipr ^−/− mice were fed a normal diet (ND) with or without anagliptin for 5 weeks. Oral glucose tolerance test (OGTT) was performed at 12 weeks of age. (a) Body weight and (b) food intake. (c) Blood glucose and area‐under‐the‐curve (AUC)_{0–120 min}‐glucose during OGTT (a–c, n = 7–10/group). (d) Plasma insulin and (e) insulinogenic index during OGTT. (f) Biologically intact GIP and (g) biologically intact GLP‐1 (d–g, n = 7–10/group). Values are mean ± SEM. Black and Blue lines/bars, untreated; Black and Blue dotted lines/Gray and Light blue bars, anagliptin‐treated. *P < 0.05 vs untreated.

DPP‐4 inhibition suppresses diet‐induced obesity only in Gipr ^+/+ mice

We next evaluated the metabolic effects of anagliptin in HFD‐fed Gipr ^+/+ and Gipr ^−/− mice. In Gipr ^+/+ mice, anagliptin markedly attenuated body‐weight gain and reduced epididymal and mesenteric fat masses without changing food intake (Figure 2a–c). OGTT confirmed improved glucose tolerance (Figure 2d), and fasting insulin levels were lower, with a trend toward increased insulinogenic index (Figure 2e,f). By contrast, anagliptin had no effect on body weight, adiposity, food intake, glucose tolerance, or insulin secretion in HFD‐fed Gipr ^−/− mice (Figure 2a–f). Biologically intact GIP and GLP‐1 increased similarly in both genotypes (Figure 2g,h). Linagliptin administration recapitulated these findings. In HFD‐fed Gipr ^+/+ mice, linagliptin reduced body weight, improved glucose tolerance, and enhanced insulin response without altering food intake (Figure S2a–e). In contrast, HFD‐fed Gipr ^−/− mice showed no metabolic response (Figure S2a–e), while incretin levels increased in both groups (Figure S2f,g). In the light phase, anagliptin increased biologically intact GLP‐1 and GIP in both HFD‐fed mice, regardless of genotype (Figure 2i–l). Despite these elevations, glucose and insulin levels did not change in HFD‐fed Gipr ^−/− mice, whereas Gipr ^+/+ mice exhibited improved insulin sensitivity with anagliptin.

Figure 2.

Effects of anagliptin on body weight, adiposity, and glucose metabolism in HFD‐fed Gipr ^+/+ and Gipr ^−/− mice. Seven‐week‐old Gipr ^+/+ and Gipr ^−/− mice were fed a high‐fat diet (HFD) with or without anagliptin for 8 weeks. Oral glucose tolerance test (OGTT) was performed at 15 weeks of age. (a) Body weight and (b) epididymal and mesenteric fat mass, and (c) food intake. (d) Blood glucose and area‐under‐the‐curve (AUC)_{0–120 min}‐glucose during OGTT (a–d, n = 8‐10/group). (e) Plasma insulin and (f) insulinogenic index during OGTT (e, f, n = 8–10/group). (g) Biologically intact GIP and (h) biologically intact GLP‐1 (g, h, n = 4–6/group). (i) Blood glucose and (j) plasma insulin during light phase. (k) Biologically intact GIP and (l) biologically intact GLP‐1 during light phase (i–l, n = 8–10/group). Values are mean ± SEM. Black and blue lines/bars, untreated; black and blue dotted lines/gray and light blue bars, anagliptin‐treated. *P < 0.05 vs untreated.

GLP‐1 receptor agonism restores metabolic effects in Gipr ^−/− mice

Finally, to confirm GLP‐1 pathway integrity, dulaglutide was administered with anagliptin. As expected, anagliptin improved glucose tolerance only in Gipr ^+/+ mice; Gipr ^−/− mice were unresponsive. Remarkably, dulaglutide restored glucose lowering and reduced body weight in Gipr ^−/− mice (Figure 3a,b). Therefore, GLP‐1 signaling remains functional in Gipr ^−/− mice, and endogenous GLP‐1 elevation alone is insufficient to mediate the metabolic effects of DPP‐4 inhibition.

Figure 3.

Effects of pharmacologic GLP‐1R activation in Gipr ^−/− mice. Seven‐week‐old Gipr ^+/+ and Gipr ^−/− mice were fed a high‐fat diet (HFD) with or without anagliptin for 5 weeks. After this period, mice receiving HFD with anagliptin were allocated to two groups: continued anagliptin alone and anagliptin plus dulaglutide. Beginning at 12 weeks of age, mice in the anagliptin/dulaglutide‐treated group received intraperitoneal injections of dulaglutide (0.6 mg/kg body weight) for 3 weeks. Oral glucose tolerance test (OGTT) was performed at 15 weeks of age. (a) Body weight and (b) blood glucose and area‐under‐the‐curve (AUC)_{0–120 min}‐glucose during OGTT (n = 5–8 per group). Values are mean ± SEM. Black and blue symbols/bars, non‐treated group; dotted lines/gray and light blue bars, anagliptin‐treated group; open symbols/white bars, the anagliptin/dulaglutide‐treated group. *P < 0.05 untreated group vs anagliptin‐treated group; ^† P < 0.05 untreated group vs anagliptin/dulaglutide‐treated group; ^§ P < 0.05 anagliptin‐treated group vs anagliptin/dulaglutide‐treated group.

DISCUSSION

The contribution of GIP signaling to the metabolic efficacy of DPP‐4 inhibitors has long been debated. In the GLP‐1–centric era driven by the remarkable clinical success of GLP‐1 receptor agonists for glucose lowering and weight reduction, GIP has often been viewed as a secondary or even obesogenic hormone. Indeed, the limited clinical utility of GIP receptor agonists and the diverse extra‐pancreatic actions of incretins fueled the prevailing assumption that GIP contributes only modestly, if at all, to the antihyperglycemic effects of DPP‐4 inhibitors. Our findings challenge this paradigm. We demonstrate that the glucose‐lowering effect of DPP‐4 inhibition, clearly observed in Gipr ^+/+ mice, is fully abolished in Gipr ^−/− mice. Thus, endogenous GIP signaling is indispensable for the glucoregulatory action of DPP‐4 inhibitors. Moreover, although DPP‐4 inhibition suppressed weight gain in diet‐induced obese mice, this protective effect was also absent in Gipr ^−/− mice. Of note, HFD feeding markedly increased circulating biologically intact GIP levels, and DPP‐4 inhibition further augmented this elevation. These results suggest that sustained GIP signaling is required not only for glucose control but also for the anti‐obesity effect of chronic DPP‐4 inhibition under obesogenic conditions.

Interestingly, previous studies have reported that Gipr ^−/− mice exhibit resistance to HFD‐induced obesity compared with wild‐type controls ²¹ . Historically, GIP was considered an obesogenic hormone due to its lipogenic actions in adipocytes ²² , ²³ . Consistent with previous reports, our HFD‐fed Gipr ^−/− mice exhibited resistance to obesity compared with their wild‐type counterparts. In contrast to this obesogenic role, GIP is also known to reduce food intake and body weight in mice under pharmacological stimulation, acting both directly and indirectly via the central nervous system ²⁴ , ²⁵ , ²⁶ , ²⁷ . Our data now demonstrate that enhancing endogenous GIP signaling via DPP‐4 inhibition similarly elicits a weight‐reducing effect. We propose that the weight‐suppressive effects of DPP‐4 inhibitors observed in our model are independent of their insulinotropic activity, as circulating insulin levels did not differ between groups. Consistent with this interpretation, teneligliptin has been shown to reduce body weight without affecting food intake, possibly via increased energy expenditure ²⁸ . In addition, adipocyte‐specific GIP receptor expression enhances lipid oxidation ²⁹ . Further supporting the context‐dependent actions of GIP, long‐term stimulation with GIPR agonists has been shown to differentially regulate adipose tissue function in fed versus fasted states; they enhance glucose and lipid clearance in coordination with insulin when fed, while promoting lipid release when insulin levels are low during fasting ³⁰ . Notably, our data also show that DPP‐4 inhibition augmented endogenous GIP secretion during the light phase, a period of reduced food intake for mice. Taken together, these data point to a pleiotropic GIP network, wherein both central and peripheral mechanisms contribute to energy balance beyond insulin secretion. This highlights the profoundly context‐dependent nature of GIP's role in energy balance, suggesting that the metabolic outcomes may differ between the complete genetic ablation of its receptor versus the pharmacological augmentation of GIP signaling.

The most salient observation in our study is the complete loss of the glucose‐lowering effect of chronic DPP‐4 inhibition in Gipr ^−/− mice. Although DPP‐4 inhibition elevated endogenous GLP‐1 levels in both genotypes, GLP‐1 alone was insufficient to mediate glycemic benefit in the absence of GIP receptors. This may reflect fundamental differences in their intracellular signaling mechanisms. The inability of GLP‐1 to compensate for the loss of this unique GIP‐dependent machinery could explain its lack of glycemic benefit in our model. Importantly, GLP‐1 receptor agonism restored glucose tolerance in Gipr ^−/− mice, establishing that GLP‐1 signaling remains intact. Combined with prior findings that DPP‐4 inhibitors retain efficacy in Glp1r ^−/− mice ¹⁵ , our results provide converging evidence that endogenous GIP, rather than GLP‐1, is the dominant mediator of DPP‐4 inhibitor–induced glucose lowering in mice. Future studies are warranted to determine whether this reflects GIP‐dependent enhancement of early‐phase insulin release, improved insulin sensitivity, or extra‐pancreatic mechanisms.

This study has limitations. First, our findings were obtained exclusively in mice, which requires careful consideration before extrapolating to human physiology. Notably, the anti‐obesity effect of chronic DPP‐4 inhibition observed in our mouse model, which was dependent on GIP signaling, contrasts with the generally weight‐neutral profile of DPP‐4 inhibitors in human clinical practice. This translational gap may stem from species‐specific differences in GIPR distribution and function, especially in tissues critical for appetite and energy expenditure, such as the central nervous system and adipose tissue. Second, incretin efficacy varies by metabolic state; thus, nutritional context, obesity severity, and incretin sensitivity may influence outcomes. Finally, the composition and duration of high‐fat feeding could affect metabolic phenotypes. Nevertheless, our data offer mechanistic clarity by directly interrogating GIP signaling in vivo and advance our understanding of incretin biology.

CONCLUSION

In this study, we demonstrate that endogenous GIP signaling is essential for both the glucose‐lowering and weight‐suppressive effects of DPP‐4 inhibitors. DPP‐4 inhibition improved glucose tolerance and attenuated diet‐induced weight gain in wild‐type mice, whereas these effects were completely abolished in Gipr ^−/− mice, despite comparable enhancement of circulating GLP‐1 levels. These findings reveal that GIP is a critical physiological mediator of DPP‐4 inhibitor efficacy. By directly interrogating GIP receptor dependence in vivo, our results refine the mechanistic understanding of this widely used drug class and highlight the context‐dependent, bidirectional roles of GIP in energy and glucose homeostasis. This work contributes to the emerging paradigm in which GIP is recognized not merely as a classical incretin but as a central metabolic regulator, informing future incretin‐based therapeutic strategies.

FUNDING

This work was supported by grants from Japan Society for the Promotion of Sciences (KAKENHI Grant Number: No. 24K23801[SKO], 24K23825 [SK], 24K23776 [TI] and 23K28017 [DY]), from Japan Association for Diabetes Education and Care (SK, TI and DY), and from Japan Society for Metabolism and Clinical Nutrition (DY).

AUTHOR CONTRIBUTIONS

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship and take responsibility for the integrity of the work as a whole. SKO, SK, and DY contributed to the conception and design of the study and to data analysis, interpretation, and manuscript drafting. YS provided the Gipr ^−/− mice, contributed to data analysis and interpretation, and critically reviewed the manuscript for important intellectual content. HT, LY, SB, TI, TF, YT, TK, YH, KI, YF, HK, YY, and ST contributed to data analysis and interpretation and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript. SK and DY are the guarantors of this work.

DISCLOSURE

TK received honoraria for lectures from Eli Lilly Japan K.K.; YH received joint research grants from Nippon Boehringer Ingelheim Co., Ltd., and honoraria for lectures from Sumitomo Pharma Co., Ltd.; TM received joint research grants from Sumitomo Pharma Co., Ltd. and Mitsubishi Tanabe Pharma Corporation; YY received honoraria for lectures from Sumitomo Pharma Co., Ltd., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., and Mitsubishi Tanabe Pharma Corporation; YS received grants from Nippon Boehringer Ingelheim Co., Ltd., ARKRAY Marketing, Inc., Taisho Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., Terumo Corporation, and Sumitomo Pharma Co., Ltd., and honoraria for lectures from Taisho Pharmaceutical Co., Ltd., Nippon Becton Dickinson Company, Ltd., Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., Sumitomo Pharma Co., Ltd., and Ono Pharmaceutical Co., Ltd.; DY received clinically commissioned/joint research grants from Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Terumo Corporation, and ARKRAY, Inc., and also received honoraria for lectures from Sumitomo Pharma Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., MSD K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Takeda Pharmaceutical Company Limited.

Approval of the research protocol: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: All procedures were approved by the Animal Care and Use Committee of Gifu University Graduate School of Medicine (Approval No. AG‐P‐N‐20240128).

Animal studies: Animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 8023, revised 1978).

Supporting information

Figure S1. Effects of linagliptin on glucose metabolism in normal diet–fed Gipr^+/+ and Gipr^−/− mice.

Figure S2. Effects of linagliptin on body weight and glucose metabolism in high‐fat diet–fed Gipr^+/+ and Gipr^−/− mice.

DATA AVAILABILITY STATEMENT

Original data generated and analyzed during this study are included in this published article.